Policy #: 105 Latest Review Date: January 2016

Transcription

1 Name of Policy: Adoptive Immunotherapy Policy #: 105 Latest Review Date: January 2016 Category: Therapy Policy Grade: B Background/Definitions: As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage. The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage: 1. The technology must have final approval from the appropriate government regulatory bodies; 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 3. The technology must improve the net health outcome; 4. The technology must be as beneficial as any established alternatives; 5. The improvement must be attainable outside the investigational setting. Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are: 1. In accordance with generally accepted standards of medical practice; and 2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient s illness, injury or disease; and 3. Not primarily for the convenience of the patient, physician or other health care provider; and 4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient s illness, injury or disease. Page 1 of 19

2 Description of Procedure or Service: The spontaneous regression of certain cancers, such as renal cell cancer or melanoma, supports the idea that a patient s immune system can delay tumor progression and, on rare occasions, can eliminate the tumor altogether. These observations have led to research interest in a variety of immunologic therapies designed to stimulate a patient s own immune system. Adoptive immunotherapy is a method of activating lymphocytes for the treatment of cancer and other diseases. Cells are removed from the patient, processed for some period of time, and then infused back into the patient. Adoptive immunotherapy uses activated lymphocytes as a treatment modality. Both nonspecific and specific lymphocyte activation are used therapeutically. Non-specific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy (ALT), increases the number of activated lymphocytes. Initially, this was done by harvesting peripheral lymphokine-activated killer (LAK) cells and activating them in vitro with the T-cell growth factor interleukin-2 (IL-2) and other cytokines. More recent techniques yield select populations of cytotoxict-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, 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. Cytokine-induced killer (CIK) cells have recently been recognized as a new type of anti-tumor effector cells, which can proliferate rapidly in vitro, with stronger anti-tumor activity and broader spectrum of targeted tumor than other reported anti-tumor effector cells. 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, two methods are studied: adoptive cellular therapy (ACT) and antigen-loaded dendritic cell infusions. ACT is the administration of a patient s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lymphodepleting preparative regimen. 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 ELISA 4) lymphodepletion of the host with immunosuppressive agents 5) adoptive transfer (i.e., 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 transfused back into the patient, where they present antigen to effector lymphocytes (CD4+ T cells, CD8+ T cells, and in some cases, B cells). This Page 2 of 19

3 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 further regulate the host immune system, recent protocols use various cytokines (e.g., 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 the lymphocytes to the tumorbearing host. Note: Allogeneic stem-cell transplantation following nonmyeloablative conditioning of the recipient (known as reduced-intensity conditioning or RIC) may also be referred to as adoptive immunotherapy in the literature. However, RIC stem-cell transplantation relies on a donorversus-malignancy effect of donor lymphocytes, while the adoptive immunotherapy techniques described in this policy enhance autoimmune effects primarily. The use of RIC in stem-cell transplantation is discussed for specific cancers in individual policies related to stem-cell transplantation. Policy: Adoptive immunotherapy, using adoptive cellular therapy (ACT) for the administration of cytotoxic T-lymphocytes, cytokine-induced killer (CIK) cells, lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TIL), or antigen-loaded autologous dendritic cells, or genetically-engineered T-cells (ADC) does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered as investigational. Other applications of adoptive immunotherapy do not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational. Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administer benefits based on the member s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. Key Points: The most recent literature search was performed for the period through November 10, Adoptive immunotherapy has been investigated for 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. Page 3 of 19

4 Systematic Reviews of Adoptive Immunotherapy Modalities Three systematic reviews have been published on adoptive immunotherapy that included different adoptive immunotherapy methods. Conditions treated in these reviews were renal cell carcinoma, and postoperative hepatocellular carcinoma. Renal Cell Carcinoma In 2013, Tang et al published a meta-analysis of randomized controlled trials (RCTs) to investigate the efficacy of adoptive immunotherapy in patients with metastatic renal cell carcinoma Four RCTs (three studies published between 1990 and 1999, and the fourth study by Liu in 2012 below) including 469 patients met all selection criteria; three were U.S. studies and one was conducted in China. The interventions used across studies included a combination of cytokine-induced killer cells (CIK) cells, lymphokine-activated killer (LAK) cells, and tumorinfiltrating lymphocytes (TIL). Most of adoptive immunotherapy-related adverse reactions were Grade 1 or 2 and reversible. On combined analysis, the main outcome measures were superior for patients treated with adoptive immunotherapy, including rates of objective response (risk ratios [RR], 1.65; 95% confidence interval [CI], 1.15 to 2.38; p=0.007), one-year survival (RR=1.30; 95% CI, 1.12 to 1.52; p=0.0008), three-year survival (RR=2.76; 95% CI, 1.85 to 4.14; p<0.001), and five-year survival (RR=2.42; 95% CI, 1.21 to 4.83; p=0.01). Heterogeneity among individual studies across these measures was acceptable. However, the limitations of this review included use of different protocols for adoptive immunotherapy across studies and lack of clearly reporting the randomization method, allocation concealment, blinding or withdrawals which may lead to distribution and implementation bias in this meta-analysis. Hepatocellular Carcinoma Xie and colleagues performed a meta-analysis of randomized controlled trials (RCTs) comparing adoptive immunotherapy with no adjuvant treatment in patients with hepatocellular carcinoma who had undergone curative resection. Six RCTs (published between 1995 and 2009) including 494 patients met the selection criteria. All six trials were conducted in Asia (four in China, and two in Japan) with two studies published in the Chinese language. Two trials used CIK cells as adoptive immunotherapy, one used CIK plus interleukin-2 (IL-2), and the remaining three used LAK plus IL-2. The outcome measures were one- and three-year recurrence and survival rates. The overall analysis revealed a significantly reduced risk of both one-year recurrence (odds ratio [OR]: 0.35; 95% CI: ; p=0.003), and of three-year recurrence (OR: 0.31; 95% CI: ; p=0.001) in patients receiving adoptive immunotherapy. However, no statistically significant difference was observed in three-year survival rates between the two study groups (OR: 0.91; 95% CI: ; p=0.792). It is difficult to reach any conclusions regarding the results of this meta-analysis given the treatment context of the studies, variation in immunotherapy regimens, limited sample size and follow-up period, and the low-to-moderate methodologic quality of the included trials. Zhong and colleagues also performed a systematic review of RCTs published to May 2011 to evaluate the clinical efficacy of adjuvant adoptive immunotherapy for post-operative patients with hepatocellular carcinoma. Four RCTs (published between 1995 and 2009) including 423 patients met the eligibility criteria. As with the Xie meta-analysis above, all four trials were conducted in Asia. Three (of four) trials in this review were also included in the Xie metaanalysis. The primary outcomes evaluated in this review were OS rate, disease-free survival, and Page 4 of 19

5 recurrence rates. The secondary outcome was the adverse effects of treatment/toxicity. Owing to the clinical heterogeneity (including operation methods, dose, and type of cytokines) among studies, meta-analysis was not performed. All RCTs reported significantly improved disease-free survival rate or reduced recurrence rate after treatment with adjuvant adoptive immunotherapy (p<0.05). However, no statistically significant differences were observed in OS between the two study groups across the three studies reporting this outcome. The main adverse effect of adoptive immunotherapy was fever (persistent or transient), reported in three (of four) trials. The conclusions of this systematic review are subject to similar limitations as with the above metaanalysis by Xie and colleagues. Section Summary: Systematic Reviews of Adoptive Immunotherapy Modalities Three systematic reviews provide limited evidence for improved health outcomes with adoptive immunotherapy due to heterogeneity of adoptive immunotherapy methods, low methodological quality of included trials, and restricted applicability of the findings. In hepatocellular carcinoma, recurrence rates and disease-free survival were improved with various adoptive immunotherapy treatments (CIK cells ± IL-2, LAK cells) compared with controls, but not overall survival. In renal cell carcinoma, objective response and one-, three-, and five-year survival was improved with various adoptive immunotherapy treatments (CIK cells, LAK cells, TILs) compared with controls. Cytotoxic T-Lymphocytes Epstein-Barr Virus Associated Cancers Bollard et al in 2014 conducted an international prospective cohort study of CTL therapy in patients with Epstein-Barr virus (EBV) -positive Hodgkin or non-hodgkin lymphoma. Patients had either active, relapsed disease (n=21) or were in remission with 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. Eleven (52%) of 21 patients with active disease achieved complete response, and two patients (10%) achieved partial response; two-year event-free survival in this cohort was approximately 50%. Twenty-seven (93%) of 29 patients in remission achieved complete response; two-year event-free survival was 82%. Immediate or delayed toxicity related to CTL infusion was not observed. Chia et al in 2014 studied 35 patients with EBV-positive nasopharyngeal cancer at a single center in China. Patients received standard chemotherapy with gemcitabine and carboplatin followed by EBV-specific CTL infusion. Median progression-free and overall survival was eight months and 30 months, respectively. One-, two-, and three-year overall survival was 77%, 63%, and 37%, respectively. In comparison, median overall survival in a group of similar historical controls treated at the same institution with chemotherapy only was months, and two- and three-year overall survival was 30%-43% and 16%-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 three patients developed grade 1 skin rash. Grade 3 or higher hematological or nonhematological toxicities were not observed during CTL therapy. In a Japanese series of seven patients who received CTLs for advanced oral and maxillofacial cancers, one-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. Page 5 of 19

6 Cytomegalovirus-Associated Cancers Schuessler et al in 2014 administered CTLs with or without chemotherapy to 13 patients with recurrent glioblastoma multiforme. CTLs with activity against cytomegalovirus (CMV) were generated by incubating peripheral blood monocytes with synthetic peptide epitopes. Median overall survival was 1.1 years (range, 4.4 months to 6.6 years). Adverse events were minor. Section Summary: Cytotoxic T Lymphocytes Small, prospective cohort studies in patients with relapsed disease indicated response to infused CTLs directed against cancer-associated viral antigens. Adverse events were mild or moderate. Although one single-center study in Chinese patients with nasopharyngeal cancer reported improved survival compared with historical controls, larger, comparative trials are needed to demonstrate net health benefit of CTL therapy. Cytokine-Induced Killer (CIK) Cells Nasopharyngeal Carcinoma Li and colleagues conducted an RCT to evaluate the efficacy of autologous CIK transfusion used in combination with gemcitabine and cisplatin (GC) chemotherapy to treat nasopharyngeal carcinoma in patients with distant metastasis after radiotherapy. From September 2007 to August 2008, 60 patients with distant metastasis after radiotherapy were followed up in a university cancer center in China. The study patients were randomly divided into two groups (30 patients in the GC+CIK group were treated with adoptive autologous CIK cell transfusion in combination with GC chemotherapy; 30 patients in the GC group were treated with chemotherapy alone). For the GC+CIK group, the one- and two-year OS rates were 90.0% (27/30) and 70% (21/30), respectively, and for the GC group, they were 83.3% (25/30) and 50% (15/30), respectively. The median progression-free survival (PFS) rates were 26 months for the GC+CIK group and 19 months for the GC group. Average survival time was close to 32 months for the GC+CIK group and 26 months for the GC group. Kaplan-Meier survival analysis showed that the OS of the GC+CIK group was higher than that of the GC group, but the difference was not significant (p=0.1374, log-rank test). However, the PFS of the GC+CIK group was significantly higher than that of the GC group (p=0.0234, log-rank test). The findings of this small single-center RCT indicate that the combination of CIK cells and GC regimen chemotherapy may be a viable treatment option for patients with advanced nasopharyngeal carcinoma. Renal Cell Carcinoma Liu and colleagues 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. From June 2005 to June 2008, 148 patients were randomized to autologous CIK cell immunotherapy (arm 1, n=74), or IL-2 treatment combination with human interferon (IFN)-alpha-2a (arm 2, n=74). Primary endpoint was OS and secondary endpoint was PFS evaluated by Kaplan Meier analyses and treatment hazard ratios (HRs) with the Cox proportional hazards model. The three-year PFS and OS in arm one were 18% and 61%, as compared with 12% and 23% in arm two (p=0.031 and <0.001, all respectively). Median PFS and OS in arm one were significantly longer than those in arm two (PFS, 12 vs. 8 months, p=0.024; OS, 46 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% CI: ; p<0.001) and OS (HR: 0.58; 95% CI: ; p<0.001) in Page 6 of 19

7 arm one. These findings suggest that CIK cell immunotherapy has the potential to improve the prognosis of metastatic renal cell carcinoma, and increased frequency of this immunotherapy could result in additional benefits. Zhang et al in 2013 in China conducted a small RCT of 20 patients with unilateral, locally advanced renal cell carcinoma after nephrectomy. Patients were randomized 1:1 to postoperative CIK therapy or usual care (chemotherapy with or without radiation therapy, additional surgery, or no further treatment). Method of randomization was not described. At median followup of 44 months, six patients in the CIK group and five controls achieved complete response; two patients in the CIK group and no controls achieved partial response (overall objective response: 80% vs 50% in the CIK and control groups, respectively; Fisher exact test, p=0.175). Mean PFS was significantly longer in the CIK group, but OS was not (mean PFS: 32 months vs 22 months; log-rank test, p=0.032; mean OS: 35 months vs 34 months; log-rank test, p=0.214). Adverse events included mild arthralgia, laryngeal edema, fatigue, and low-grade fever in three patients. Grade 3 or higher adverse events were not observed. Zhao et al in 2015 conducted an RCT in China among operable and inoperable patients with renal cell carcinoma. Dendritic cells were also incorporated into treatment. Among the 60 operable patients, the three-year DFS 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). There were no severe adverse reactions observed. Gastric Cancer In 2012, Shi et al published a nonrandomized, comparative Chinese study to determine the longterm efficacy of adjuvant immunotherapy with autologous CIK cells in 151 patients with locally advanced gastric cancer. The five-year OS and five-year DFS rates for immunotherapy versus no immunotherapy/control group were 32% versus 23% (p=0.07) and 28% versus 10% (p=0.04), respectively. For patients with intestinal-type tumors, the five-year OS and DFS rates were significantly higher for immunotherapy (OS, 47% vs 31%; p= 0.045; DFS, 42% vs 16%; p=0.02). Larger and well-defined multicenter studies are needed to confirm these findings. Pancreatic Cancer Chung et al in 2014 in Korea administered CIKs to 20 patients with gemcitabine-refractory pancreatic cancer. Four patients withdrew before the first response evaluation at eight weeks after treatment. Of the remaining 16 patients, none responded. Median PFS and OS were 11 weeks and 27 weeks, respectively. These results were similar to other studies using salvage chemotherapy for gemcitabine-refractory patients. Grade 3 adverse events were asthenia in two patients and thrombocytopenia in one patient. No grade 4 adverse events were observed. Hepatocellular Carcinoma Yu et al in 2014 in China conducted an RCT of 132 patients with previously-untreated hepatocellular carcinoma. Patients were randomized 1:1 to receive CIK therapy plus standard treatment (surgical resection in eligible patients, local treatment, or best supportive care) or standard treatment only. At median follow-up of 19 months, median PFS was 14 months in the CIK group versus seven months in the control group (log-rank test for all comparisons, p=0.019). Estimated one-, two-, and three-year PFS was 56% versus 35% (p=0.004), 36% versus 18% Page 7 of 19

8 (p=0.004), and 27% versus 18% (p=0.017) respectively. Median OS was 25 months in the CIK group versus 11 months in the control group (p=0.008). Estimated one-, two-, and three-year OS was 74% versus 50% (p=0.002), 53% versus 30% (p=0.002), and 42% versus 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 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 lymphocyte) infusion (median PFS: not reached) compared with 32 patients who received radiofrequency ablation alone (median PFS: 12.0 months). Lee et al in 2015 conducted an RCT in Korea of 230 patients being treated for hepatocellular carcinoma by surgical resection, radiofrequency ablation, or percutaneous ethanol injection. Patients were randomized 1:1 to receive adjuvant CIK cell injections 16 times during 60 weeks or 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 reactions associated with CIK included pyrexia, chills, myalgia, and fatigue. Non-Small-Cell Lung Cancer Wang et al in 2014 conducted a systematic review of RCTs of CIK cells for the treatment of nonsmall-cell lung cancer (NSCLC). 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 dendritic cell 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. Section Summary: Cytokine-Induced Killer Cells Several RCTs from Asia have evaluated the efficacy of CIK in different cancer types. These studies have generally reported some benefits in recurrence rates and/or disease-free survival. This body of evidence is limited by the context of the studies (non-u.s.), the small sample sizes, the heterogeneity of treatment groups, and by other methodologic weaknesses. This evidence is insufficient to determine whether use of CIK in any specific cancer type leads to health outcome benefits. Tumor-Infiltrating Lymphocytes (TIL) Melanoma Dudley et al in 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. A nonmyeloablative seven-day chemotherapy regimen (n=43) was compared with ablative regimens comprising five-day chemotherapy plus either 200 cgy (n=25) or 1200 cgy (n=25) total-body irradiation. Ninety-five percent of patients had progressive disease after Page 8 of 19

9 prior systemic treatment. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) were 49%, 52%, and 72%, respectively, and did not differ significantly among groups. Responses occurred at multiple metastatic sites, including brain, and many were durable; 10 patients who achieved complete response 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 one to two days compared with the other treatment groups, somnolence requiring intubation, renal insufficiency, and posterior uveitis. Rosenberg et al in 2011 reported updated results of these patients with median follow-up of 62 months. Ten patients who previously had been classified as partial responders were reclassified as complete responders by RECIST (one, three, and six 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 three years. Actuarial three- and five-year survival for the entire group was 36% and 29%, respectively, but for the 20 complete responders, 100% and 93%, respectively. Likelihood of achieving a complete response was similar regardless of prior therapy. Dreno and colleagues reported on the results of a trial that randomized 88 patients with malignant melanoma without detectable metastases to receive TIL and IL-2 versus IL-2 alone. There was no significant difference in the duration of the relapse-free interval or overall survival. Figlin and colleagues reported the results of a study that randomized 178 patients with metastatic renal cell cancer and resectable renal tumors to receive adjunctive continuous low-dose IL-2 therapy, with or without additional TIL. The TILs were harvested from the surgical specimens. The outcomes were similar in both groups, and for this reason the study was terminated early. Section Summary: Tumor-Infiltrating Lymphocytes One small RCT compared TILs plus IL-2 to 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%-72% with TIL plus nonmyeloablative or myeloablative regimens, respectively. Durable responses in the majority of patients who achieved complete response were observed beyond three years. Toxicities appeared primarily associated with myeloablative regimen. Dendritic Cells Antigen-loaded dendritic cells (ADC) have been explored primarily through early-stage trials in various malignancies including lymphoma, myeloma, subcutaneous tumors, melanoma, nonsmall cell lung cancer, renal cell cancer, and uterine cervical cancer. A 2012 review article highlights recent progress on dendritic cell-based immunotherapy in epithelial ovarian cancer. Glioblastoma Multiforme In 2013, Bregy et al published a systematic review of observational studies of active immunotherapy using autologous dendritic cells in the treatment of glioblastoma multiforme. A total of 21 studies published through early 2013 including 403 patients were included in this review. Vaccination with dendritic cells loaded with autologous tumor cells resulted in increased median OS in patients with recurrent disease ( weeks across eight studies), as well as those newly diagnosed ( weeks across 11 studies) compared to average survival of 58 weeks. Complications in the treated patients and safety of the vaccine were assessed in all Page 9 of 19

10 studies. No study indicated any sign of autoimmune reaction. The majority of side effects analyzed fall under injection site reactions (22%); the most common symptoms included fatigue (19.5%), constipation/diarrhea (1.6%), myalgia/malaise (1.6%), shivering (1.4%) and vomiting (0.5%). Because of the nature of the current literature available, the studies reviewed are subject to publication bias and selection bias, which has the potential to lessen or amplify the true potential of adoptive immunotherapy. Larger controlled trials are required to assess survival and the effect on quality of life of adoptive immunotherapy in this patient population. Non-Small-Cell Lung Cancer Shi and colleagues conducted a randomized study within a university cancer center in China to evaluate the role of dendritic cell (DC)/CIK combination immunotherapy as maintenance treatment of advanced non-small cell lung cancer. From October 2008 to June 2010, 60 patients with stage IIIB and IV disease after treatment with four cycles of a platinum-based chemotherapy regimen were randomly divided into two groups. One group was treated with DC and CIK cell therapy (n=30), and the other was taken as a control group with no adoptive immunotherapy (n=30). The outcome measures were PFS and the adverse effects of treatment/toxicity. PFS was reported to be prolonged in the DC/CIK group (3.20 months; 95% CI: ) compared to the control group (2.56 months; 95% CI: ; 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 cells and CIK cells may offer a viable option as maintenance therapy for patients with advanced non-small cell lung cancer. Chen et al in 2014 in China conducted a systematic review and meta-analysis of RCTs that compared DC/CIK combination immunotherapy to any other treatment (placebo, no intervention, conventional treatment, or other complementary and alternative medicines) for any cancer type and stage. Two included RCTs that compared DC/CIK plus chemotherapy to chemotherapy alone in patients with stage III/IV non-small cell lung cancer reported OS estimates (total N=150). Pooled risk ratios (RR) favored DC/CIK therapy at two years but not at one year (RR for one-year OS, 1.38 [95% CI, 1.00 to 1.90]; p=0.05; I2=35%; RR for two-year OS, 2.88 [95% CI, 1.38 to 5.99]; p=0.005; I2=0%). The systematic review by Wang et al mentioned previously included many studies that used DC in combination with CIK. Medullary Thyroid Cancer In a 2009 phase 1 pilot study, ten patients with metastatic medullary thyroid cancer (MTC) were treated with ADCs pulsed with allogeneic MTC tumor cell lysate. At median follow-up of 11 months, three patients (30%) had stable disease and seven patients (70%) progressed. No World Health Organization grade 3 or 4 toxicities or autoimmune reactions were observed. Of note, human leukocyte antigen (HLA) 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. Page 10 of 19

11 Pancreatic Cancer A 2009 Phase I study of five patients with inoperable pancreatic cancer reinfused ADCs and lymphokine-activated killer (LAK) cells with gemcitabine; antigen priming of the ADCs was presumed to occur in vivo from apoptosis of gemcitabine-exposed tumor cells. One patient had a partial response, two had stable disease for more than six months, and two patients had disease progression. Toxicities included Grade 1 anemia and Grade 2 leukocytopenia, nausea, and constipation. Section Summary: Dendritic Cells Observational studies and small RCTs have examined the role of adoptive immunotherapy with ADCs in glioblastoma multiforme, non-small cell lung cancer, medullary thyroid cancer, and pancreatic cancer. All patients had advanced disease; however, treatment protocols varied across studies (e.g., co-administration with other types of primed cells and/or chemotherapy). Treatment-associated toxicities were generally acceptable, but response rates varied across cancer types. The RCT in patients with non-small lung cancer showed increased PFS with ADC/CIK adoptive immunotherapy compared with controls. Although results of this RCT and of some observational studies (e.g., in glioblastoma multiforme) are encouraging, the overall body of evidence does not demonstrate improved net health outcome in any of the cancers studied. Genetically Engineered T-Cells Engineered T cell-based anti-tumor immunotherapy uses gene transfer of tumor-antigen-specific T-cell receptor or synthetic chimeric antigen receptors (CAR). Review articles highlight recent progress in this field for solid and hematologic malignancies. T-Cell Receptor (TCR) Therapy In Phase II trials, Johnson et al transfected autologous peripheral lymphocytes of 36 metastatic melanoma patients with genes encoding TCRs highly reactive to melanoma/melanocyte antigens (MART-1:27-35 and gp100: ). Nine patients (25%) experienced an objective response: eight patients had a partial response lasting three months to more than 17 months, and one patient (in the gp100 group) had a complete response lasting more than 14 months. Treatment toxicities included erythematous rash, anterior uveitis, and 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, the eye, and the inner ear. This suggests that ideal targets for TCR gene therapy may be antigens that arise in cancers of nonessential organs (e.g., prostate, ovary, breast, and thyroid) or are not expressed on normal adult tissues (e.g., cancer-testes antigens). Additional studies have examined TCR gene therapy in Hodgkin and non-hodgkin lymphoma, prostate tumors, and neuroblastoma. Chimeric Antigen Receptor Therapy Chimeric antigen receptor (CAR) therapy generates T cells that express artificial T-cell receptors that bind tumor cell surface antigens but do not need to match the patient s immune type. Preliminary U.S. studies have investigated add-on CAR therapy in eight patients with relapsed chronic lymphocytic leukemia (CLL). Four (50%) of eight patients achieved complete remission. Adverse events included significant cytokine-mediated toxicities (fever, hypotension, and mental Page 11 of 19

12 status changes) requiring high-dose, lymphotoxic steroid therapy in three patients who had high tumor burden at the time of CAR therapy. Section Summary: Genetically Engineered T Cells One small cohort study in patients with metastatic melanoma reported a 25% response rate with T-cell receptor 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. Chimeric antigen receptor therapy is in a preliminary stage of development. Summary The evidence for adoptive immunotherapy in patients who have various types of cancer includes randomized controlled trials (RCTs) for many of the cancers, nonrandomized comparative studies, and uncontrolled trials. Relevant outcomes are overall survival, disease-specific survival, and treatment-related morbidity. Clinical studies using adoptive immunotherapy are primarily small, early-stage investigations for a variety of cancers. The available RCTs are from non-u.s. centers in heterogeneous patient populations and interventions, and have methodologic shortcomings that limit conclusions. Studies of cytotoxic T lymphocytes, lymphokine-activated killer cells, tumor-infiltrating lymphocytes, autologous dendritic cells, and genetically engineered T cells suggest that some adoptive immunotherapies may improve outcomes in some cancer types. However, the impact of adoptive immunotherapy on patient outcomes (e.g., increased survival, improved quality of life) has yet to be clarified in large RCTs. Specifically, high-quality RCTs with adequate follow-up are needed to show that there is a significant survival advantage for adoptive immunotherapy. The evidence is insufficient to determine the effects of the technology on health outcomes. Practice Guidelines and Position Statements Current clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) do not include recommendations for adoptive immunotherapy to treat cancers of the bladder central nervous system, head and neck, hepatobiliary system, kidney, pancreas, stomach, or thyroid; melanoma, Hodgkin or non-hodgkin s lymphomas; or non-small cell lung cancer. U.S. Preventive Services Task Force Recommendations The U.S. Preventive Services Task Force has not addressed the treatment of adoptive immunotherapy. Key Words: Adoptive immunotherapy (AI), lymphokine-activate killer (LAK) cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, autolymphocyte therapy (ALT), leukophoresis, and interleukin-2 (IL- 2), cytotoxic T-lymphocytes, genetically engineered T-cells, cytokine-induced killer cells Approved by Governing Bodies: Adoptive immunotherapy is not a U.S. Food and Drug Administration (FDA)-regulated procedure. Page 12 of 19

13 Benefit Application: Coverage is subject to member s specific benefits. Group specific policy will supersede this policy when applicable. ITS: Home Policy provisions apply FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Current Coding: HCPCS codes: S2107 Adoptive immunotherapy, i.e., development of specific anti-tumor reactivity (e.g., tumor infiltrating lymphocyte therapy) per course of treatment References: 1. Antony PA, Piccirillo CA, Akpinarli A et al. CD8+ T cell immunity against a tumor/selfantigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 2005; 174(5): Bachleitner-Hofmann T, Friedl J, Hassler M et al. 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): Bedrosian I, Mick R, Xu S et al. Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol 2003; 21(20): Bollard CM, Gottschalk S, Torrano V, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol. Mar ; 32 (8): Bregy A, Wong TM, Shah AH et al. Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme. Cancer Treat Rev 2013; 39(8): Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. Mar ; 5 (177):177ra Bukowski, Ronald M. Biologictherapy.Org: Renal cell carcinoma: Interleukin-2 and adoptive immunotherapy. 8. Chang AE, Li Q, Jiang G et al. Phase II trial of autologous tumor vaccination, anti-cd3- activated vaccine-primed lymphocytes and interleukin-2 in stage IV renal cell cancer. J Clin Oncol 2003; 21(5): Chen R, Deng X, Wu H, et al. Combined immunotherapy with dendritic cells and cytokineinduced killer cells for malignant tumors: a systematic review and meta-analysis. Int Immunopharmacol. Oct 2014; 22 (2): Chia WK, Teo M, Wang WW, et al. Adoptive T-cell transfer and chemotherapy in the firstline treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther. Jan 2014; 22 (1): Page 13 of 19

14 11. Chung MJ, Park JY, Bang S, et al. Phase II clinical trial of ex vivo-expanded cytokineinduced killer cells therapy in advanced pancreatic cancer. Cancer Immunol Immunother. Sep 2014; 63 (9): Cui J, Wang N, Zhao H, et al. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int J Cancer. Jan ; 134 (2): Curiel-Lewandrowski, Clara and Demierre, Marie-France. Advances in specific immunotherapy of malignant melanoma, Journal of the American Academy of Dermatology, August 2000, Vol. 43, No Dreno B, Nguyen JM, Khammari A et al. Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother 2002; 51(10): Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following nonmyeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol, April 2005; 23(10): Dudley ME and Rosenberg SA. Adoptive cell transfer therapy. Semin Oncol, December 2007; 34(6): Dudley ME, Yang JC, Sherry R et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 2008; 26(32): Ehtesham M, Black Keith L and Yu John S. Recent progress in immunotherapy for malignant glioma: Treatment strategies and results from clinical trials. Cancer Control 2004; 11(3): Figlin RA, Thompson JA, Bukowski RM et al. 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): Gattinoni L, Finkelstein SE, Klebanoff CA et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 2005; 202(7): Haas, Gabriel P. Update on the role of immunotherapy in the management of kidney cancer, Cancer Control Journal: Tumor Biology, Vol. 3, No Hayes RL, Arbit E, Odaimi M et al. Adoptive cellular immunotherapy for the treatment of malignant gliomas. Crit Rev Oncol Hematol 2001; 39(2-Jan): Hirooka Y, Itoh A, Kawashima H et al. A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Pancreas 2009; 38(3):e Hoffman, D.M. Adoptive cellular therapy, Seminars in Oncology, April 1, 2000; 27(2): (Abstract) 25. Hontscha C, Borck Y, Zhou H et al. Clinical trials on CIK cells: first report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 2011; 137(2): Humphries C. Adoptive cell therapy: Honing that killer instinct. Nature. Dec ; 504 (7480):S Johnson LA, Morgan RA, Dudley ME et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 2009; 114(3): Page 14 of 19

15 28. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. Aug ; 3 (95):95ra Kaufman, H.L. Immunotherapy for pancreatic cancer: Current concepts, Hematology Oncology Clinics of North America, February 1, 2002; 16(1): (Abstract) 30. Kirschner, D. and Panetta, J.C. Modeling immunotherapy of the tumor immune interaction, Journal of Mathematical Biology, 1998; 37: Khammari A, Labarriére N, Vignard V et al. Treatment of metastatic melanoma with autologous Melan-A/Mart-1-specific cytotoxic T lymphocyte clones. J Invest Dermatol 2009; 129(12): Khammari A, Nguyen JM, Pandolfino MD, et al. Long-term follow-up of patients treated by adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother, November 2007; 56(11): Kimura H, Iizasa T, Ishikawa A, Shingyouji M, et al. Prospective phase II study of postsurgical adjuvant chemo-immunotherapy using autologous dendritic cells and activated killer cells from tissue culture of tumor-draining lymph nodes in primary lung cancer patients. Anticancer Res, Mar-Apr 2008; 28(2B): Knutson, K.L. Adoptive T-cell therapy for the treatment of solid tumors, Expert Opinion on Biological Therapy, January 1, 2002; 2(1): (Abstract) 35. Kobari M, Egawa S, Shibuya K et al. Effect of intraportal adoptive immunotherapy on liver metastases after resection of pancreatic cancer. Br J Surg 2000; 87(1): Kondo H, Hazama S, Kawaoka T, et al. Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res, Jan-Feb 2008; 28(1B): Lacy MQ, Wettstein P, Gastineau DA et al. Dendritic cell-based idiotype vaccination in post-transplant multiple myeloma. Blood 1999; 94(10 suppl part 1):122a. 38. Lee JH, Lee JH, Lim YS, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. Jun 2015; 148(7): e Leplina OY, Stupak, VV, Kozlov, YP, et al. Use of interferon-alpha-induced dendritic cells in the therapy of patients with malignant brain gliomas. Bull Exp Biol Med, April 2007; 143(4): Li JJ, Gu MF, Pan K et al. Autologous cytokine-induced killer cell transfusion in combination with gemcitabine plus cisplatin regimen chemotherapy for metastatic nasopharyngeal carcinoma. J Immunother 2012; 35(2): Liu L, Zhang W, Qi X et al. Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res 2012; 18(6): Mackensen A, Meidenbauer N, Vogl S, et al. Phase I study of adoptive T-cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma. J Clin Oncol, November 2006; 24(31): Margolin, K.A. Interleukin-2 in the treatment of renal cancer, Seminars in Oncology. April 1, 2000; 27(2); (Abstract) 44. Morgan RA, Dudley ME, Wunderlich JR et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, October 2006; 314(5796): Morse, M.A. Current status of adoptive immunotherapy of malignancies, Expert Opinion on Biological Therapy, March 1, 2002; 2(3): (Abstract) Page 15 of 19

16 46. Motta MR, Castellani S, Rizzi S et al. 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 2003; 121(2): National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Available online at: National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: bladder cancer, version National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: central nervous system cancers, version National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: gastric cancer, version National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: head and neck cancers, version National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: hepatobiliary cancers, version National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: Hodgkin lymphoma, version National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: kidney cancer, version National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: melanoma, version (discussion update in progress) National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: non-hodgkin's lymphomas, version (discussion update in progress) National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: non-small cell lung cancer, version (discussion update in progress) National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: pancreatic adenocarcinoma, version National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: thyroid carcinoma, version Ngo MC, Rooney CM, Howard JM, et al. Ex vivo gene transfer for improved adoptive immunotherapy of cancer. Hum Mol Genet 2011; 20(R1):R Ochi T, Fujiwara H, Yasukawa M. 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): Page 16 of 19

17 62. Oelke M, Krueger C, and Schneck JP. Technological advances in adoptive immunotherapy. Drugs of Today 2005; 41(1): Ohtani T, Yamada Y, Furuhashi A, et al. Activated cytotoxic T-lymphocyte immunotherapy is effective for advanced oral and maxillofacial cancers. Int J Oncol. Nov 2014; 45 (5): Pinthus JH, Waks T, Malina V et al. Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes. J Clin Invest 2004; 114(12): Plautz, G.E. Adoptive immunotherapy of CNS malignancies, Cancer Chemotherapy and Biological Response Modifiers, January 1, 2001; 19: Plautz GE, Miller DW, Barnett GH, et al. T cell adoptive immunotherapy of newly diagnosed gliomas. Clin Cancer Res. 2000; 6 (6): Powell DJ Jr, Dudley ME, et al. Adoptive transfer of vaccine0-induced peripheral blood mononuclear cells to patients with metastatic melanoma following lymphodepletion. J Immunol, November 2006; 177(9): Pule MA, Savoldo B, Myers GD et al. Virus-specific T cells engineered to coexpress tumorspecific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 2008; 14(11): Rosenberg SA, Lotze MT, Yang JC et al. 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. J Natl Cancer Inst 1993; 85(8): Rosenberg SA, Nicholas PR, Yang JC et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008; 8(4): Rosenberg SA, Yang JC, Sherry RM et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17(13): Santin AD, Bellone S, Palmieri M et al. 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 2003; 89(2): Savoldo B, Rooney CM, Di Stasi A et al. Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-cd30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood 2007; 110(7): Schuessler A, Smith C, Beagley L, et al. Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res. Jul ; 74(13): Semino, C., et al. Adoptive immunotherapy of advanced solid tumors: An eight year clinical experience, Anticancer Research. Nov-Dec 1999; 19(6C): Shi L, Zhou Q, Wu J et al. Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol Immunother 2012; 61(12): Shi SB, Ma TH, Li CH et al. Effect of maintenance therapy with dendritic cells: cytokineinduced killer cells in patients with advanced non-small cell lung cancer. Tumori 2012; 98(3): Straten P, Becker JC. Adoptive cell transfer in the treatment of metastatic melanoma. J Invest Dermatol 2009; 129(12): Page 17 of 19

18 79. Su Z, Dannull J, Heiser A et al. Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res 2003; 63(9): Takayama T, Sekine T, Makuuchi M et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 2000; 356(9232): Tang X, Liu T, Zang X et al. Adoptive cellular immunotherapy in metastatic renal cell carcinoma: a systematic review and meta-analysis. PLoS One 2013; 8(5):e Tanyi JL, Chu CS. Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: a systematic review. Immunotherapy 2012; 4(10): Thiounn T, Pages F, Mejean A et al. Adoptive immunotherapy for superficial bladder cancer with autologous macrophage activated killer cells. J Urol 2002; 168(6): Till BG, Jensen MC, Wang J et al. Adoptive immunotherapy for indolent non-hodgkin lymphoma and mantel cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 2008; 112(6): Timmerman JM, Czerwinski DK, Davis TA et al. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune response in 35 patients. Blood 2002; 99(5): Triozzi PL, Khurram R, Aldrich WA et al. Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer 2000; 89(12): Wang M, Cao JX, Pan JH, et al. Adoptive immunotherapy of cytokine-induced killer cell therapy in the treatment of non-small cell lung cancer. PLoS One. 2014; 9(11):e Xie F, Zhang X, Li H et al. Adoptive immunotherapy in postoperative hepatocellular carcinoma: a systemic review. PloS One 2012; 7(8):e Yang L, Ren B, Li H et al. 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 2013; 62(1): Yee Cassian. Adoptive T-cell therapy of cancer. Hematology/Oncology Clinics of North America 2006; 20: Yu X, Zhao H, Liu L, et al. A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol. Feb 2014; 34 (2): Zhang Y, Wang J, Wang Y, et al. Autologous CIK cell immunotherapy in patients with renal cell carcinoma after radical nephrectomy. Clin Dev Immunol. 2013; 2013: Zhang G, Zhao H, Wu J, et al. 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): Zhao X, Zhang Z, Li H, et al. Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma. Cancer Lett. Jul ; 362(2): Zhong JH, Ma L, Wu LC et al. Adoptive immunotherapy for postoperative hepatocellular carcinoma: a systematic review. Int J Clin Pract 2012; 66(1):21-7. Page 18 of 19

19 Policy History: Medical Policy Group, April 2003 (1) Medical Policy Administration Committee, August 2003 Available for comment August 11-September 25, 2003 Medical Policy Group, April 2005 (1) Medical Policy Group, April 2007 (1) Medical Policy Group, January 2009 (1) Medical Policy Group, June 2011 (1): Update to Key Points and References Medical Policy Group, March, 2012 (1): Update to Key Points and References related to MPP update; no change in policy statement Medical Policy Group, September 2013 (1): Update to the policy statement under adoptive cellular therapy was changed to include cytokine-induced killer (CIK) cells; however, the intent of both policy statement (i.e., investigational) is unchanged; update to Description, Key Points and References Medical Policy Administration Committee, September 2013 Medical Policy Panel, December 2013 Medical Policy Group, January 2014 (1): Update to Key Points and References; no change in policy statement Medical Policy Panel, December 2014 Medical Policy Group, December 2014 (4): Updates to Description, Key Points, Approved Governing Bodies, Key Words and References. Update to policy statement adding cytotoxic T- lymphocytes, autologous dendritic cells and genetically engineered T-cells. Also updated Policy section to include other applications of adoptive immunotherapy are considered investigational Medical Policy Panel, December 2015 Medical Policy Group, January 2016 (3): Updates to Description, Key Points & References; no change in policy statement This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a caseby-case basis according to the terms of the member s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment. This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield s administration of plan contracts. Page 19 of 19