Coverage Policy Manual
Policy #: 1998109
Category: Medicine
Initiated: February 1998
Last Review: July 2018
  Adoptive Immunotherapy

Description:
ADOPTIVE IMMUNOTHERAPY
Adoptive immunotherapy uses “activated” lymphocytes as a treatment modality. Both nonspecific and specific lymphocyte activation are used therapeutically. Nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes.
 
T Lymphocytes and Killer Cells
Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T-cell growth factor interleukin-2 (IL-2) and other cytokines. More recent techniques have yielded select populations of cytotoxic T lymphocytes with specific reactivity to tumor antigens. Peripheral lymphocytes are propagated in vitro with antigen-presenting dendritic cells that have been pulsed with tumor antigens. Alternatively, innate tumor-infiltrating lymphocytes (TIL) from the tumor biopsy are propagated in vitro with IL-2 and anti-CD3 antibody, a T-cell activator. Expansion of TIL for clinical use is labor intensive and requires laboratory expertise. Only a few cancers are infiltrated by T cells in significant numbers; of these, TIL can be expanded in only approximately 50% of cases. These factors limit the widespread applicability of TIL treatment. Recently, cytokine-induced killer cells have been recognized as a new type of antitumor effector cells, which can proliferate rapidly in vitro, with stronger antitumor activity and a broader spectrum of targeted tumors than other reported antitumor effector cells (Berry, 2017).
 
Cellular Therapy and Dendritic Cell Infusions
The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing patients. In current trials, 2 methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions.
 
Adoptive cellular therapy is “the administration of a patient’s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lympho-depleting preparative regimen” (Rosenberg, 2008).  Protocols vary, but include these common steps:
 
1. lymphocyte harvesting (either from peripheral blood or from tumor biopsy)
 
2. propagation of tumor-specific lymphocytes in vitro using various immune modulators
 
3. selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay
 
4. lymphodepletion of the host with immunosuppressive agents
 
5. adoptive transfer (ie, transfusion) of lymphocytes back into the tumor-bearing host
 
Dendritic cell-based immunotherapy uses autologous dendritic cells (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigens in vivo. ADCs harvested from the patient are either pulsed with antigen or transfected with a viral vector bearing a common cancer antigen. The activated ADCs are then retransfused into the patient, where they present antigen to effector lymphocytes (CD4-positive T-cells, CD8-positive T-cells, and in some cases, B cells). This initiates a cytotoxic response against the antigen and against any cell expressing the antigen. In cancer immunotherapy, ADCs are pulsed with tumor antigens; effector lymphocytes then mount a cytotoxic response against tumor cells expressing these antigens.
 
In an attempt to regulate the host immune system further, recent protocols use various cytokines (eg, IL-7 and IL-15 instead of IL-2) to propagate lymphocytes. Protocols also differ in the extent of host lymphodepletion induced prior to transfusing lymphocytes to the tumor-bearing host.
 
Note: Allogeneic cell transplantation following nonmyeloablative conditioning of the recipient (known as reduced-intensity conditioning) also may be referred to as “adoptive immunotherapy” in the literature. However, reduced-intensity conditioning cell transplantation relies on a donor-vs-malignancy effect of donor lymphocytes. In contrast, the adoptive immunotherapy techniques described in this evidence review enhance autoimmune effects primarily. The use of reduced-intensity conditioning in cell transplantation is discussed for specific cancers in individual policies related to cell transplantation.
 
ACUTE LYMPHOBLASTIC LEUKEMIA
Acute lymphoblastic leukemia (ALL) is a malignancy (clonal) of the bone marrow in which the early lymphoid precursors of the white blood cells (called lymphoblasts) proliferate and replace the normal hematopoietic cells of the marrow. This results in overcrowding of the bone marrow, as well as the peripheral organs (particularly the liver, spleen, and lymph nodes) by the lymphoblasts. As a consequence, the leukemic blasts displace the normal hematopoietic bone marrow and cause cytopenias in all 3 cell lineages (anemia, thrombocytopenia, granulocytopenia). Leukostasis affecting brain and lung may also occur. Death occurs commonly due to severe pancytopenia and resulting infections. Refractory (resistant) disease is defined as those patients who fail to obtain complete response with induction therapy, ie, failure to eradicate all detectable leukemia cells (<5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (>25% marrow cellularity and normal peripheral blood counts). Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission. Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. MRD positivity is defined as the presence of 0.01% or more ALL cells and has been shown to be a strongest prognostic factor to predict the risk of relapse and death when measured during and after induction therapy in both newly diagnosed and relapsed ALL. In a 2017 meta-analysis of 20 studies of 11,249 pediatric ALL, the hazard ratio for event-free survival in MRD-negative patients compared with MRD-positive patients was 0.23 (95% confidence interval, 0.18 to 0.28) (Berry, 2017).
 
Approximately 5000 cases of B-cell ALL are diagnosed every year in the United States,4 and approximately 620 pediatric and young adult patients with B-cell ALL will relapse each year in the United States (Maude, 2015). It is largely a disease of the young with approximately 60% of cases occurring in patients younger than 20 years old with a median age at diagnosis of 15 years.4 While it is treatable in 85% cases, approximately 15% of children and young adults with ALL will relapse while 2% to 3% of ALL patients are primary refractory (Pui, 2011). Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate.7 The 2-year survival rate among patients with ALL who relapse after hematopoietic cell transplantation is 15% (Bajwa, 2013). The Food and Drug Administration approved clofarabine (as a single agent or in combination) in 2004 and blinatumomab in 2014 for relapsed and refractory ALL. Reported median objective response rates in the pivotal trials of the 2 agents were 19.7% and 33%, the median durations of response was 2.5 months and 6 months, and median overall survival durations were 3 months and 7.5 months, respectively (Jeha, 2006; von Stackelberg, 2016). Note that the percentages of patients treated with 3 or more prior treatments of clofarabine and blinatumomab trial were 62% and 7%, respectively. Nevertheless, treatment options for patients with relapsed or refractory ALL are limited, associated with poor outcomes and high toxicity and the disease remains incurable.
 
Tisagenlecleucel
Tisagenlecleucel is an adoptive immunotherapy in which the T cells of a patient are modified by genetic engineering using lentiviral vector. The resulting genetic modified cells express a CD-19 directed chimeric antigen receptor protein that consists of an extracellular portion that has a murine anti-CD19 single-chain antibody fragment as well as an intracellular portion that contains T-cell signaling and co-stimulatory domains. Once injected, the genetically modified T cells selectively target and bind to CD19 antigen expressed on the surface of B cells and tumors derived from B cells. Subsequently, the intracellular signaling domains play crucial roles in T-cell activation, persistence, and effector functions (Novartis Pharmaceuticals, 2017).
 
DIFFUSE LARGE B-CELL LYMPHOMA
Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and accounts for approximately 25% of non-Hodgkin lymphoma cases (Swerdlow, 2016). DLBCL exhibits large heterogeneity in morphologic, genetic, and clinical aspects and multiple clinicopathologic entities are defined by the 2016 World Health Organization classification, which are sufficiently distinct to be considered separate diagnostic categories.
 
It has been estimated that 27,650 new cases of DLBCL were diagnosed in the United States in 2016 (Teras, 2016). Treatment in the first-line setting (particularly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) is associated with a 5-year survival rate ranging from 60% to 70%.14 However, based on a number of prognostic factors, 20% to 50% of DLBCL cases are refractory or relapse after first-line chemotherapy (International Non-Hodgkin's Lymphoma Prognostic Factors P., 1993; Sehn, 2007). The response to subsequent salvage chemotherapy and consolidation with autologous cell transplantation is suboptimal. A 2017 retrospective analysis of the SCHOLAR-1 study, which pooled data from 2 phase 3 clinical trials and 2 observational cohorts, included 636 patients with refractory DLBCL (Crump, 2017). The objective response rate to the next line of therapy was 26%, with 7% achieving a complete response. Median overall survival was 6.3 months and 2-year survival was 20%. Refractory DLBCL was defined as progressive disease or stable disease as best response at any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-line therapy) or as relapse 12 or fewer months after autologous cell transplantation.
 
Axicabtagene Ciloleucel
Similar to tisagenlecleucel, axicabtagene ciloleucel is an adoptive immunotherapy in which the T cells of a patient are modified genetically using a retroviral vector. The resulting genetically modified cells express a CD-19 directed chimeric antigen receptor protein that has a murine single-chain variable fragment with specificity for CD19. Once injected, the genetically modified T cells selectively target and bind to CD19 antigen expressed on the surface of normal and malignant B cells (Kite Pharma Inc., 2017).
 
REGULATORY STATUS
Adoptive immunotherapy is not a U.S. Food and Drug Administration (FDA)‒regulated procedure.
 
On August 30, 2017, tisagenlecleucel (Kymriah™; Novartis) was approved by the FDA for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.
 
On October 18, 2017, axicabtagene ciloleucel (Yescarta™; Kite Pharma) was approved by the FDA for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
 
Tisagenlecleucel and axicabtagene ciloleucel have a black box warning because of the risk of cytokine release syndrome and neurologic toxicities that include fatal or life-threatening reactions. It should not be administered to patients with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Patients should be monitored for neurologic events after treatment.
 
Tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) are available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS and Yescarta REMS, respectively. The requirement for the REMS components are as follows:
 
    • Health care facilities that dispense and administer tisagenlecleucel or axicabtagene ciloleucel must be enrolled and comply with the REMS requirements.
 
    • Certified health care facilities must have onsite, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hours after tisagenlecleucel or axicabtagene ciloleucel infusion, if needed for treatment of cytokine release syndrome.  
    • Certified health care facilities must ensure that health care providers who prescribe, dispense or administer tisagenlecleucel or axicabtagene ciloleucel are trained to manage cytokine release syndrome and neurologic toxicities.  

Policy/
Coverage:
Effective July 2018
 
Prior Approval is required for tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta).
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Tisagenlecleucel (Kymriah)
 
Tisagenlecleucel intravenous infusion as a one time, single administration treatment meets member benefit certificate primary coverage criteria for relapsed (see definition below) or refractory (see definition below) patients if they meet all of the following criteria and provided the member has not received other adoptive immunotherapies or genetic therapies, and is a not or has not been a subject of a clinical trial for any of these therapies:  
        • Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts)  
        • Are up to 25 years old at the time of infusion  
        • Have not received prior treatment with tisagenlecleucel or any other gene therapy or are being considered for treatment with any other gene therapy  
        • Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis  
        • Do not have any of the following:  
            • Burkitt lymphoma  
            • Active hepatitis B, C, or any uncontrolled infection  
            • Grade 2 to 4 graft-versus-host disease  
            • Concomitant genetic syndrome with the exception of Down syndrome  
            • Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to tisagenlecleucel infusion  
            • Patient has active central nervous system 2 or 3 acute lymphoblastic leukemia (ie, white blood cell count ≥5 cells/μL in cerebrospinal fluid with presence of lymphoblasts).  
 
*Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission with chemotherapy and/or allogeneic cell transplant.
 
*Refractory (resistant) disease is defined as those patients who fail to obtain complete response with induction therapy, ie, failure to eradicate all detectable leukemia cells (<5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (>25% marrow cellularity and normal peripheral blood counts).
 
Dosing
The recommended dosage of tisagenlecleucel for patients 50 kg or less is 0.2 to 5.0×106 chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously; for patients above 50 kg, dose is 0.1 to 2.5×108 total chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.
 
Axicabtagene ciloleucel (Yescarta) or Tisagenlecleucel (Kymriah)
 
Axicabtagene ciloleucel or Tisagenlecleucel intravenous infusion as a one time, single administration treatment meets member benefit certificate primary coverage criteria for relapsed or refractory( see definition below) patients if they meet all of the following criteria and provided the member has not received other adoptive immunotherapies or genetic therapies and is not or has not been a subject in a clinical trial for any of these therapies:
 
    • Are adults (age ≥18) at the time of infusion  
    • Histologically confirmed diagnosis of diffuse large B-cell lymphoma, not otherwise specified; or primary mediastinal large B-cell lymphoma* or high-grade B-cell lymphoma or diffuse large B-cell lymphoma arising from follicular lymphoma.  
    • Received adequate prior therapy including all of the following:
        • Anti-CD20 monoclonal antibody for CD20-positive tumor
        • Anthracycline-containing chemotherapy regimen  
        • For subjects with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to diffuse large B-cell lymphoma  
    • Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist
    • Have not received prior CD19-directed CAR T-cell therapy treatment or any other gene therapy or are being considered for treatment with any other gene therapy AND
    • Do not have primary central nervous system lymphoma
 
*Relapsed or refractory disease, defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
 
*Tisagenlecleucel intravenous infusion is considered investigational for the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma.
 
Dosing
The recommended target dose of tisagenlecleucel for patients with large B-cell lymphoma is 0.6 to 6.0 × 108 chimeric antigen receptor−positive viable T cells intravenously.
 
The recommended target dose of axicabtagene ciloleucel for patients with large B-cell lymphoma is 2×106 CAR-positive viable T cells per kg body weight, with a maximum of 2×108 chimeric antigen receptor− positive viable T cells intravenously.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Other applications of adoptive immunotherapy do not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, other applications of adoptive immunotherapy are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to July 2018
 
Prior Approval is required for tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta).
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Tisagenlecleucel (Kymriah)
 
Tisagenlecleucel intravenous infusion as a one time, single administration treatment meets member benefit certificate primary coverage criteria for relapsed (see definition below) or refractory (see definition below) patients if they meet all of the following criteria and provided the member has not received other adoptive immunotherapies or genetic therapies, and is a not or has not been a subject of a clinical trial for any of these therapies:
 
    • Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts)
 
    • Are up to 25 years old at the time of infusion
 
    • Have not received prior treatment with tisagenlecleucel or any other gene therapy or are being considered for treatment with any other gene therapy
 
    • Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis
 
    • Do not have any of the following:
 
        • Burkitt lymphoma
        • Active hepatitis B, C, or any uncontrolled infection
        • Grade 2 to 4 graft-versus-host disease
        • Concomitant genetic syndrome with the exception of Down syndrome
        • Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to tisagenlecleucel infusion
        • Patient has active central nervous system 2 or 3 acute lymphoblastic leukemia (ie, white blood cell count ≥5 cells/μL in cerebrospinal fluid with presence of lymphoblasts).
 
*Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission with chemotherapy and/or allogeneic cell transplant.
 
*Refractory (resistant) disease is defined as those patients who fail to obtain complete response with induction therapy, ie, failure to eradicate all detectable leukemia cells (<5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (>25% marrow cellularity and normal peripheral blood counts).
 
Dosing
The recommended dosage of tisagenlecleucel for patients 50 kg or less is 0.2 to 5.0×106 chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously; for patients above 50 kg, dose is 0.1 to 2.5×108 total chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.
 
Axicabtagene ciloleucel (Yescarta)
Axicabtagene ciloleucel intravenous infusion as a one time, single administration treatment meets member benefit certificate primary coverage criteria for relapsed or refractory( see definition below) patients if they meet all of the following criteria and provided the member has not received other adoptive immunotherapies or genetic therapies and is not or has not been a subject in a clinical trial for any of these therapies:
 
    • Are adults (age ≥18) at the time of infusion
 
    • Histologically confirmed diagnosis of diffuse large B-cell lymphoma, not otherwise specified; or primary mediastinal large B-cell lymphoma or high-grade B-cell lymphoma or diffuse large B-cell lymphoma arising from follicular lymphoma.
 
    • Received adequate prior therapy including all of the following:
 
        • Anti-CD20 monoclonal antibody for CD20-positive tumor
        • Anthracycline-containing chemotherapy regimen
        • For subjects with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to diffuse large B-cell lymphoma
 
    • Documentation of all of the following:
        • Absolute neutrophil count ≥1000/μL
        • Absolute lymphocyte count >100/μL
        • Platelet count ≥75,000/μL
 
    • Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis
 
    • Have not received prior treatment with axicabtagene ciloleucel or any other gene therapy or are being considered for treatment with any other gene therapy.
 
*Relapsed or refractory disease, defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Other applications of adoptive immunotherapy do not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, other applications of adoptive immunotherapy are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to January 2018
Adoptive immunotherapy, using adoptive cellular therapy for the administration of cytotoxic T-lymphocytes, cytokine-induced killer cells, lymphokine-activated killer cells, tumor-infiltrating lymphocytes, antigen-loaded autologous dendritic cells, or genetically-engineered T-cells does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, the following adoptive immunotherapy, using adoptive cellular therapy for the administration of cytotoxic T-lymphocytes, cytokine-induced killer cells, lymphokine-activated killer cells, tumor-infiltrating lymphocytes, antigen-loaded autologous dendritic cells, or genetically-engineered T-cells are considered investigational.  Investigational services are specific contract exclusions in most member certificates of coverage.
 
Effective Prior to September 2015
The following:
    • adoptive immunotherapy using peripheral lymphocytes (e.g., tumor-infiltrating lymphocytes, lymphokine-activated killer [LAK] cells) activated in vitro by recombinant or natural IL-2 or other lymphokines, for advanced renal cell carcinoma, melanoma, or other malignancies
    • autolymphocyte therapy (ALT) using peripheral T-cells stimulated in vitro by OKT3 monoclonal antibody in conjunction with IL-2
    • other applications of adoptive immunotherapy
are not covered based on benefit certificate primary coverage criteria, which excludes coverage for services that are being studied in phase I, II or III trials.
 
For contracts without primary coverage criteria, the following:
    • adoptive immunotherapy using peripheral lymphocytes (e.g., tumor-infiltrating lymphocytes, lymphokine-activated killer [LAK] cells) activated in vitro by recombinant or natural IL-2 or other lymphokines, for advanced renal cell carcinoma, melanoma, or other malignancies
    • autolymphocyte therapy (ALT) using peripheral T-cells stimulated in vitro by OKT3 monoclonal antibody in conjunction with IL-2
    • other applications of adoptive immunotherapy
are considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
 
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is balance of benefits and harms.
 
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when randomized clinical trials show efficacy. The selected studies included only new randomized clinical trials.
 
ADOPTIVE IMMUNOTHERAPY MODALITIES
Three systematic reviews on adoptive immunotherapy combining studies using different adoptive immunotherapy methods have been published. Conditions treated in these reviews were renal cell carcinoma, (Tang, 2013) and postoperative hepatocellular carcinoma (Xie, 2012; Zhong, 2012).
 
CYTOTOXIC T LYMPHOCYTES
Epstein-Barr Virus‒Associated Cancers
Bollard et al (2014) conducted an international prospective cohort study of cytotoxic T lymphocytes (CTL) therapy in patients with Epstein-Barr virus (EBV)‒positive Hodgkin or non-Hodgkin lymphoma (Bollard, 2014). Patients had either active, relapsed disease (n=21) or were in remission with a high risk of relapse (n=29). CTLs with activity against EBV antigens were generated by incubating peripheral blood monocytes with EBV antigen-infected dendritic cells (DCs). Eleven (52%) of 21 patients with active disease achieved complete response (CR), and 2 (10%) patients achieved partial response; 2-year event-free survival in this cohort was approximately 50%. Twenty-seven (93%) of 29 patients in remission achieved CR; 2-year event-free survival was 82%. Immediate or delayed toxicity related to CTL infusion was not observed.
 
Chia et al (2014) studied 35 patients with EBV-positive nasopharyngeal cancer at a single center in China (Chia, 2014). Patients received standard chemotherapy with gemcitabine and carboplatin followed by EBV-specific CTL infusion. Median progression-free survival (PFS) and overall survival (OS) were 8 months and 30 months, respectively. One-, 2-, and 3-year OS rates were 77%, 63%, and 37%, respectively. In comparison, median OS in a group of similar historical controls treated at the same institution with chemotherapy only was 18 to 21 months, and 2- and 3-year OS rates were 30% to 43% and 16% to 25%, respectively. The most common adverse events associated with CTL infusion were grade 1 and 2 fatigue and grade 1 myalgia. Two patients developed transient fever, and 3 patients developed grade 1 skin rash. Grade 3 or higher hematologic or nonhematologic toxicities were not observed during CTL therapy. In a 2014 Japanese series of 7 patients who received CTLs for advanced oral and maxillofacial cancers, 1-year survival in patients who achieved response (n=3) and in those with progressive disease (n=4) were 100% and 25%, respectively, although definitions of response were unclear (Ohtani, 2014).
 
Two small, prospective noncomparative cohort studies in patients with relapsed disease indicated response to infused CTLs directed against cancer-associated viral antigens. Adverse events were mild or moderate. There are no RCTs comparing CTL with standard of care and therefore no conclusions can be made about the efficacy of CTL in EBV-associated cancers. To establish efficacy, the following is needed: large, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Cytomegalovirus-Associated Cancers
Schuessler et al (2014) administered CTLs with or without chemotherapy to 13 patients with recurrent glioblastoma multiforme (Schuessler, 2014). CTLs with activity against Cytomegalovirus were generated by incubating peripheral blood monocytes with synthetic peptide epitopes. Median OS was 1.1 years (range, 4.4 months to 6.6 years). Adverse events were minor.
 
A single case series in 13 patients with glioblastoma multiforme treated with CTL has been published. Adverse events were mild. There are no RCTs comparing CTL with standard of care and therefore no conclusions can be made about the efficacy of CTL in Cytomegalovirus-associated cancers. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
CYTOKINE-INDUCED KILLER CELLS
Nasopharyngeal Carcinoma
Li et al (2012) conducted an RCT to evaluate the efficacy of autologous cytokine-induced killer (CIK) transfusion in combination with gemcitabine and cisplatin (GC) chemotherapy to treat nasopharyngeal carcinoma in patients with distant metastasis after radiotherapy (Li, 2012). From 2007 to 2008, 60 patients with distant metastasis after radiotherapy were followed in a university cancer center in China. Patients were randomized to 2 groups; 30 patients in the GC plus CIK group received adoptive autologous CIK cell transfusion in combination with GC chemotherapy, and 30 patients in the GC group received chemotherapy alone. One- and 2-year OS rates were 90% (27/30) and 70% (21/30), respectively, in the GC plus CIK group vs 83% (25/30) and 50% (15/30), respectively, in the GC group. Mean OS was 31 months for the GC plus CIK group and 26 months for the GC group (p=0.137). Median PFS was 26 months for the GC plus CIK group and 19 months for the GC group (p=0.023). This small, single-center RCT indicates that the combination of CIK cells and GC regimen chemotherapy may be a viable treatment option for patients with advanced nasopharyngeal carcinoma.
 
A single RCT from China reported numerically favorable but statistically insignificant effect on PFS and OS. This body of evidence is limited by the context of the studies (non-U.S.), small sample size, and other methodologic weaknesses (inadequate reporting of randomization, allocation concealment, and power). To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Renal Cell Carcinoma
Liu et al (2012) conducted an RCT to evaluate the effects of autologous CIK cell immunotherapy in patients with metastatic renal cell carcinoma followed up in another university cancer center in China (Liu, 2012). From 2005 to 2008, 148 patients were randomized to autologous CIK cell immunotherapy (arm 1, n=74) or IL-2 treatment combination with human interferon-α-2a (arm 2, n=74). The primary end point was OS, and the secondary end point was PFS evaluated by Kaplan-Meier analyses and hazard ratios (HRs) with Cox proportional hazards models. Three-year PFS and OS rates in arm 1 were 18% and 61%, respectively, vs 12% and 23%, respectively, in arm 2 (p=0.031 and p<0.001, respectively). Median PFS and OS in arm 1 were significantly longer than those in arm 2 (PFS, 12 months vs 8 months, p=0.024; OS, 46 months vs 19 months, p<0.001). Multivariate analyses indicated that the cycle count of CIK cell immunotherapy as a continuous variable was significantly associated with prolonged PFS (HR=0.88; 95% confidence interval], 0.84 to 0.93; p<0.001) and OS (HR=0.58; 95% CI, 0.48 to 0.69; p<0.001) in arm 1. These findings suggest that CIK cell immunotherapy has the potential to improve the prognosis of patients with metastatic renal cell carcinoma.
 
Zhang et al (2013) conducted a small RCT in China with 20 patients who had unilateral, locally advanced renal cell carcinoma after nephrectomy (Zhang, 2013). Patients were randomized 1:1 to postoperative CIK therapy or usual care (chemotherapy with or without radiotherapy, additional surgery, or no further treatment). Method of randomization was not described. At a median follow-up of 44 months, 6 patients in the CIK group and 5 controls achieved CR; 2 patients in the CIK group and no controls achieved partial response (overall objective response, 80% vs 50% in the CIK and control groups, respectively; p=0.175). Mean PFS was significantly longer in the CIK group, but OS was not (mean PFS, 32 months vs 22 months; p=0.032; mean OS, 35 months vs 34 months; p=0.214). Adverse events included mild arthralgia, laryngeal edema, fatigue, and low-grade fever in 3 patients. Grade 3 or higher adverse events were not observed.
 
Zhao et al (2015) conducted an RCT in China among operable and inoperable patients with renal cell carcinoma (Zhao, 2015). Dendritic cells were also incorporated into treatment. Among the 60 operable patients, the 3-year disease-free survival (DFS) rate was 96.7% compared with 57.7% in the control group. PFS was also better in the CIK group (p=0.021). Among the 62 inoperable patients, OS was better in the CIK group (p=0.012). No severe adverse reactions were observed.
 
Three RCTs from China have evaluated the efficacy of CIK cell immunotherapy in renal cell carcinoma. The largest of the 3 RCTs reported statistically significant gain in PFS and OS with CIK cell immunotherapy compared with interleukin-2 (IL-2) plus interferon-α-2. This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator. The remaining 2 RCTs also reported response rate in favor of CIK therapy with inconsistent effect on survival. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Gastric Cancer
In 2012, Shi et al in China published a nonrandomized, comparative study to determine the long-term efficacy of adjuvant immunotherapy with autologous CIK cells in 151 patients with locally advanced gastric cancer (Shi, 2012). Five-year OS and 5-year DFS rates for immunotherapy vs no immunotherapy (control group) were 32% vs 23% (p=0.07) and 28% vs 10% (p=0.04), respectively. For patients with intestinal-type tumors, 5-year OS (47% vs 31%; p=0.045) and DFS (42% vs 16%; p=0.02) rates were significantly higher for immunotherapy.
 
A single nonrandomized prospective study from China has reported statistically significant effects on DFS and OS in favor of immunotherapy with autologous CIK vs no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Colorectal Cancer
Zhao et al (2016) reported the results of a controlled trial in which 122 patients with metastatic colorectal cancer were randomized to CIK cell immunotherapy plus chemotherapy (n=61) or chemotherapy alone (n=61) (Zhao, 2016). The primary study end point was OS. The median OS was significantly greater with CIK cell immunotherapy plus chemotherapy (36 months) than with chemotherapy alone (16 months; p<0.001). The 3-year OS rates for both groups were 48% and 23%, respectively (p<0.001).
 
A single RCT from China has reported a statistically significant effect on OS in favor of immunotherapy with CIK immunotherapy vs chemotherapy alone. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Hepatocellular Carcinoma
Cai et al (2017) reported the results of a meta-analysis of 9 RCTs and 3 quasi-RCTs that compared outcomes of conventional treatments plus sequential CIKs with conventional treatments alone (total N=1387 patients) (Cai, 2017). None of the 12 studies were rated as low risk of bias in all 7 domains as assessed by the Cochrane risk of bias tool. Of the 12 RCTs and quasi-RCTs, 5 reported a statistically significant favorable survival benefit for patients receiving conventional treatments plus sequential CIKs. All 12 studies were from Asia (1 Japan, 1 Korea, 10 China). Results of meta-analysis reported a statistical significant reduction in the hazard of death by 41% (HR=0.59; 95% CI, 0.46 to 0.77; p<0.005). However, the heterogeneity among the included studies was statistically significant (p=0.03, I2=48).
 
Yu et al (2014) conducted an RCT in China of 132 patients who had previously untreated hepatocellular carcinoma (Yu, 2014). Patients were randomized 1:1 to CIK therapy plus standard treatment (surgical resection in eligible patients, local treatment, or best supportive care) or standard treatment only. At a median follow-up of 19 months, median PFS was 14 months in the CIK group and 7 months in the control group (p=0.019). Estimated 1-, 2-, and 3-year PFS rates were 56% vs 35% (p=0.004), 36% vs 18% (p=0.004), and 27% vs 18% (p=0.017), respectively. Median OS was 25 months in the CIK group vs 11 months in the control group (p=0.008). Estimated 1-, 2-, and 3-year OS rates were significantly higher for immunotherapy: 74% vs 50% (p=0.002), 53% vs 30% (p=0.002), and 42% vs 24% (p=0.005), respectively. In the subgroup of operable patients, 3-year and median OS did not differ statistically between groups. Common adverse events attributed to CIK therapy were grade 1 or 2 fever, allergy, and headache. Grade 3 or 4 adverse events were not observed. A 2014 nonrandomized study from China reported improved PFS in 30 patients who received radiofrequency ablation plus CIK/natural killer cell/gamma delta T-cell (a type of tumor-infiltrating lymphocytes [TIL]) infusion (median PFS, not reached) compared with 32 patients who received radiofrequency ablation alone (median PFS, 12.0 months) (Cui, 2014).
 
Lee et al (2015) conducted an RCT in Korea of 230 patients being treated for hepatocellular carcinoma by surgical resection, radiofrequency ablation, or percutaneous ethanol injection (Lee, 2015). Patients were randomized 1:1 to adjuvant CIK cell injections 16 times during 60 weeks or to no adjuvant therapy. The primary end point was recurrence-free survival; secondary end points included OS and cancer-specific survival. The median recurrence-free survival was 44 months in the CIK group and 30 months in the control group (p=0.010). OS was longer in the CIK group than in the control group (HR=0.21, p=0.008). Cancer-specific survival was longer in the CIK group than in the control group (HR=0.19, p=0.02). Adverse events occurred more frequently in the CIK group than in the control group, but grade 3 or 4 adverse events did not differ significantly between groups. Adverse events associated with CIK included pyrexia, chills, myalgia, and fatigue.
 
Several RCTs and quasi-RCTs have evaluated the efficacy of CIK cells in hepatocellular cancers. These studies have generally reported some benefits in response rates and/or survival. Results of meta-analysis of these trials also reported a statistical significant reduction in the hazard of death by 41%, but there was considerable heterogeneity among the included studies. Most trials were from Asia and did not use standard of care as the control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Non-Small-Cell Lung Cancer
Wang et al (2014) conducted a systematic review of RCTs of CIK cells for the treatment of non-small-cell lung cancer (NSCLC) (Wang, 2014). Overall, 17 RCTs (total N=1172 patients) were included in the analysis. The studies generally had small sample sizes; the largest had 61 CIK-treated patients and 61 control patients. Most studies also incorporated DC therapy. All were conducted in China. A significant effect of CIK was found for median time to progression and median survival time. OS at various time points significantly favored CIK.
 
A single systematic review of RCTs of CIK cells for the treatment of NSCLC that included trials conducted in China reported some benefits in median time to progression and median survival time. The included body of evidence trials in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
TUMOR-INFILTRATING LYMPHOCYTES
Melanoma
Dudley et al (2008) conducted a series of nonrandomized phase 2 studies examining TIL plus IL-2 in patients with metastatic melanoma under various conditions of preinfusion lymphodepletion (Dudley, 2008). A nonmyeloablative 7-day chemotherapy regimen (n=43) was compared with ablative regimens comprising 5-day chemotherapy plus either 200 centigray (cGy; n=25) or 1200 cGy (n=25) total-body irradiation. Ninety-five percent of patients had progressive disease after prior systemic treatment. Objective response rates by Response Evaluation Criteria in Solid Tumors were 49%, 52%, and 72%, respectively, and did not differ significantly among groups. Responses occurred at multiple metastatic sites, including the brain, and many were durable; 10 patients who achieved CR had no relapse at a median follow-up of 31 months. Toxicities of treatment occurred primarily in the 1200-cGy group and included a delay in marrow recovery of 1 to 2 days compared with the other treatment groups, somnolence requiring intubation, renal insufficiency, and posterior uveitis. Rosenberg et al (2011) reported updated results of these patients with median follow-up of 62 months (Rosenberg, 2011). Ten patients who previously had been classified as partial responders were reclassified as complete responders by Response Evaluation Criteria in Solid Tumors (1, 3, and 6 patients in the nonmyeloablative, 200-cGy, and 1200-cGy groups, respectively). Of these 20 patients (22% of the original cohort), 19 (95%) had ongoing complete regression longer than 3 years. Actuarial 3- and 5-year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders, 100% and 93%, respectively. Likelihood of achieving a CR was similar regardless of prior therapy.
 
Dreno et al conducted an RCT of 88 patients with malignant melanoma without detectable metastases who were randomized to TIL plus IL-2 or to IL-2 alone (Dreno, 2002). There was no significant difference in the duration of relapse-free interval or OS. Figlin et al (1999) randomized 178 patients with metastatic renal cell carcinoma or resectable renal tumors to adjuvant continuous low-dose IL-2 therapy, with or without additional TIL (Figlin, 1999). TILs were harvested from surgical specimens. Outcomes were similar in both groups and, for this reason, the trial was terminated early.
 
One small RCT compared TILs plus IL-2 with IL-2 alone in patients with nonmetastatic melanoma and reported no difference between treatment groups in relapse or survival outcomes. Cohort studies in patients with refractory metastatic melanoma demonstrated response rates of 49% and 52% to 72% with TIL plus nonmyeloablative or myeloablative regimens, respectively. Durable responses in the majority of patients who achieved CR were observed beyond 3 years. Toxicities appeared primarily associated with myeloablative regimen. Larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and use of appropriate standard of care as control arm showing treatment benefit are needed to establish.
 
DENDRITIC CELLS
Antigen-loaded autologous dendritic cells (ADCs) have been explored primarily in early-stage trials in various malignancies including lymphoma,41 myeloma,42,43 subcutaneous tumors,44 melanoma,45 NSCLC,46,47 renal cell cancer,48 and cervical cancer.49 A 2012 systematic review highlighted progress in DC-based immunotherapy in epithelial ovarian cancer (Tanyi, 2012).
 
Glioblastoma Multiforme
In 2013, Bregy et al published a systematic review of observational studies of active immunotherapy using ADCs in the treatment of glioblastoma multiforme.51 Twenty-one studies published through early 2013 were included in this review (total N=403 patients). Vaccination with DCs loaded with autologous tumor cells resulted in an increased median OS in patients with recurrent disease (72-138 weeks across 8 studies), as well as in those newly diagnosed (65-230 weeks across 11 studies) compared with average survival of 58 weeks. Complications and safety of the vaccine were assessed in all studies. No study indicated any sign of autoimmune reaction. Most adverse events were injection-site reactions (22%). Other adverse events included fatigue (19.5%), constipation/diarrhea (1.6%), myalgia/malaise (1.6%), shivering (1.4%), and vomiting (0.5%).
 
A systematic review of observational studies has examined the role of ADC-based adoptive immunotherapy in glioblastoma multiforme. Because of the observational and noncomparative nature of the available evidence, the review is subject to publication and selection bias, which has the potential to lessen or amplify the true potential of adoptive immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Non-Small-Cell Lung Cancer
Shi et al (2012) conducted an RCT at a university cancer center in China to evaluate the role of DC/CIK combination immunotherapy as maintenance treatment of advanced NSCLC (Shi, 2012). From 2008 to 2010, 60 patients with stage IIIB or IV disease after treatment with 4 cycles of a platinum-based chemotherapy regimen were randomized into 2 groups. One group was treated with DC/CIK cell therapy (n=30), and the other was a control group who received no adoptive immunotherapy (n=30). Outcome measures were PFS and adverse events of treatment/toxicity. PFS was 3.2 months in the DC/CIK group (95% CI, 2.9 to 3.5 months) vs 2.6 months control group (95% CI, 2.39 to 2.73 months; p<0.05). No significant toxic reactions were observed in the DC/CIK group, including bone marrow toxicity and gastrointestinal reactions. The findings of this small single-center RCT indicate that combination immunotherapy with dendritic and CIK cells may offer a viable option as maintenance therapy for patients with advanced NSCLC.
 
Chen et al in China conducted a systematic review and meta-analysis of RCTs that compared DC/CIK combination immunotherapy with any other treatment (placebo, no intervention, conventional treatment, or other complementary and alternative medicines) for any cancer type and stage (Chen, 2014). Two included RCTs that compared DC/CIK plus chemotherapy with chemotherapy alone in patients with stage III or IV NSCLC reported OS estimates (total N=150). Pooled relative risk (RRs) favored DC/CIK therapy at 2 years but not at 1 year (RR for 1-year OS=1.38; 95% CI, 1.00 to 1.90; p=0.05; I2=35%; RR for 2-year OS=2.88; 95% CI, 1.38 to 5.99; p=0.005; I2=0%).
 
The 2014 systematic review by Wang (discussed previously) also included many studies that used DC in combination with CIK (Wang, 2014).
 
Two RCTs and a meta-analysis of these RCTs have evaluated the efficacy of DC/CIK cells in NSCLC. The RCTs have generally reported some benefits in response rates and/or survival. Results of meta-analysis of these trials also reported a statistical significant reduction in the hazard of death. However, the effect was inconsistent. Most were from Asia and did not use standard of care as control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Medullary Thyroid Cancer
In a 2009 phase 1 pilot study, 10 patients with metastatic medullary thyroid cancer (MTC) were treated with ADCs pulsed with allogeneic MTC tumor cell lysate (Bachleitner-Hofmann, 2009). At median follow-up of 11 months, 3 (30%) patients had stable disease, and 7 (70%) patients progressed. No World Health Organization grade 3 or 4 toxicities or autoimmune reactions were observed. Of note, human leukocyte antigen match between patients and tumor cell lines did not predict disease stabilization or progression, suggesting that, should future studies demonstrate efficacy of ADC therapy for MTC using allogeneic tumor lysate, an unlimited source of tumor material may be available for lysate preparation.
 
A small prospective noncomparative study in 10 MTC patients with treated with ADCs has been published. There are no RCTs comparing DC-based adoptive immunotherapy with standard of care and therefore no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
Pancreatic Cancer
A 2009 phase 1 study of 5 patients with inoperable pancreatic cancer reinfused ADCs and lymphokine-activated killer cells with gemcitabine; antigen priming of the ADCs was presumed to occur in vivo from apoptosis of gemcitabine-exposed tumor cells (Hirooka, 2009). One patient had a partial response, two had stable disease for more than 6 months, and two had disease progression. Toxicities included grade 1 anemia and grade 2 leukocytopenia, nausea, and constipation.
 
A small prospective noncomparative study in 5 patients with pancreatic cancer treated with ADCs and lymphokine-activated killer has been published. There are no RCTs comparing DC-based adoptive immunotherapy with standard of care and therefore no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight and the use of an appropriate standard of care as the control arm showing treatment benefit.
 
GENETICALLY ENGINEERED T CELLS
Engineered T cell‒based antitumor immunotherapy uses gene transfer of tumor antigen-specific T-cell receptors (TCR) or synthetic chimeric antigen receptors. Review articles have highlighted recent progress in this field for solid and hematologic malignancies (Ngo, 2011; Ochi, 2011; Humphries, 2013).
 
TCR Therapy
In a phase 2 study, Johnson et al transfected autologous peripheral lymphocytes of 36 patients who had metastatic melanoma with genes encoding TCRs highly reactive to melanoma/melanocyte antigens (MART-1:27-35 and gp100:154-162) (Johnson, 2009). Nine (25%) patients experienced an objective response; 8 patients had a partial response lasting 3 months to more than 17 months; and 1 patient (in the gp100 group) had a complete response lasting more than 14 months. Treatment toxicities included erythematous rash, anterior uveitis, hearing loss, and dizziness, suggesting that these were attributable to recognition by the genetically modified lymphocytes of normally quiescent cells expressing the targeted cancer antigens; melanocytic cells exist in the skin, eye, and the inner ear. Ideal targets for TCR gene therapy may be antigens that arise in cancers of nonessential organs (eg, prostate, ovary, breast, thyroid) or are not expressed on normal adult tissues (eg, cancer-testes antigens).
 
Additional studies have examined TCR gene therapy in Hodgkin (Savoldo, 2007) and non-Hodgkin lymphoma (Till, 2008), prostate tumors (Pinthus, 2004), and neuroblastoma (Pule, 2008).
 
One small cohort study in patients with metastatic melanoma reported a 25% response rate with TCR gene therapy and broad treatment-related toxicities. This evidence does not demonstrate net health benefit with genetically engineered T cells in patients with metastatic melanoma.
 
Tisagenlecleucel
In the pivotal trial phase 2 single-arm, international, multicenter trial (study B2202), 68 patients ages 3 to 21 years at screening, with CD19-positive second or greater bone marrow relapse or primary refractory B-cell acute lymphoblastic leukemia were treated with tisagenlecleucel and followed for 12 months. This trial has not been published; information was obtained from the Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee Meeting held in July 2017. Sixty-three patients received U.S.-manufactured product while 5 patients received EU-manufactured product. Patients were required to have more than 5% blasts at screening and either ineligible for, or have relapsed after, allogeneic cell transplant. Refractory was defined by not achieving an initial CR after 2 cycles of a standard chemotherapy regimen (primary refractory). Subjects who were refractory to subsequent chemotherapy regimens after an initial remission were considered chemo-refractory.
 
The prespecified primary efficacy end point was the proportion of patient who achieved objective remission rate (CR or CR with incomplete blood count recovery [CRi]) as assessed by an independent review committee within 3 months after tisagenlecleucel infusion. The trial would meet its primary objective if the lower bound of the 2-sided 95% confidence intervals for objective remission rate was greater than 20%. The key secondary outcome was proportion of patients who achieve best objective remission rate (CR or CRi with an minimal residual disease [MRD]–negative bone marrow) within 3 months of receiving tisagenlecleucel. Key secondary end points were tested sequentially (after primary end point was significant) to control for overall type I error.
 
Of 107 patients who were screened, 88 met the trial inclusion criteria and of these 68 (77.3%) were infused with tisagenlecleucel. In 7 (8%) patients, tisagenlecleucel could not be manufactured. The median time from enrollment to infusion was 44 days. Of the 68 patients, 63 patients received tisagenlecleucel infusion at least 3 months prior to the data cutoff date. Patients received investigator choice bridging chemotherapy as needed to control their leukemia while waiting for tisagenlecleucel infusion. Patients also received protocol mandated lymphocyte-depleting chemotherapy 2 to 14 days prior to tisagenlecleucel infusion. The median age was 12 years (range, 3-23 years), 82% were male, 75% were white, median Karnofsky/Lansky Performance Status score was 90 (range, 50-100), 79% had relapsed disease, 12% had chemo-refractory disease, and 9% had primary refractory disease. The enrolled patient population was heavily pretreated as evident by the following statistics; 87% (59) of patients had received a prior hematopoietic cell transplant with a median of 3 previous treatments. Results show that 52 (82.5%) patients who received tisagenlecleucel infusion achieved a CR or CRi within 3 months. Of the 52 patients who achieved a CR or CRi within 3 months, 29 (56%) were still in remission, 13 (25%) had relapsed, 12 (23%) were censored prior to the data cutoff. The reasons for censoring were six received hematopoietic cell transplant, five received a new cancer therapy, and one was lost to follow-up. The estimated relapse-free rate among responders at month 6 was 75.4% (95% CI, 57.2% to 86.7%). Among the responders, four died (three after disease relapse, one after new cancer therapy was initiated while in remission).
 
Supportive Studies
Two single-arm studies that included a total of 84 patients were conducted using product manufactured at a university cell and vaccine production facility (Novartis Briefing Document, 2017; Novartis Presentations for the July 12, 2017 Meeting of the Oncologic Drugs Advisory Committee, 2017). The first study was a phase 1/2a single-center study in 55 patients enrolled between March 2012 and November 2015. The ORR rate (CR or CRi) was 95% (52/55), and best ORR (CR or CRi with MRD-negative bone marrow) was 89% (49/55). Median OS was 32.7 months (95% CI, 21.0 to inestimable). First pediatric patient treated in the study has been in remission for 5 years. The second study was a phase 2 multicentric study that enrolled 29 patients between August 2014 and February 2016. The ORR rate (CR or CRi) was 69% (20/29).
 
Safety
Safety data included 68 patients (63 patients received who U.S.-manufactured product plus 5 patients who received EU-manufactured product) (FDA, 2017). Cytokine release syndrome (CRS) was the most common serious life-threatening adverse event in the pivotal study and required aggressive supportive measures. One fatality due to CRS-related coagulopathy was observed in the pivotal study. Any grade CRS occurred in 78% (53/68) patients while 47% (32/68) experienced a grade 3 or 4 CRS. The severity of CRS was associated with high tumor burden of greater than 50% blasts in the bone marrow at screening. CRS occurred after a median of 3 days (range, 1-22 days) after tisagenlecleucel infusion and lasted for a median duration of 8 days. CRS resulted in significant morbidity burden as indicated by intensive care unit admission (31 [46%]), ventilatory support (10 [15%]), dialysis (7 [10%]), hypotension (35 [51%]), and hypotension requiring high-dose vasopressor support (17 [25%]).
 
The next most important adverse event of tisagenlecleucel was neurotoxicity such as encephalopathy and seizures. Any grade neurotoxicity was reported in 44% (30/68) patients, and grade 3 neurotoxicity was reported in 15% (10/68) patients. No cases of grade 4 neurotoxicity were reported. Although neurotoxicity was reversible with the use of optimal and best supportive care, the severity of these toxicities requires monitoring for airway protection.
 
The FDA also noted infection as a special adverse event of interest. In the first 8 weeks after infusion, 43% (29/68) of patients developed infection of which 24% (16/68) were grade 3 and 3% (2/68) were grade 4. Infection included gram-positive, gram-negative systemic infections, Clostridium difficile, candida, herpes simplex, and encephalitis due to herpesvirus 6. Three deaths occurring within 60 days and related to infection with herpesvirus 6, bacterial infection, and fungal sepsis was reported. Other adverse events of special interest included prolonged cytopenia, cardiac disorders, and B-cell aplasia. Three patients experienced congestive heart failure that required treatment. Most patients in the pivotal trial had previously been treated with chemotherapy and radiotherapy that predisposed them to cardiotoxicity; it is an anticipated risk in the intended population that would receive treatment with tisagenlecleucel. Acquired hypogammaglobulinemia is an expected side effect of tisagenlecleucel because it not only kills pre-B acute lymphoblastic leukemia cells but also normal B cells because they are CD19-positive. Patients in the trial were maintained on supplemental treatment with intravenous gamma globulin after tisagenlecleucel. It is unclear as to how long intravenous gamma globulin would be required.
 
Multiple design features of the tisagenlecleucel retroviral vector such as minimal homology between packaging plasmids and vector sequences, segregation on 4 different DNA plasmids, deletion of HIV accessory genes, and use of “self-inactivating” vector design aim to reduce the risk the potential of replication competent virus generation and insertional mutagenesis. However, the theoretical risk of formation of replication competent virus, their clonal growth or neoplastic transformation of transduced cells cannot be ruled out. If approved each vector batch and production cells will be tested for the presence of replication competent retrovirus. However, Novartis does not plan to collect patient samples for replication competent retrovirus testing. It is expected that over next 5 years, approximately 5000 patients may be enrolled in the first 5 years in a postmarketing registry that will follow-up patients up to 15 years after tisagenlecleucel infusion.
 
Observed outcomes in a single-arm study design cannot be attributed solely to the intervention itself because they could occur as a result of a placebo effect, the natural course of the disease, or confounding by time-varying factors. However, it is unlikely that the 83% response rate (measured by CR or CRi) seen in the pivotal single-arm trial of tisagenlecleucel in patients with relapsed or refractory acute lymphoblastic leukemia could be the result of noninterventional effect. An unbiased estimate of the safety of tisagenlecleucel cannot be ascertained from this evidence base because of the lack of control arm, which makes it difficult to determine whether the observed adverse reactions are a consequence of background disease or the drug itself. However, tisagenlecleucel is a biologic drug and therefore observed adverse reactions that have immunologic basis are likely drug-mediated. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse reactions. CRS was observed in more than half (63%) of the patients and approximately 40% had an adverse event at grade 4 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of tisagenlecleucel efficacy and safety outside of a clinical trial setting.
 
Axicabtagene Ciloleucel
The approval of axicabtagene ciloleucel was based on the results of an open-label, multicenter phase 1/2 study called ZUMA-1, which reported complete remission rates and duration of response demonstrated in the phase 2 portion of the study. This trial has not been published; information was obtained from FDA documents and the approved label (Kite Pharma Inc., 2017; FDA, 2017; Center for Biologics Evaluation and Research, Food and Drug Administration, 2017). Adults with aggressive B-cell non-Hodgkin lymphoma that was primary refractory, refractory to a second or greater line of therapy, or relapsed within 1 year after autologous hematopoietic cell transplantation were enrolled in the study. Patients with prior allogeneic hematopoietic cell transplantation, any history of central nervous system lymphoma, Eastern Cooperative Oncology Group Performance Status score of 2 or greater, absolute lymphocyte count less than 100/μL, creatinine clearance less than 60 mL/min, hepatic transaminases more than 2.5 times the upper limit of normal, cardiac ejection fraction less than 50%, or active serious infection were excluded. Most patients (74%) had de novo diffuse large B-cell lymphoma and 32% had double- or triple-hit lymphoma. The median age was 58, with 24% being aged 65 years or older; the median number of prior therapies was 3; 77% had refractory disease to a second or greater line of therapy; and 21% had relapsed within 1 year after autologous HCT.
 
All patients received a lymphodepleting regimen consisted of cyclophosphamide and fludarabine prior to infusion of axicabtagene ciloleucel. Of the 111 patients who underwent leukapheresis, 101 received the infusion (9 were not treated due to progressive disease or serious adverse reactions following leukapheresis and there was a manufacturing failure in 1 patient). Study protocol mandated hospitalization of patients for infusion and 7 days after infusion. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. The median time from leukapheresis to product delivery was 17 days (range, 14-51 days). The primary end point was objective response rate based on a modified intention-to-treat population, which was defined as all patients treated with at least 1.0 × 106 chimeric antigen receptor (CAR)-positive T cells per kilogram.
 
Safety
Safety data assessed 108 patients treated with axicabtagene ciloleucel. All patients experienced at least 1 adverse event following infusion and 94% (n=102) experienced grade 3 or higher events. Serious adverse events were observed in 56 (52%) of patients, and serious adverse events that were grade 3 or higher occurred in 48 (44%) patients. Overall, 34 deaths were reported from the time of informed consent to the trial data cutoff (January 27, 2017). Thirty patients died of progressive disease and 4 deaths were attributed to axicabtagene ciloleucel as per FDA analysis, of which 3 occurred within 30 days of infusion.
 
The median time to onset for CRS was 2 days (range, 1-12 days), and the median time to resolution was 7 days (range for CRS duration, 2-58 days). Forty-five percent (49/108) of patients received tocilizumab for CRS management. The median time to onset of neurologic toxicity was 4 days (range, 1-43 days). The median duration was 17 days. Prolonged encephalopathy lasting up to 173 days was noted. Most common neurologic toxicities included encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, and anxiety. Neurologic toxicities were managed with supportive care and/or corticosteroids. Almost all neurologic toxicities at grade 2 or higher occurred within 7 days following infusion.
 
Observed outcomes in a single-arm study design cannot be attributed solely to the intervention itself because they could occur as a result of a placebo effect, the natural course of the disease, or confounding by time-varying factors. However, it is unlikely that the high response rate (measured by CR/CRi or CR plus PR) seen in the pivotal trials of axicabtagene ciloleucel could be the result of noninterventional effect. An unbiased estimate of the safety of these CAR T cells cannot be ascertained from this evidence base because of the lack of control arm, which makes it difficult to determine whether the observed adverse reactions are a consequence of background disease or the drug itself. However, axicabtagene ciloleucel is a biologic drug and therefore observed adverse reactions that have immunologic basis are likely drug-mediated. The observed benefits seen with axicabtagene ciloleucel were offset by a high frequency and severity of adverse reactions. CRS was observed in more than half of the patients in the pivotal trials and more than 40% patients had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of efficacy and safety of axicabtagene ciloleucel outside of a clinical trial setting.
 
SUMMARY OF EVIDENCE
 
Cytotoxic T Lymphocytes
For individuals with Epstein-Barr virus-associated cancers who receive cytotoxic T lymphocytes, the evidence includes 2 small, prospective noncomparative cohort studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The cohort studies have shown a treatment response to infused cytotoxic T lymphocytes directed against cancer-associated viral antigens. To establish efficacy, the following is needed: large, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with Cytomegalovirus-associated cancers who receive cytotoxic T lymphocytes, the evidence includes a single case series. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. In the absence of an RCT comparing cytotoxic T lymphocytes with standard of care, no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Cytotoxic-Induced Killer Cells
For individuals with nasopharyngeal carcinoma who receive CIK cells, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The RCT reported a numerically favorable but statistically insignificant effect on progression-free survival and overall survival. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with renal cell carcinoma who receive CIK cells, the evidence includes multiple RCTs. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The largest of the RCTs reported statistically significant gains in progression-free survival and overall survival with CIK cell-based immunotherapy compared with interleukin-2 plus interferon-α-2. This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator. The other 2 RCTs have also reported response rates in favor of CIK therapy with inconsistent effect on survival. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with gastric cancer who receive CIK cells, the evidence includes a single nonrandomized prospective study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The prospective cohort study reported statistically significant effect on disease-free survival and overall survival in favor of immunotherapy vs no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with colorectal cancer who receive CIK cells, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Results of the RCT showed a statistically significant effect on overall survival in favor of immunotherapy vs chemotherapy alone. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with hepatocellular carcinoma who receive CIK cells, the evidence includes several RCTs. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Several RCTs from Asia have generally reported some benefits in response rates and/or survival. The results of a meta-analysis of these trials have also shown a statistically significant 41% reduction in the hazard of death, but there was considerable heterogeneity across the included studies. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with non-small-cell lung cancer who receive CIK cells, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. A single systematic review of RCTs reported some benefits in median time to progression and median survival time. The included body of evidence trials in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Tumor-Infiltrating Lymphocytes
For individuals with melanoma who receive tumor-infiltrating lymphocytes, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Results of a small RCT have reported no difference in relapse or survival outcomes. Cohort studies in patients with refractory metastatic melanoma have demonstrated response rates of 49% with immunotherapy and 52% to 72% with no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Dendritic Cells
For individuals with glioblastoma multiforme who receive dendritic cells, the evidence includes a systematic review of observational studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Because of the observational and noncomparative nature of the available evidence, it is difficult to draw any meaningful conclusions. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with non-small-cell lung cancer who receive dendritic cells, the evidence includes 2 RCTs and a meta-analysis. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The RCTs have generally reported some benefits in response rates and/or survival. The results of a meta-analysis of these trials also reported a statistical significant reduction in the hazard of death. Most trials were from Asia and did not use standard of care as the control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with medullary thyroid cancer who receive dendritic cells, the evidence includes one prospective noncomparative study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. A small prospective noncomparative study in 10 medullary thyroid cancer patients treated with autologous dendritic cells has been published. There are no RCTs comparing dendritic cell-based adoptive immunotherapy with standard of care and, therefore, no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals with pancreatic cancer who receive dendritic cells, the evidence includes a small prospective noncomparative study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The study reported on treatment outcomes for 5 patients with pancreatic cancer. Because of the noncomparative nature of the available evidence and small sample base, it is difficult to draw any meaningful conclusions. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Genetically Engineered T Cells
 
Peripheral T Lymphocytes
For individuals with cancers who receive autologous peripheral T lymphocytes containing tumor antigen-specific T-cell receptors, the evidence includes multiple small observational studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Multiple observational studies have examined autologous peripheral T lymphocytes containing tumor antigen-specific T-cell receptors in melanoma, Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma. Because of the noncomparative nature of the available evidence with a small sample size, it is difficult to draw any meaningful conclusion. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Tisagenlecleucel
For individuals who are up to 25 years of age with relapsed or refractory B-cell acute lymphoblastic leukemia who receive tisagenlecleucel, the evidence includes multiple single-arm prospective trials. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trials reported an 83% response rate (measured by complete response or complete remission with incomplete blood count) in heavily pretreated patients. All patients who achieved a complete remission or complete remission with incomplete blood count were also minimal residual disease-negative, which is predictive of survival in acute lymphoblastic leukemia patients. After a median follow-up of 4.8 months, the median duration of response was not reached. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome was observed in more than half (63%) of the patients, and approximately 40% had an adverse event at grade 4 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of tisagenlecleucel efficacy and safety outside of a clinical trial setting. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
 
Axicabtagene Ciloleucel
For individuals who are adults with histologically confirmed diagnosis of aggressive non-Hodgkin lymphoma (eg, diffuse large B-cell lymphoma not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, transformed follicular lymphoma) who receive axicabtagene ciloleucel, the evidence includes a single-arm prospective trial. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trial reported a 72% overall response rate (measured by complete or partial remission) in heavily pretreated patients. After a median follow-up of 7.9 months, the median duration of response was 9.2 months. The observed benefits were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome was observed in more than half (63%) of the patients, and 44% had an adverse event at grade 3 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of axicabtagene ciloleucel efficacy and safety outside of the clinical trial setting. The manufacturer has agreed to a postmarketing requirement observational registry study to collect safety information for patients treated with the marketed product. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
Current guidelines from the National Comprehensive Cancer Network do not include recommendations for adoptive immunotherapy to treat cancers of the bladder, central nervous system, head and neck, hepatobiliary system, kidney, pancreatic, stomach, or thyroid, melanoma, Hodgkin lymphoma, or non-small-cell lung cancer (NCCN, 2017).
 
Current NCCN guidelines for acute lymphoblastic leukemia recommend (category 2A) tisagenlecleucel as a treatment option for (NCCN, 2017):
 
    • Philadelphia chromosome-positive patients 25 years or less in age with refractory disease or 2 or more relapses and failure of 2 tyrosine kinase inhibitors.
 
    • Philadelphia chromosome-negative patients 25 years or less in age with refractory disease or 2 or more relapses.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
 
Some currently unpublished trials that might influence this review are listed as follows:
 
Cytotoxic T lymphocytes
 
NCT02227641- Preventative/Preemptive Adoptive Transfer of Peptide Stimulated CMV/EBV Specific T-cells in Patients After Allogeneic Stem Cell Transplantation. Planned enrollment of 50 subjects. This study is ongoing with an estimated completion date of March 2017.
 
Cytotoxic-induced killer cells
 
NCT-2118415- Target Natural Killer(NK) Cell Based Adoptive Immunotherapy for the Treatment of Patients With Non-Small Cell Lung Cancer (NSCLC) After Radiochemotherapy (RCT). Planned enrollment of 90 patients with estimated completion date of Feb. 2018.
 
NCT02229266- Randomised Controlled Phase-2 Trial to Determine the Efficacy of Adoptive Immunotherapy With NK Cells in High-risk AML (HINKL). Planned enrollment of 56 with an estimated completion date of Sep. 2019.
  
Tumor-infiltrating lymphocytes
 
NCT01995344- TIL Therapy in Metastatic Melanoma and IL2 Dose Assessment (METILDA). Planned enrollment of 90 subjects with an estimated completion date of Dec. 2018.   
 
NCT01993719- A Phase II Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Comparing Two Different Chemotherapy. Planned enrollment of 120 subjects with an estimated completion date of Sep. 2019.  
 
NCT01966289-  SGI-110 in Combination With an Allogeneic Colon Cancer Cell Vaccine (GVAX) and Cyclophosphamide (CY) in Metastatic Colorectal Cancer (mCRC). Planned enrollment of 32 subjects with an estimated completion date of Dec. 2019.
 
NCT01319565- Prospective Randomized Study of Cell Therapy for Metastatic Melanoma Using Short-Term Cultured Tumor Infiltrating Lymphocytes Plus IL-2 Following Either a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Alone or in Conjunction w/1200 TBI. Planned enrollment of 120 subjects with an estimated completion date of Jun. 2020.
 
NCT02278887- Study Comparing TIL to Standard Ipilimumab in Patients With Metastatic Melanoma (TIL). Planned enrollment of 162 subjects with an estimated completion date of Sep. 2020.
 
Autologous dendritic cells
 
NCT00045968- Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer. Planned enrollment of 348 subjects with an estimated completion date of Nov. 2016. The study is currently ongoing.
 
NCT00338377- Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization. Planned enrollment of 189 subjects with an estimated completion date of Feb. 2019.
 
NCT01204684- Dendritic Cell Vaccine for Patients With Brain Tumors. Planned enrollment of 60 subjects with an estimated completion date of Oct. 2019.
 
Dendritic cells/cytokine-induced killer cells
 
NCT02202928- Adoptive Cell Therapy Plus Chemotherapy and Radiation After Surgery in Treating Patients With Colorectal Cancer. Planned enrollment of 60 subjects with an estimated completion date of Dec. 2017. The status of this trial is unknown.
 
NCT01691625- Concurrent Chemoradiation With or Without DC-CIK Immunotherapy in Treating Locally Advanced Esophageal Cancer. Planned enrollment of 50 subjects with an estimated completion date of Sep. 2019.
 
Tisagenlecleucel
 
NCT02445248- Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients. Planned enrollment of 130 subjects with an estimated completion date of Jan. 2024.
 
NCT02228096- Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients. Planned enrollment of 60 subjects with an estimated completion date of Oct. 2024.
 
NCT0244522- CD19 CART Long Term Follow Up (LTFU) Study. Planned enrollment of 500 subjects with an estimated completion date of Sep. 2036.
 
Axicabtagen ciloleucel
 
NCT02601313- A Phase 2 Multicenter Study Evaluating Subjects With Relapsed/Refractory Mantle Cell Lymphoma (ZUMA-2). This study has a planned enrollment of 70 patients with an estimated completion date of Jul. 2018.
 
NCT02614066- A Study Evaluating KTE-C19 in Adult Subjects With Relapsed/Refractory B-precursor
 
 

CPT/HCPCS:
0537TChimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day
0538TChimeric antigen receptor T-cell (CAR-T) therapy; preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)
0539TChimeric antigen receptor T-cell (CAR-T) therapy; receipt and preparation of CAR-T cells for administration
0540TChimeric antigen receptor T-cell (CAR-T) therapy; CAR-T cell administration, autologous
36511Therapeutic apheresis; for white blood cells
36512Therapeutic apheresis; for red blood cells
96365Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure)
96367Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); additional sequential infusion of a new drug/substance, up to 1 hour (List separately in addition to code for primary procedure)
96368Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); concurrent infusion (List separately in addition to code for primary procedure)
C9399Unclassified drugs or biologicals
Q2040Tisagenlecleucel, up to 250 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per infusion
Q2041Axicabtagene Ciloleucel, up to 200 million autologous Anti-CD19 CAR T Cells, Including leukapheresis and dose preparation procedures, per infusion
Q2042Tisagenlecleucel, up to 600 million car-positive viable t cells, including leukapheresis and dose preparation procedures, per therapeutic dose
S2107Adoptive immunotherapy i.e. development of specific antitumor reactivity (e.g., tumor-infiltrating lymphocyte therapy) per course of treatment

References: AMCP(2018) AMCP Formulary Dossier Version 4: Kymriah (Tisagenlecleucel[CTL019]): Version Date: May 2018. Accessed June 27, 2018.

Bachleitner-Hofmann T, Friedl J, Hassler M et al.(2009) Pilot trial of autologous dendritic cells loaded with tumor lysate(s) from allogeneic tumor cell lines in patients with metastatic medullary thyroid carcinoma. Oncol Rep 2009; 21(6):1585-92.

Bajwa R, Schechter T, Soni S, et al.(2013) Outcome of children who experience disease relapse following allogeneic hematopoietic SCT for hematologic malignancies. Bone Marrow Transplant. May 2013;48(5):661-665.

Bedrosian I, Mick R, Xu S, et al.(2003) Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol. Oct 15 2003;21(20):3826-3835.

Belldegrun A, Figlin R, Danella l, et al.(1992) Immunotherapy for renal cell carcinoma. Semin Urol 1992; 10:25-27.

Berry DA, Zhou S, Higley H, et al.(2017) Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. Jul 13 2017;3(7):e170580.

Bollard CM, Gottschalk S, Torrano V, et al.(2014) Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol. Mar 10 2014;32(8):798-808.

Bollard CM, Gottschalk S, Torrano V, et al.(2014) Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol. Mar 10 2014;32(8):798-808. PMID 24344220

Bregy A, Wong TM, Shah AH, et al.(2013) Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme. Cancer Treat Rev. Dec 2013;39(8):891-907.

Brentjens RJ, Davila ML, Riviere I, et al.(2013) CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. Mar 20 2013;5(177):177ra138. PMID 23515080

Cai XR, Li X, Lin JX, et al.(2017) Autologous transplantation of cytokine-induced killer cells as an adjuvant therapy for hepatocellular carcinoma in Asia: an update meta-analysis and systematic review. Oncotarget. May 09 2017;8(19):31318-31328.

Center for Biologics Evaluation and Research, Food and Drug Administration(2017) Yescarta BLA Approval Letter. 2017 Available online at https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM581259.pdf. Accessed November 15, 2017.

Chang AE, Suyu S.(1992) Immunotherapy with sensitized lymphocytes. Cancer Invest 1992; 10:357-9.

Chen R, Deng X, Wu H, et al.(2014) Combined immunotherapy with dendritic cells and cytokine-induced killer cells for malignant tumors: a systematic review and meta-analysis. Int Immunopharmacol. Oct 2014;22(2):451-464. PMID 25073120

Chia WK, Teo M, Wang WW, et al.(2014) Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther. Jan 2014;22(1):132-139. PMID 24297049

Chung MJ, Park JY, Bang S, et al.(2014) Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer. Cancer Immunol Immunother. Sep 2014;63(9):939-946. PMID 24916038

Crump M, Neelapu SS, Farooq U, et al.(2017) Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. . Blood. Oct 19 2017;130(16):1800-1808.

Cui J, Wang N, Zhao H, et al.(2014) Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int J Cancer. Jan 15 2014;134(2):342-351. PMID 23825037

Dillman RO, Church C, Oldham RK, et al.(1995) Inpatient continuous-infusion of interleukin-2 in 788 patients with cancer. The National Biotherapy Study Group Experience. Cancer 1995; 71:2358-2370.

Dreno B, Nguyen JM, Khammari A, et al.(2002) Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother. Nov 2002;51(10):539-546.

Dudley ME, Yang JC, Sherry R, et al.(2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. Nov 10 2008;26(32):5233-5239.

Figlin RA, Thompson JA, Bukowski RM, et al.(1999) Multicenter, randomized, phase III trial of CD8+ tumor- infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 1999; 17(8):2521-9.

Food and Drug Administration (FDA).(2017) FDA Briefing Document: Oncologic Drugs Advisory Committee Meeting (BLA 125646,Tisagenlecleucel). n.d. Available online at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM566166.pdf. Accessed July 24, 2017.

Food and Drug Administration (FDA).(2017) FDA Presentations for the July 12, 2017 Meeting of the Oncologic Drugs Advisory Committee. 2017 Available online at https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM567383.pdf. Accessed July 24, 2017.

Food and Drug Administration (FDA).(2017) Summary Basis for Regulatory Action for Yescarta (BLA 125643). 2017 Available online at https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM584335.pdf. Accessed November 15, 2017.

Friedberg JW.(2011) Relapsed/refractory diffuse large B-cell lymphoma. Hematology Am Soc Hematol Educ Program. 2011;2011:498-505.

Gambacorti-Passerini C, Hank JA, Albertini MR, et al.(1993) A pilot phase II trial of continuous infusion interleukin -2 followed by lymphokine-activated killer cell therapy and bolus-infusion interleukin-2 in renal cancer. J Immunother 1993; 13:43-48.

Haas GP, Hillman GG, Redman BG, et al.(1993) Immunotherapy of renal cell carcinoma. Cancer J Clin 1993; 43:177-186.

Hayes RL, Arbit E, Odaimi M, et al.(2001) Adoptive cellular immunotherapy for the treatment of malignant gliomas. Crit Rev Oncol Hematol 2001; 39(1-2):31-42.

Herberman RB.(1993) Miniseries on the interleukins: Part I: T-and NK-cell growth factors. Cancer Invest 1993; 11:458-459.

Heserodt JC.(1993) Lymphokine-activated killer cells: biology and relevance to disease. Cancer Invest 1993; 11:420-439.

Hirooka Y, Itoh A, Kawashima H et al.(2009) A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Pancreas 2009; 38(3):e69-74.

Hontscha C, Borck Y, Zhou H et al.(2011) . Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 2011; 137(2):305-10.

Hrouda D, et al.(1997) The role of immunotherapy for urological tumors. Br J Urol 1997; 79:307-16.

Humphries C.(2013) Adoptive cell therapy: Honing that killer instinct. Nature. Dec 19 2013;504(7480):S13-15. PMID 24352359

Hunger SP, Mullighan CG.(2015) Acute lymphoblastic leukemia in children. N Engl J Med. Oct 15 2015;373(16):1541-1552.

International Non-Hodgkin's Lymphoma Prognostic Factors P.(1993) A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. Sep 30 1993;329(14):987-994.

Jeha S, Gaynon PS, Razzouk BI, et al.(2006) Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. Apr 20 2006;24(12):1917-1923.

Johnson LA, Morgan RA, Dudley ME et al.(2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 2009; 114(3):535-46.

Kalos M, Levine BL, Porter DL, et al.(2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. Aug 10 2011;3(95):95ra73. PMID 21832238

Khammari A, Labarriére N, Vignard V et al.(2009) Treatment of metastatic melanoma with autologous Melan-A/Mart-1-specific cytotoxic T lymphocyte clones. J Invest Dermatol 2009; 129(12):2835-42.

Kite Pharma Inc(2017) Prescribing Label: Yescarta™ (axicabtagene ciloleucel) suspension for intravenous infusion. 2017 Available online at https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM581226.pdf. Accessed November 20, 2017

Kobari M, Egawa S, Shibuya K, et al.(2000) Effect of intraportal adoptive immunotherapy on liver metastases after resection of pancreatic cancer. Br J Surg 2000; 87(1):43-8.

Kuebler JP, Whitehead RP, Ward DL, et al.(1993) Treatment of metastatic renal cell carcinoma with recombinant interleukin-2 in combination with vinblastine or lymphokine-activated killer cells. J Urol 1993; 150:814-820.

Lacy MQ, Wettstein P, Gastineau DA, et al.(1999) Dendritic cell-based idiotype vaccination in post transplant multiple myeloma. Blood 1999; 94(10 sup part 1):122a.

Lanzavecchia A.(1993) Identifying strategies for immune intervention. Science 1993; 260:937-944.

Lee JH, Lee JH, Lim YS, et al.(2015) Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. Jun 2015;148(7):1383-1391 e1386.

Li JJ, Gu MF, Pan K et al.(2012) Autologous cytokine-induced killer cell transfusion in combination with gemcitabine plus cisplatin regimen chemotherapy for metastatic nasopharyngeal carcinoma. J Immunother 2012; 35(2):189-95.

Liau LM, Ashkan K, Tran DD, et al.(2018) First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. May 29 2018;16(1):142. PMID 2984381

Liu L, Zhang W, Qi X et al.(2012) Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res 2012; 18(6):1751-9.

Maude SL, Teachey DT, Porter DL, et al.(2015) CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. Jun 25 2015;125(26):4017-4023.

Motta MR, Castellani S, Rizzi S, et al.(2003) Generation of dendritic cells from CD14+ monocytes positively selected by immunomagnetic adsorption for multiple myeloma patients enrolled in a clinical trial of anti-idiotype vaccination. Br J Haematol. Apr 2003;121(2):240-250.

National Comprehensive Cancer Network (NCCN)(2017) NCCN clinical practice guidelines in oncology Avaiable online at http://www.nccn.org. Accessed October 4, 2017

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: gastric cancer, version 1.2014. http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed November 24, 2014.

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: head and neck cancers, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. Accessed November 13, 2014.

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: hepatobiliary cancers, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed November 14, 2014.

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: Hodgkin lymphoma, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed November 24, 2014.

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: kidney cancer, version 2.2015 http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed November 13, 2014.

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: non-Hodgkin's lymphomas, version 5.2014 (discussion update in progress). http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed November 24, 2014.

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: pancreatic adenocarcinoma, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed November 14, 2014.

National Comprehensive Cancer Network (NCCN).(2014) Clinical practice guidelines in oncology: thyroid carcinoma, version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Accessed November 24, 2014.

National Comprehensive Cancer Network (NCCN).(2015) Clinical practice guidelines in oncology: melanoma, version 1.2015 (discussion update in progress). http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed November 13, 2014.

National Comprehensive Cancer Network (NCCN).(2015) Clinical practice guidelines in oncology: non-small cell lung cancer, version 1.2015 (discussion update in progress). http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed November 14, 2014

National Comprehensive Cancer Network (NCCN).(2018) NCCN clinical practice guidelines in oncology: B-Cell lymphomas. Version 4.2018. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed June 19, 2018.

Ngo MC, Rooney CM, Howard JM, et al.(2011) Ex vivo gene transfer for improved adoptive immunotherapy of cancer. Hum Mol Genet 2011; 20(R1):R93-9.

Novartis Pharmaceuticals.(2017) Prescribing Label: Kymriah™ (tisagenlecleucel) suspension for intravenous infusion. N.d. Available online at https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf. Accessed November 20, 2017.

Novartis Pharmaceuticals.(2018) . Prescribing Label: Kymriah™ (tisagenlecleucel) suspension for intravenous infusion. 2018; https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/kymriah.pdf. Accessed June 19, 2018.

Ochi T, Fujiwara H, Yasukawa M.(2011) Requisite considerations for successful adoptive immunotherapy with engineered T-lymphocytes using tumor antigen-specific T-cell receptor gene transfer. Expert Opin Biol Ther 2011; 11(6):699-713.

Ohtani T, Yamada Y, Furuhashi A, et al.(2014) Activated cytotoxic T-lymphocyte immunotherapy is effective for advanced oral and maxillofacial cancers Int J Oncol. Nov 2014;45(5):2051-2057. PMID 25120101

Osband ME, Lavin PT, Babayan RK, et al.(1990) Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma. Lancet 1990; 335(8696):994-8.

Pinthus JH, Waks T, Malina V, et al.(2017) Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes. J Clin Invest. Dec 2004;114(12):1774-1781.

Plautz GE, Miller DW, Barnett GH, et al.(2000) T cell adoptive immunotherapy of newly diagnosed gliomas. Clin Cancer Res 2000; 6(6):2209-18.

Pui CH, Carroll WL, Meshinchi S, et al.(2011) Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. Feb 10 2011;29(5):551-565.

Pule MA, Savoldo B, Myers GD, et al.(2017) Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. Nov 2008;14(11):1264-1270.

Rosenberg SA, Lotze MT, Yang JC, et al.(1993) Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. JNCI 1993; 85:622-632.

Rosenberg SA, Yang JC, Sherry RM, et al.(2011) Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy Clin Cancer Res 2011; 17(13):4550-7.

Rosenberg SA.(1992) The immunology and gene therapy of cancer. J Clin Oncol 1992; 10:180-199.

Rubin JT.(1993) Interleukin-2: Its biology and clinical application in patients with cancer. Cancer Invest 1993; 11:460-472.

Santin AD, Bellone S, Palmieri M, et al.(2003) Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix. Gynecol Oncol. May 2003;89(2):271-280.

Savoldo B, Rooney CM, Di Stasi A, et al.(2007) Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood. Oct 01 2007;110(7):2620-2630.

Schuessler A, Smith C, Beagley L, et al.(2014) Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res. Jul 1 2014;74(13):3466-3476. PMID 24795429

Sehn LH, Berry B, Chhanabhai M, et al.(2007) The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. Mar 01 2007;109(5):1857-1861.

Shi SB, Ma TH, Li CH et al.(2012) Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer. Tumori 2012; 98(3):314-9.

Small EJ, Fratesi P, Reese DM, et al.(2000) Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol 2000; 18(23):3894-903.

Su Z, Dannull J, Heiser A, et al.(2003) Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res. May 01 2003;63(9):2127-2133.

Swerdlow SH, Campo E, Pileri SA, et al.(2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. May 19 2016;127(20):2375-2390.

Takayama T, Sekine T, Makuuchi M, et al.(2000) Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomized trial. Lancet 2000;356(9232):802-7.

Tallen G, Ratei R, Mann G, et al.(2010) Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. May 10 2010;28(14):2339-2347.

Tang X, Liu T, Zang X, et al.(2013) Adoptive cellular immunotherapy in metastatic renal cell carcinoma: a systematic review and meta-analysis. PLoS One. May 2013;8(5):e62847.

Tanyi JL, Chu CS.(2012) Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: a systematic review. Immunotherapy 2012; 4(10):995-1009.

Teras LR, DeSantis CE, Cerhan JR, et al.(2016) 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. Sep 12 2016;66(6):443-459.

Till BG, Jensen MC, Wang J, et al.(2008) Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. Sep 15 2008;112(6):2261-2271.

Timmerman JM, Czerwinski DK, Davis TA, et al.(2002) Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune response in 35 patients. Blood 2002; 99(5):1517-29.

Triozzi PL, Khurram R, Aldrich WA, et al.(2000) Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer 2000; 89(12):2646-54.

Villani F Galimberti M, Rizzi M, et al.(1993) Pulmonary toxicity of recombinant interleukin-2 plus lymphokine-activated killer cell therapy. Eur Respir J 1993; 6:828-833.

von Stackelberg A, Locatelli F, Zugmaier G, et al.(2016) Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. Dec 20 2016;34(36):4381-4389.

Wallace PK, Palmer LD, Perry-Lalley D, et al.(1993) Mechanisms of adoptive immunotherapy: improved methods for in-vivo tracking of tumor-infiltrating lymphocytes and lymphokine-activated killer cells. Cancer Res 1993; 5-5:2558-2367.

Wang M, Cao JX, Pan JH, et al.(2014) Adoptive immunotherapy of cytokine-induced killer cell therapy in the treatment of non-small cell lung cancer. PLoS One. Nov 2014;9(11):e112662.

www.cancer.gov/cancer_information.

Xie F, Zhang X, Li H et al.(2012) Adoptive immunotherapy in postoperative hepatocellular carcinoma: a systemic review. PloS One 2012; 7(8):e42879.

Yang L, Ren B, Li H, et al.(2013) Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients. Cancer Immunol Immunother. Jan 2013;62(1):65-73.

Yu X, Zhao H, Liu L, et al.(2014) A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol. Feb 2014;34(2):194-203. PMID 24337625

Zhang G, Zhao H, Wu J, et al.(2014) Adoptive immunotherapy for non-small cell lung cancer by NK and cytotoxic T lymphocytes mixed effector cells: retrospective clinical observation. Int Immunopharmacol. Aug 2014;21(2):396-405. PMID 24881900

Zhang Y, Wang J, Wang Y, et al.(2013) Autologous CIK cell immunotherapy in patients with renal cell carcinoma after radical nephrectomy. Clin Dev Immunol. 2013;2013:195691. PMID 24382970

Zhao H, Wang Y, Yu J, et al.(2016) Autologous cytokine-induced killer cells improves overall survival of metastatic colorectal cancer patients: results from a phase II clinical trial. Clin Colorectal Cancer. Sep 2016;15(3):228-235.

Zhong JH, Ma L, Wu LC et al.(2012) Adoptive immunotherapy for postoperative hepatocellular carcinoma: a systematic review. Int J Clin Pract 2012; 66(1):21-7.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.