National Medical Policy

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1 National Medical Policy Subject: Policy Number: Adoptive Immunotherapy for Cancer NMP265 Effective Date*: May 2006 Updated: May 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for coverage guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other X None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. Adoptive Immunotherapy for Cancer May 15 1

2 If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Health Net, Inc. considers adoptive immunotherapy for the treatment of malignancies (see Note*) investigational because although there are ongoing studies and clinical trials, there continues to be inadequate scientific evidence in the peerreviewed medical literature to support that its efficacy is more beneficial than interleukin-2 (L-2)alone. *Note: For minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer, please refer to the medical policy on Sipuleucel-T (Provenge). Specifically, HealthNet Inc. considers any of the following investigational: 1. For treatment of renal cell carcinoma, melanoma or other malignancies using either tumor-infiltrating lymphocytes (TILs) or lymphokine-activated killer (LAK) cells that are activated in vitro by recombinant or natural interleukin-2 (IL-2) or other lymphokines 2. Antigen-loaded dendritic cells, for advanced renal cell carcinoma, melanoma, breast cancer or other malignancies, excluding asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer [i.e. Provenge (Sipuleucel-T) is FDA approved for this indication] 3. Autolymphocyte therapy (ALT) using peripheral T-cells stimulated in vitro by OKT3 monoclonal antibody in conjunction with IL-2 4. Cellular therapy (also known as fresh cell treatment) 5. Genetic modification of donor lymphocytes because the clinical value of this approach in the treatment of hematological malignancies has not been established 6. Other applications of adoptive immunotherapy Scientific Rationale Update May 2015 Khammari et al. (2015) Tumor immune escape has recently been shown to be related to the development of an immune tolerance state of the microenvironment. Cytokines activating the immune system such as IFN-γ can be used to reverse the immune escape and thus to potentiate the efficacy of immunotherapy. A clinical study was conducted in 18 stage IIIc/IV melanoma patients treated with tumorinfiltrating lymphocytes (TILs) in combination with intratumoral TG1042 injection (adenovirus expressing IFN-γ). The primary objective was to investigate the safety of treatment. Secondary objectives were to study the clinical response and translational research. The treatment was well tolerated. Among the 13 patients evaluable for tumor response, 38.5 % had an overall objective response (OOR = CR + PR) and disease control rate (DCR = CR + PR + S) of 46 %. The clinical response of the 37 targeted lesions led to an OOR of 51 % and a DCR of 75 %. Translational research on predictive markers did not significantly differ between responder and non-responder patients. However, specifically regarding injected lesions, the clinical response correlated with CD3-/CD56+ NK cells which could be activated by TG1042. Adoptive Immunotherapy for Cancer May 15 2

3 Further larger studies of this combined immunotherapy are needed to confirm our findings. Intralesional TG1042 combined with antigen-selected TILs should be discussed. There are a number of Clinical Trials on adoptive immunotherapy for cancer in which the study has been completed but there are no study results posted. There was a Clinical Trial on Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and Interleukin-2 in Treating Patients With Metastatic Melanoma which has been completed and was last updated in March The ClinicalTrials.gov Identifier is NCT , there were 34 individuals enrolled and the study was from September 2004 to January 2009, but only 21 completed the study. The primary objective of this trial was to determine complete clinical tumor regression in patients with metastatic melanoma treated with a myeloablative lymphoid-depleting preparative regimen comprising cyclophosphamide, fludarabine, and total body irradiation followed by autologous tumor-reactive tumor-infiltrating lymphocyte infusion, autologous CD34+ stem cell transplantation, and low-dose or high-dose interleukin-2; and to evaluate the safety of this regimen in these patients. The secondary objective was to determine the survival of the infused lymphocytes by analyzing the sequence of the variable region of the T-cell receptor or flow cytometry in patients treated with this regimen. Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement led to unreliable or uninterpretable data. There is another Clinical Trial on Lymphodepletion Plus Adoptive Cell Transfer With High Dose IL-2 in Patients With Metastatic Melanoma which is ongoing but not currently recruiting participants. The ClinicalTrials.gov Identifier is NCT and is ongoing but not recruiting participants. This study was last updated on February 4, 2015, The original primary outcome was to determine whether patients have acceptable side effects, sustained persistence of infused T cells and exhibit objective anti-tumor responses by Response Evaluation Criteria In Solid Tumors (RECIST). Patients are being offered admission to this study to test the side effects of an investigational treatment prepared from special immune cells (T cells) specific for melanoma. A T-cell is a type of lymphocyte. Lymphocytes are a type of white blood cell that protect people from viral infections; help other cells fight bacterial and fungal infections; produce antibodies; fight cancers; and coordinate the activities of other cells in the immune system. These special immune cells will be taken from a sample of the patient's tumor tissue that will be surgically removed from their body and grown in the laboratory. They will then given back to the patient in their veins. These cells are called tumor infiltrating lymphocytes (TIL). We wish to study the side effects of TIL when they are given with two chemotherapy drugs to temporarily decrease the patient's own immune cells and a drug called Interleukin-2 (IL-2). The two chemotherapy drugs called fludarabine and cytoxan are used to greatly reduce the number of normal lymphocytes circulating in the patient's body, called lymphodepletion, so that there will be more "space" for the cancer fighting lymphocytes (T-cells) that will be infused in their veins. We wish to find out how often these cells can shrink or slow the growth of the patient's melanoma. We also wish to find out the effects of lymphodepletion followed by TIL and high dose IL-2 on the patient's immune system. The lymphodepletion followed by TIL and high dose IL- 2 is experimental, and has not been proven to help treat melanoma. The IL-2 has been approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma that cannot be surgically removed. The chemotherapy drugs Adoptive Immunotherapy for Cancer May 15 3

4 cytoxan and fludarabine used for lymphodepletion have been approved by the FDA, but not for the treatment of metastatic melanoma. The combination of lymphodepletion followed by TIL and high dose IL-2 is not FDA approved but the FDA is permitting its use in this study. Scientific Rationale Update May 2014 Wang et al (2014) investigated the clinical efficacy of cytokine-induced killer (CIK) cell therapy in patients with metastatic renal cell carcinoma (MRCC) and explores whether the levels of peripheral myeloid-derived suppressor cells (MDSCs) are associated with the prognosis of patients receiving this therapy. Twenty-nine patients with measurable MRCC were treated with an adoptive transfer of autologous CIK cells, followed by 5 consecutive days of interleukin-2 administration. The tumor response and 1-year survival were observed. The proportion of MDSCs in the peripheral blood was detected, and the correlation of MDSCs with prognosis was analyzed. Of 29 evaluable patients, no complete responses were seen; 4 patients exhibited a partial response (13.8%), 18 patients displayed stable disease (62.1%), and 7 patients showed progressive disease (24.1%). Twenty patients (69.0%) were alive months at the time of the last follow-up (median follow-up=20.2 mo). The 1-year survival was 82.8% (24/29). Peripheral blood MDSCs were elevated in almost all MRCC patients and decreased after CIK-cell infusion. Subgroup analysis indicated that patients with a relatively low proportion of MDSCs exhibited prolonged survival. Investigators concluded the data suggest that transfusion of autologous CIK cells can induce regression of MRCC, and MDSCs can serve as a potential marker for the prognosis of patients receiving a CIK-based therapy. Hunyadi et al (2013) investigated the safety and tolerability of vaccination by autologous tumor cell lysates (oncolysate)- or carcinoembriogenic antigen (CEA)- loaded DCs in patients with colorectal cancer was investigated in a phase I-II trial. The study included 12 patients with histologically confirmed colorectal cancer (Dukes B2-C stages). Six of the patients received oncolysate-pulsed, whereas the other six received recombinant CEA-loaded autologous DCs. The potential of the tumor antigen-loaded DCs to provoke the patient's immune system was studied both in vivo and in vitro. The clinical outcome of the therapy evaluated after 7 years revealed that none of the six patients treated with oncolysate-loaded DCs showed relapse of colorectal cancer, whereas three out of the six patients treated with CEAloaded DCs died because of tumor relapse. Immunization with both the oncolysateand the CEA-loaded autologous DCs induced measurable immune responses, which could be detected in vivo by cutaneous reactions and in vitro by lymphocyte proliferation assay. Investigators concluded the results show that vaccination by autologous DCs loaded with autologous oncolysates containing various tumor antigens represents a well tolerated therapeutic modality in patients with colorectal cancer without any detectable adverse effects. Demonstration of the efficacy of such therapy needs further studies with increased number of patients Scientific Rationale Update May 2013 Zhong et al (2012) sought to evaluate the immune mechanism and clinical effect of immunotherapy of dendritic cells (DC) and cytokine-induced killer cell (CIK) combined with chemotherapy on multiple myeloma (MM). 60 patients with MM were randomly divided into two groups. 30 patients in chemotherapy group were treated by chemotherapy only, 30 patients in joint group were treated by adoptive immunotherapy (DC-CIK) combined with chemotherapy. A variety of immunological indexes (Hsp70, Th1/Th2, TGF-β) of all patients before and after chemotherapy were Adoptive Immunotherapy for Cancer May 15 4

5 recorded; Also the clinical outcomes between two groups were compared. After chemotherapy, the immunological indexes of all patients were better than those of before chemotherapy (P < 0.05); After treatment, quality of life, clinical index and survival in joint group were better than in chemotherapy group (P < 0.05). Investigators concluded chemotherapy could break the immunosuppression of MM and improve the anti-tumor response of DC-CIK; Chemotherapy and DC-CIK may have synergistic effect for MM. Radvanvi et al (2012) reported adoptive cell therapy (ACT) using autologous tumorinfiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. They reported the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irrc) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8(+) T cells in the infusion product, a more differentiated effector phenotype of the CD8(+) population, and a higher frequency of CD8(+) T cells coexpressing the negative costimulation molecule "B- and T-lymphocyte attenuator" (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. Investigators concluded the results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8(+) T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. Pilon-Thomas et al (2012) performed a single-institution pilot clinical trial combining nonmyeloablative chemotherapy and the adoptive transfer of tumor-infiltrating lymphocytes with interleukin-2 in patients with metastatic melanoma. Nineteen patients were enrolled with 13 patients (68%) successfully completing treatment. An overall response rate (partial and complete responses) of 26% by intention to treat was achieved with a median follow-up time of 10 months. Of the 13 treated patients, there were 2 complete responses and 3 partial responses (38% response rate among treated patients), along with 4 patients with stable disease ranging from 2+ to 24+months. Three of the 4 patients with stable disease have had disease control without additional therapy, including one at 24+ months. Investigators concluded adoptive therapy with infiltrating lymphocytes is labor intensive but feasible and has a high response rate in treated patients. Shi et al (2012) investigated the role of DC/CIK (dendritic cell/cytokine-induced killer cells) immunobiological cancer therapy in maintenance therapy of advanced nonsmall cell lung cancer. When 60 cases of non-small cell lung cancer patients in stage IIIb and IV reached stable disease after treatment with 4 cycles of a two-drug regimen with platinum, they were randomly divided into two groups. One group was treated with DC/CIK immunobiological cancer therapy, and the other was taken as a control group. Finally, cancer progression time and toxicity reaction of the two groups were evaluated. DC/CIK treatment prolongs progression-free survival (3.20 Adoptive Immunotherapy for Cancer May 15 5

6 months [95% CI, ] vs 2.56 months [95% CI, ]; P <0.05). In the treatment group, the proportion of NK cells, T-cell subgroups CD3+, CD4+ and CD8+ had a significant change before and after treatment. Liver and kidney function and blood tests of the treatment group were within the normal range before and after treatment. In the treatment group, 1 case suffered from chest distress, 3 cases suffered from acratia, and 4 cases suffered from pyrexia. Investigators concluded DC/CIK treatment had potential benefit for patients with advanced non-small cell lung cancer compared with the control group and had no obvious side effects. DC/CIK treatment is a safe and effective method for maintenance therapy of advanced non-small cell lung cancer. Scientific Rationale Update May 2012 Clinical trials investigating adoptive immunotherapy for a variety of cancers are ongoing. Iwai et al (2012) sought to clarify the long-term effect of immunotherapy, the effect of adoptive activated T lymphocyte immunotherapy on advanced lung cancer in terms of survival time. In addition, the performance status of cancer patients under immunotherapy was examined. Over 5 10(9) alpha-beta T lymphocytes cultured ex vivo with an immobilized anti-cd3 antibody and interleukin-2 were injected intravenously into patients, once every 2 weeks for 3 months or longer. Follow-up of these patients was carried out using clinical records and by telephone interview questionnaire. Patients undergoing immunotherapy in immunotherapy clinics and those undergoing other anticancer therapies without immunotherapy in seven hospitals in Tokyo were enrolled in this study. Data were analyzed by a third-party statistician. Performance status was studied on another series of various cancer patients who underwent immunotherapy. The overall median survival time of the patients with the best supportive care, which was obtained using Kaplan-Meier's model, was 5.6 months, and those with immunotherapy alone, chemotherapy alone, and immuno-chemotherapy were 12.5, 15.7, and 20.8 months, respectively. Using Cox' proportional hazard model, we examined the possible factors on survival time by univariate analysis. Then, the patients were stratified by gender and histological type for multivariate analysis. Significantly low hazard ratios were observed for immunotherapy and radiotherapy in males with squamous cancer; for chemotherapy and radiotherapy in male with adenocarcinoma; and for immunotherapy in females with adenocarcinoma. Addition of immunotherapy to chemotherapy resulted in a statistically significant decrease in hazard ratio in females with adenocarcinoma. Studies on the performance status (PS), determined according to the European Cooperative Oncology Group criteria, revealed a continuous high level of PS under immunotherapy until around 2 months before death, in contrast to the gradual increase of tumor marker level. Investigators concluded the effectiveness of immunotherapy on advanced lung cancer is limited but may extend life span under certain conditions. Immunotherapy itself provided no clinical benefit by itself as compared with chemotherapy, but a significant additive effect of immunotherapy on chemotherapy was observed in females with adenocarcinoma. Moreover, immunotherapy can maintain good quality of life of the patients until near the time of death. Zhong et al (2012) performed a systematic review of randomized controlled trials (RCTs) to evaluate the clinical efficacy of adjuvant adoptive immunotherapy (AIT) for post-operative hepatocellular carcinoma (HCC) patients. Four RCTs totalling 423 Adoptive Immunotherapy for Cancer May 15 6

7 patients met the eligibility criteria. All RCTs reported significantly improved diseasefree survival rate or reduced recurrence rate after treating with adjuvant AIT (p < 0.05). The overall survival rates of AIT group are slightly higher than those of the control group in one study. Moreover, AIT was a safe treatment, with fever as the main adverse effects. This study adds to the evidence that postoperative HCC patients treated with adjuvant AIT show an improvement in disease-free survival rate or recurrence rate. Geller et al (2011) evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m(2) 5 doses, cyclophosphamide 60 mg/kg 2 doses, and, in seven patients, 200 cgy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)- 2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week 6 doses after NK cell infusion to promote expansion, defined as detection of 100 donor-derived NK cells/μl blood 14 days after infusion, based on molecular chimerism and flow cytometry. Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30-65) years. Mean NK cell dose was (7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. Investigators concluded adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed. In a phase 1/2 two-arm trial, Rapoport et al (2011), investigated 54 patients with myeloma received autografts followed by ex vivo anti-cd3/anti-cd28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. Kurosaki et al (2011) enrolled Seventeen patients with head and neck squamous cell carcinoma (HNSCC) to evaluate optimal administration route of tumor-specific antigen-presenting cells (APCs) for inducing effective immunological responses via Adoptive Immunotherapy for Cancer May 15 7

8 cancer immunotherapy. Human NKT cells are known to have strong anti-tumor activities and are activated by the specific ligand, namely, α-galactosylceramide (αgalcer). Patients received an injection of αgalcer-pulsed APCs into the nasal, or the oral floor submucosa. Then total body image and single photon emission computed tomography (SPECT) images were examined. The immunological responses including the number of peripheral blood NKT cells, anti-tumor activities and the CD4(+) CD25(high) Foxp3(+) T cells (Tregs) induced following APCs were also compared. APCs injected into the nasal submucosa quickly migrated to the lateral lymph nodes and those injected into the oral floor submucosa dominantly migrated to the submandibular nodes rather than the lateral lymph nodes. An increase in the absolute number of NKT cells and the IFN-γ producing cells was observed in peripheral blood after injection of the APCs into the nasal submucosa, however, these anti-tumor activities were not detected and the increased frequency of Treg cells were observed after administration into oral floor. Investigators concluded the results indicate that a different administration route of APCs has the potential to bring a different immunological reaction. The submucosal administration of αgalcer into the oral submucosa tends to induce immunological suppression. Yamasaki et al (2011) performed a phase II clinical study in patients with head and neck squamous cell carcinoma (HNSCC) using ex vivo expanded Vα24 NKT cells and α-galactosylceramide (αgalcer; KRN7000)-pulsed antigen-presenting cells (APCs) to investigate the efficacy and induction of NKT cell-specific immune responses. The subjects were 10 patients with locally recurrent and operable HNSCC. One course of nasal submucosal administration of αgalcer-pulsed APCs and intra-arterial infusion of activated NKT cells via tumor-feeding arteries was given before salvage surgery. Anti-tumor effects, NKT cell-specific immune responses in extirpated cancer tissue and peripheral blood, safety, and pathological effects were evaluated. Five cases achieved objective tumor regression. The number of NKT cells increased in cancer tissues in 7 cases and was associated with tumor regression. The combination therapy induced NKT cell-specific immune responses in cancer tissues that were associated with beneficial clinical effects Scientific Rationale Update June 2010 Great strides have been made in the field of cancer immunotherapy. Provenge (Sipuleucel-T), an autologous cellular immunotherapy, was recently approved by the U.S FDA (Apr 2010) for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Manufactured by the Dendreon Corporation, Provenge consists of autologous peripheral blood mononuclear cells, including antigen presenting cells (APCs), that have been activated during a defined culture period with a recombinant human protein, PAP- GM-CSF, consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The patient s peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure approximately 3 days prior to the infusion date. Each dose of Provenge contains a minimum of 50 million autologous CD54+ cells activated with PAPGM- CSF, suspended in 250 ml of Lactated Ringer s Injection, USP in a sealed, patient-specific infusion bag. Provenge is administered intravenously in a 3-dose schedule, which is given at approximately 2-week intervals. Due to the autologous nature of Provenge, it is important that the patient and physician adhere to the personalized leukapheresis and infusion schedules. Adoptive Immunotherapy for Cancer May 15 8

9 The adoptive transfer of tumor-reactive cells is a promising approach for the treatment of melanoma and some other cancers. Peer review literature is limited to small phase I and II clinical trials. Jiang et al (2010) retrospectively analyzed the clinical data of 156 patients with gastric cancer divided into two groups, chemotherapy group (n=81) and chemotherapy combined with cytokine-induced killer (CIK) cell therapy group (n=75). B7-H4 expression was detected in the surgical specimens of gastric cancer patients by immunohistochemistry assay. Disease-free survival was compared between the chemotherapy group and the CIK group at different expression levels of B7-H4. The authors reported the difference was not statistically significant in all clinical and pathological data between the chemotherapy group and the CIK treatment group. The postoperative median tumor-free survival in two groups was 18.0 and 45.0 months, respectively. The postoperative median survival time was 27.0 and 49.0 months, respectively. The author notes these differences were statistically significant. In 86 patients with low B7-H4 expression, the median tumorfree survival time was 32.0 and 62.0 months, respectively. In 70 patients with high B7-H4 expression, the median tumor-free survival time was 11.0 and 18.0 months, respectively, and again the author notes these differences were statistically significant. The authors concluded the median tumor-free survival time of patients with gastric cancer may be further improved by chemotherapy combined with CIK cell therapy, regardless of the level of B7-H4 expression. Li et al (2009) evaluated the clinical efficacy of dendritic cell (DC)-activated CIK cell treatment following regular chemotherapy and the effects of this therapy on immune responses in patients with non-small cell lung cancer (NSCLC) after surgery. A paired study, with 42 patients in each group with stage I-IIIa NSCLC after surgery, was performed. Patients received chemotherapy alone (CT) or chemotherapy and DCactivated CIK cell treatment (immuno-ct). Disease-free survival (DFS) and overall survival were evaluated. CIK cell cytotoxicity against tumor cells was detected using a lactate dehydrogenase-based method. Serum cytokine levels in the immuno-ct group were detected using cytokine antibody arrays. The authors reported the cytotoxicity of CIK cells was significantly enhanced by DC activation. The 2-year overall survival rate in the immuno-ct group was significantly improved compared with the CT group (94.7 +/- 3.6% versus /- 7.0%, P < 0.05). The 2-year DFS of these two groups showed no significant difference. DC-activated CIK cell treatment increased production of cytokines that have known anti-tumor effects, including IFN-gamma, MIG, TNF-alpha and TNF-beta, in patients who had no progression, but they were not found in patients who developed recurrence/metastasis. The authors concluded the study suggests that the role of DC-activated CIK cells in improvement of chemotherapy for malignant tumor treatment is associated with up-regulation of the production of cytokines involved in the anti-tumor effect. Chang et al (2009) evaluated the efficacy of immunotherapy for patients with metastatic melanoma with autologous melanoma apoptotic bodies (MAB)-pulsed dendritic cells (DCs). Accessible tumors from eligible patients with refractory metastatic melanoma were surgically removed and processed for primary culture. The autologous tumor cells were treated with dactinomycin to obtain MAB. To generate DCs, adherent peripheral blood mononuclear cells were cultured in complete medium containing granulocyte macrophage-colony stimulating factor and interleukin-4. MAB-pulsed DCs were given either intradermally (i.d.) or intravenously. Patients were immunized at monthly intervals and boosted with Adoptive Immunotherapy for Cancer May 15 9

10 keyhole limpet hemocyanin (KLH) and MAB 2 weeks post-vaccination, with a maximum of four cycles. Of the 10 patients enrolled in this trial, nine were treated with MAB-pulsed DCs; two were given intravenous vaccinations and the other seven were i.d. injected. Mild tenderness in the draining lymph nodes lasting for less than 48 h and enlargement of the draining lymph nodes were noted in all seven i.d. cases. Treatment-related grade 3-4 toxicity, neutropenia, skin ulceration, tumor growth at the injection site, and sepsis were not observed in any of the patients. Delayed-type hypersensitivity to KLH was observed in all patients, whereas no delayed-type hypersensitivity to autologous tumor antigens was observed. One patient achieved partial response with reduction in lung metastatic tumor mass, and a presence of vesicles in the post-vaccination KLH response. Two patients had stable disease for more than 24 months; one was still alive at the time of submission of this report, the other eventually developed multiple metastases. The author concluded that MABpulsed DC immunotherapy is well tolerated in patients with malignant melanoma; however, its efficacy is only modest. Combination with other modalities is required to enhance DC-based immunotherapy. Motohashi et al (2009) evaluate the safety, immune responses, and antitumor responses after the administration of alpha-galactosylceramide (alphagalcer) KRN7000-pulsed PBMC cultured with IL-2 and GM-CSF (IL-2/GM-CSF-cultured PBMCs), a phase I-II study in patients with non-small cell lung cancer was conducted. Patients with advanced non-small cell lung cancer or recurrent lung cancer refractory to the standard therapy were eligible. alphagalcer-pulsed IL-2/GM- CSF-cultured PBMCs (1 x 10(9)/m(2)) were i.v. administered four times. Immune responses were monitored weekly. Twenty-three patients were enrolled in this study and 17 cases (73.9%) completed. No severe adverse event related to the treatment was observed. After the injection of alphagalcer-pulsed IL-2/GM-CSF-cultured PBMCs, an increased number of IFN-gamma-producing cells in the peripheral blood were detected in 10 patients (58.8%). Five cases remained as stable disease, and the remaining 12 cases were evaluated as progressive disease. The estimated median survival time (MST) of the 17 cases was 18.6 mo (range, 3.8 to 36.3 mo). Ten patients who displayed increased IFN-gamma-producing cells (> or =2-fold) showed prolonged MST (31.9 mo; range, 14.5 to 36.3 mo) as compared with poorresponder patients (n = 7) MST (9.7 mo; range, 3.8 to 25.0 mo) (log-rank test, p = ). The administration of alphagalcer-pulsed IL-2/GM-CSF-cultured PBMCs was well tolerated and was accompanied by the successful induction of NKT celldependent immune responses. The increased IFN-gamma-producing cells that result from alphagalcer stimulation in PBMCs were significantly associated with prolonged MST. These results are encouraging and warrant further evaluation for survival benefit of this immunotherapy. Wu et al (2008) evaluated the clinical efficacy of chemotherapy in combination with cytokine-induced killer (CIK) biotherapy compared to the chemotherapy alone. Fiftynine advanced non-small cell lung cancer (NSCLC) patients were randomly divided into two groups, group A (chemotherapy alone, including docetaxel 75 mg/m2, day 1; cisplatin, 25 mg/m2, days 1-4, tri-weekly) and group B (chemotherapy plus CIK cell transfusion). Autologous CIK cells were induced from the patients' peripheral mononuclear cells in vitro and separated by cytometry and then transfused back the patients. The host cellular immune function, clinical curative effects and quality of life (QOL) were examined and were compared between the two groups. The host immune function was enhanced and QOL was improved in the patients treated by chemotherapy plus CIK biotherapy compared to the patients treated by chemotherapy alone. The overall response rate (ORR) was 43.3% and 44.8% in Adoptive Immunotherapy for Cancer May 15 10

11 groups A and B, respectively. The disease control rate (DCR) was higher in group B than in group A (89.7% vs. 65.5%, p = 0.030). The time to progression was 4.67 months (95% CI months) in group A and 6.65 months (95% CI months) in group B and the median survival time was 11.0 months (95% CI months) in group A and 15.0 months (95% CI months) in group B. Compared to patients in group A, the patients in group B had significantly longer progression-free survival (p = 0.042) and overall survival (p = 0.029). No severe side-effects occurred in the CIK cell transfusion patients. The authors concluded that chemotherapy plus CIK cells has potential benefits compared to chemotherapy alone in patients suffering from advanced NSCLC and autologous CIK cell transfusion has no obvious side-effects. Palmer et al (2009) reported on a phase II clinical trial investigating the safety and efficacy of intravenous vaccination with mature autologous dendritic cells (DCs) pulsed ex vivo with a liver tumor cell line lysate (HepG2) in patients with advanced hepatocellular carcinoma (HCC). The authors noted that HCC is an attractive target for immunotherapy as evidenced by an active recruitment of tumor-infiltrating lymphocytes that are capable of lysing autologous tumor cells in ex vivo studies. DCs are the most potent antigen-presenting cells, with the capacity to take up, process, and present tumor antigens to T cells and stimulate an immune response, thus providing a rational platform for vaccine development. Thirty-five patients with advanced HCC and not suitable for radical or loco-regional therapies received a maximum of six DC vaccinations each at 3-week intervals. In total, 134 DC infusions were administered with no significant toxicity and no evidence of autoimmunity. Twenty-five patients who received at least three vaccine infusions were assessed clinically for response. The radiologically determined disease control rate (combined partial response and stable disease > 3 months) was 28%. In 17 patients the baseline serum alpha-fetoprotein (AFP) was > 1,000 ng/ml; in four of these patients, it fell to <30% of baseline following vaccination. In one patient there was a radiological partial response associated with a fall in AFP to <10% of baseline. Immune responses were assessed using an ELIspot assay of interferon-gamma (IFNgamma) release. In several cases there was induction of T cell responses to the vaccine and/or AFP following vaccination. The authors concluded autologous DC vaccination in patients with HCC is safe and well tolerated with evidence of antitumor efficacy assessed radiologically and serologically, with generation of antigen-specific immune responses in some cases. Although multiple clinical trials focusing on different types of malignancies and adoptive immunotherapy exist, there is insufficient evidence demonstrating the safety, and efficacy of adoptive immunotherapy. Large randomized clinical trials are needed to determine efficacy, patient selection criteria, and treatment protocol. Scientific Rationale Update May 2009 The successful manipulation of a cancer-directed immune response has long been a goal of cancer immunologists. The transfusion of lymphocytes, referred to as adoptive T cell therapy, is being tested for the treatment of cancer and chronic infections. Adoptive T cell therapy has the potential to enhance antitumor immunity, augment vaccine efficacy, and limit graft-versus-host disease. This form of personalized medicine is now in various stages of clinical trials. Although adoptive T- cell immunotherapy has shown promise in the treatment of human malignancies, the challenge of isolating T cells with high avidity for tumor antigens in each patient has limited application of this approach. There is currently insufficient evidence in peerreviewed scientific literature to support the use of adoptive immunotherapy. Adoptive Immunotherapy for Cancer May 15 11

12 Scientific Rationale Initial The spontaneous regression of certain cancers, such as renal cell cancer or melanoma, supports the idea that the patient s immune system is sometimes capable of delaying tumor progression and on rare occasions can eliminate the tumor altogether. These observations have lead to research interest in a variety of immunologic therapies designed to stimulate the patent s own immune systems, which can be categorized as follows: (1) active non-specific immunotherapy, i.e., the use of interleukin-2; (2) active specific immunotherapy, e.g., immunization with a variety of therapeutic vaccines; (3) passive non-specific immunotherapy, i.e., transfer of lymphokine-activated killer cells; and (4) passive specific immunotherapy; i.e., transfer of specific immune cells such as cytotoxic T-lymphocytes or lymphocytes producing specific antibodies. Adoptive immunotherapy is a general term describing the transfer of immunocompetent cells (i.e., lymphocytes) to the tumor-bearing host and thus would include the latter two strategies listed above. The major research challenge in adoptive immunotherapy is to develop immune cells with specific anti-tumor reactivity that could be generated in large enough quantities for transfer to tumor-bearing patients. The following three techniques of adoptive immunotherapy have been explored: Lymphokine-activated killer (LAK) cell therapy: The patient s peripheral blood lymphocytes are taken from the person s blood via multiple leukaphereses. The cells are then treated in vitro with interleukin-2 (IL-2) to produce LAK cells. IL-2 is a cytokine produced by lymphocytes and is a growth and activation factor for both T-cells and natural killer cells. The stimulated cells are then subsequently reinfused into the patient to help the body s immune system fight the cancer. Tumor-infiltrating lymphocyte (TIL) therapy: The lymphocytes infiltrating a tumor are both cytotoxic and helper T cells and have been shown to have specific antitumor activity, presumably because they recognize specific tumor antigens. TIL therapy involves harvesting the tumor-infiltrating lymphocytes from the tumor itself and then isolating the cells by growing single-cell suspensions from tumors that have been surgically removed from the patient through either excision or biopsy. After several weeks of culture in the presence of IL-2, they become more aggressive at fighting the cancer, and the activated TIL cells are then transfused back into the patient. This technique may require an additional biopsy procedure for the sole purpose of harvesting a portion of tumor for subsequent isolation of the TILs. Transfer of specific immune cells: In this multistep outpatient procedure, the patient s T-cell lymphocytes or dendritic cells are collected through a pheresis procedure, and are exposed to a variety of immunogenic stimuli. For example, in autolymphocyte therapy (ALT), harvested T cells are exposed to a combination of OKT3 monoclonal antibodies and IL-2. The OKT3 antibody is thought to activate memory T cells, which theoretically have been exposed to tumor-associated antigens. The IL-2 is used for clonal expansion of the memory T cells. These cells are then injected back into the patient to help the body s immune system fight the cancer. The treatment is repeated each month for 6 months or longer. In another variant, collected dendritic cells are exposed to a variety of antigens, such as prostatic acid phosphatase. When Adoptive Immunotherapy for Cancer May 15 12

13 reinfused into the patients, these dendritic cells function as potent immunostimulators of native T cells. Cellular therapy involves the injection or ingestion of tissue (e.g., cartilage, embryonic, organs, fetal, glandular) obtained from animal (e.g., sheep, cow and shark) tissues. It has been proposed as a treatment of AIDS, arthritis, asthma, chronic fatigue, cancer, diabetes, hypertension, colonic diverticulum as well as other conditions or diseases. The intended purpose of cellular therapy is to transfer immunity or anti-disease attributes from one organism to another through the sharing of cells that are believed to impart such characteristics to the donor organism. There is very little published information available on cellular therapy and its proposed mechanisms of action. The FDA has received reports of viral and microbial infections, allergic reactions, anaphylactic shock and death following cell therapies. A randomized trial of LAK therapy by Rosenberg et al (2003) using high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer failed to show that the use of LAK cells provided any health benefit beyond that associated with IL-2 alone. Figlin and colleagues (1999) 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 cells. The TIL cells were harvested from the surgical specimens. The outcomes were similar in both groups and for this reason the study was terminated early. Early studies of ALT in patients with metastatic renal cell cancer showed promising results. Chang and associates (2003) reported on the results of a Phase II trial in patients with stage IV renal cell cancer who received irradiated autologous tumor cells admixed with Calmett-Guerin bacillus. Seven days later, vaccine primed lymph nodes were harvested and the lymphoid cells secondarily activated and then infused back into the patient. Of the 39 patients who participated in the trial, there were 4 complete responses and 5 partial responses. Dreno and colleagues (2002) reported on the results of a trial that randomized 88 patients with malignant melanoma without detectable metastases to receive tumor infiltrating cells and interleukin-2 versus interleukin-2 alone. There was no significant difference in the duration of the relapse-free interval or overall survival. Studies have also examined the role of adoptive immunotherapy for hepatocellular cancer (HCC) and pancreatic cancer. Takayama et al (2000) conducted a study that randomized 150 patients who had undergone a curative resection for HCC to receive either adjuvant adoptive immunotherapy or no additional treatment. The immunotherapy consisted of 5 injections over 24 weeks of autologous T cells, harvested from the peripheral blood, and cultured for 2 weeks with IL-2. The immunotherapy group had significantly longer recurrence-free survival and disease-specific survival, but the overall survival, the final health outcome, did not differ significantly between the two groups. Kobari et al (2000) describe the use of intraportal injections of lymphokineactivated killer (LAK) cells after tumor resection in 12 patients with advanced pancreatic cancer and compared their outcomes to a group of 17 patients who did not receive LAK cells. The overall survival between the two groups was not different. Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or non- Adoptive Immunotherapy for Cancer May 15 13

14 covered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures will be replaced by ICD-10 code sets. Health Net National Medical Policies will now include the preliminary ICD-10 codes in preparation for this transition. Please note that these may not be the final versions of the codes and that will not be accepted for billing or payment purposes until the October 1, 2015 implementation date. ICD-9 Codes Malignant neoplasm Malignant neoplasm Amyloidosis Myalgia and myositis, unspecified ICD-10 Codes (May not be all inclusive) C34.00-C34.92 Malignant neoplasm of bronchus and lung C43.0-C44 Melanoma and other malignant neoplasms of skin C C Malignant neoplasm of breast C64.1-C68.9 Malignant neoplasm of urinary tract CPT Codes Therapeutic apheresis for white blood cells Unlisted procedure, hemic or lymphatic system HCPCS Codes M0075 S2107 Review History May 2006 May 2007 May 2008 May 2009 June 2010 June 2011 May 2012 May 2013 May 2014 May 2015 Cellular therapy Adoptive immunotherapy, i.e., development of specific antitumor reactivity (e.g. tumor-infiltrating lymphocyte therapy) per course of treatment Medical Advisory Council initial approval Policy revisions Update no revisions Update. No revisions. Codes updated. Added Provenge (Sipuleucel-T), an autologous cellular immunotherapy, as medically necessary for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer when criteria is met and added link to related medical policy. Update. Added Medicare Table. No revisions. Update no revisions Update no revisions. Code updates Update no revisions. Update no revisions. Code updates. Adoptive Immunotherapy for Cancer May 15 14

15 This policy is based on the following evidence-based guidelines: 1. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Kidney Cancer. V Updated Version Updated Version National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Melanoma. V Updated Version Updated Version References Update May Clinicaltrials.gov. Cyclophosphamide, Fludarabine, and Total-Body Irradiation Followed By Cellular Adoptive Immunotherapy, Autologous Stem Cell Transplantation, and Interleukin-2 in Treating Patients With Metastatic Melanoma. ClinicalTrials.gov Identifier:NCT March Clinicaltrials.gov. Lymphodepletion Plus Adoptive Cell Transfer With High Dose IL- 2 in Patients With Metastatic Melanoma. ClinicalTrials.gov Identifier:NCT February 4, Granzin M, Soltenborn S, Müller S, et al. Fully automated expansion and activation of clinical-grade natural killer cells for adoptive immunotherapy. Cytotherapy May;17(5): doi: /j.jcyt Khammari A, Nguyen JM, Saint-Jean M, et al. Adoptive T cell therapy combined with intralesional administrations of TG1042 (adenovirus expressing interferon-γ) in metastatic melanoma patients Cancer Immunol Immunother Apr 7. [Epub ahead of print]. 5. Perica K, Carlos Varela J, Oelke M, et al. Adoptive T Cell Immunotherapy for Cancer. Rambam Maimonides Med J Jan; 6(1): e Sosman JA. Interleukin-2 and other immunotherapies for advanced melanoma. UpToDate. March 12, References Update May Bielamowicz K, Khawja S, Ahmed N. Adoptive cell therapies for glioblastoma. Front Oncol Nov 11;3: Hunyadi J, András C, Szabó I, et al. Autologous Dendritic Cell Based Adoptive Immunotherapy of Patients with Colorectal Cancer-A Phase I-II Study. Pathol Oncol Res Oct Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity Jul 25;39(1): Knorr DA, Bachanova V, Verneris MR, Miller JS. Clinical utility of natural killer cells in cancer therapy and transplantation. Semin Immunol Apr;26(2): Locatelli F, Moretta F, Brescia L, Merli P. Natural killer cells in the treatment of high-risk acute leukaemia. Semin Immunol Apr;26(2): Rapoport AP, Aqui NA, Stadtmauer EA, et al. Combination Immunotherapy after ASCT for Multiple Myeloma Using MAGE-A3/Poly-ICLC Immunizations Followed by Adoptive Transfer of Vaccine-Primed and Costimulated Autologous T Cells. Clin Cancer Res Mar 1;20(5): Tougeron D, Fauquembergue É, Latouche JB. Immunotherapy for colorectal cancer. Bull Cancer Sep;100(9): Wang Z, Zhang Y, Liu Y, et al. Association of myeloid-derived suppressor cells and efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma patients. J Immunother Jan;37(1): References Update May 2013 Adoptive Immunotherapy for Cancer May 15 15

16 1. Escudier B. Emerging immunotherapies for renal cell carcinoma. Ann Oncol Sep;23 Suppl 8:viii Ishikawa T, Kokura S, Sakamoto N, et al. Whole blood interferon-γ levels predict the therapeutic effects of adoptive T-cell therapy in patients with advanced pancreatic cancer. Int J Cancer Feb Jäkel CE, Hauser S, Rogenhofer S, et al. Clinical studies applying cytokineinduced killer cells for the treatment of renal cell carcinoma. Clin Dev Immunol. 2012;2012: Kanakry JA, Ambinder RF. EBV-Related Lymphomas: New Approaches to Treatment. Curr Treat Options Oncol Apr Knorr DA, Ni Z, Hermanson D, et al. Clinical-Scale Derivation of Natural Killer Cells From Human Pluripotent Stem Cells for Cancer Therapy. Stem Cells Transl Med Mar Linn YC, Yong HX, Niam M, et al. A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission. Cytotherapy Aug;14(7): Ma C, Cheung AF, Chodon T, et al. Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy. Cancer Discov Mar Mukherji B. Immunology of melanoma. Clin Dermatol Mar- Apr;31(2): Pilon-Thomas S, Kuhn L, Ellwanger S, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother Oct;35(8): Radvanyi LG, Bernatchez C, Zhang M, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res Dec 15;18(24): Ren J, Di L, Song G, et al. Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences. Clin Transl Oncol Jan Shi SB, Ma TH, Li CH, Tang XY. Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer. Tumori May-Jun;98(3): Stern M, Passweg JR, Meyer-Monard S, et al. Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers. Bone Marrow Transplant Mar;48(3): Visioni A, Zhang M, Graor H, Kim J. Expansion of melanoma-specific T cells from lymph nodes of patients in stage III: implications for adoptive immunotherapy in treating cancer. Surgery Oct;152(4): Xie F, Zhang X, Li H, et al. Adoptive immunotherapy in postoperative hepatocellular carcinoma: a systemic review. PLoS One. 2012;7(8):e Yang JC. The adoptive transfer of cultured T cells for patients with metastatic melanoma. Clin Dermatol Mar-Apr;31(2): Zhong GC, Yan B, Sun Y, et al. Clinical efficacy of immunotherapy of dendritic cell and cytokine-induced killer cell combined with chemotherapy for treatment of multiple myeloma. Zhonghua Xue Ye Xue Za Zhi Dec;33(12): References Update May Bernatchez C, Radvanyi LG, Hwu P. Advances in the treatment of metastatic melanoma: adoptive T-cell therapy. Semin Oncol Apr;39(2): Adoptive Immunotherapy for Cancer May 15 16

17 2. Gajewski TF. Cancer immunotherapy. Mol Oncol Jan Geller MA, Cooley S, Judson PL, et al. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy. 2011;13(1): Iwai K, Soejima K, Kudoh S, et al. Extended survival observed in adoptive activated T lymphocyte immunotherapy for advanced lung cancer: results of a multicenter historical cohort study. Cancer Immunol Immunother Mar Kimura Y, Tsukada J, Tomoda T, et al. Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. Pancreas Mar;41(2): Kurosaki M, Horiguchi S, Yamasaki K, et al. Migration and immunological reaction after the administration of αgalcer-pulsed antigen-presenting cells into the submucosa of patients with head and neck cancer. Cancer Immunol Immunother. 2011;60(2): Liu Y, Zeng G. Cancer and innate immune system interactions: translational potentials for cancer immunotherapy. J Immunother May;35(4): Mazzarella T, Cambiaghi V, Rizzo N, et al. Ex vivo enrichment of circulating antitumor T cells from both cutaneous and ocular melanoma patients: clinical implications for adoptive cell transfer therapy. Cancer Immunol Immunother Dec Rapoport AP, Aqui NA, Stadtmauer EA, et al. Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of htert and survivin after ASCT for myeloma. Blood. 2011;117(3): Richards JO, Treisman J, Garlie N, et al. Flow cytometry assessment of residual melanoma cells in tumor-infiltrating lymphocyte cultures. Cytometry A Mar West EJ, Scott KJ, Jennings VA, Melcher AA. Immune activation by combination human lymphokine-activated killer and dendritic cell therapy. Br J Cancer Sep 6;105(6): Wu R, Forget MA, Chacon J, et al. Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. Cancer J Mar;18(2): Yamasaki K, Horiguchi S, Kurosaki M, et al. Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin Immunol. 2011;138(3): Zhong JH, Ma L, Wu LC, et al. Adoptive immunotherapy for postoperative hepatocellular carcinoma: a systematic review. Int J Clin Pract Jan;66(1):21-7. References Update June Chekmasova AA, Brentjens RJ. Adoptive T cell immunotherapy strategies for the treatment of patients with ovarian cancer. Discov Med. 2010;9(44): Rolle CE, Sengupta S, Lesniak MS. et al. Challenges in clinical design of immunotherapy trials for malignant glioma. Neurosurg Clin N Am. 2010;21(1): References Update June Abe Y, Muto M, Nieda M, et al. Clinical and immunological evaluation of zoledronate-activated Vgamma9gammadelta T-cell-based immunotherapy for patients with multiple myeloma. Exp Hematol Aug;37(8): American Cancer Society. Other Active Specific Immunotherapies. Adoptive Immunotherapy for Cancer May 15 17

18 3. American Urological Association. News release. Prostate Cancer Immunotherapy Significantly Prolongs Survival in Men with Advanced Prostate Cancer. 4. Arai S, Meagher R, Swearingen M, et al. Infusion of the allogeneic cell line NK- 92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy. 2008;10(6): 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 Jun;21(6): Besser MJ, Shapira-Frommer R, Treves AJ, et al. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients. J. Immunother May;32(4): Chang JW, Hsieh JJ, Shen YC, et al. Immunotherapy with dendritic cells pulsed by autologous dactinomycin-induced melanoma apoptotic bodies for patients with malignant melanoma. Melanoma Res Oct;19(5): Emens LA, Asquith JM, Leatherman JM, et al. Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy doseranging factorial study of safety and immune activation. J Clin Oncol Dec 10;27(35): Erbayraktar Z. Adoptive T-cell therapy of cancer. J BUON Sep;14 Suppl 1:S Jiang JT, Wu CP, Shen YP, et al. Influence of co-stimulatory molecules B7-H4 expression on the prognosis of patients with gastric cancer treated with cytokine-induced killer cells adoptive immunotherapy. Zhonghua Wei Chang Wai Ke Za Zhi May;13(5): Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-t in advanced prostate cancer. Cancer Aug 15;115(16): Hirooka Y, Itoh A, Kawashima H, et al. A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Pancreas Apr;38(3):e Li H, Wang C, Yu J, Cao S, et al. Dendritic cell-activated cytokine-induced killer cells enhance the anti-tumor effect of chemotherapy on non-small cell lung cancer in patients after surgery. Cytotherapy. 2009;11(8): Motohashi S, Nagato K, Kunii N, et al. A phase I-II study of alphagalactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol Feb 15;182(4): Olioso P, Giancola R, Di Riti M, et al. Immunotherapy with cytokine induced killer cells in solid and hematopoietic tumours: a pilot clinical trial. Hematol Oncol Sep;27(3): Palmer DH, Midgley RS, Mirza N, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology Jan;49(1): Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-t (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol Jul 1;24(19): U.S. Food and Drug Administration. FDA Approves New Prostate Cancer Therapy. Available at: Adoptive Immunotherapy for Cancer May 15 18

19 df 19. Wallen H, Thompson JA, Reilly JZ, et al. Fludarabine modulates immune response and extends in vivo survival of adoptively transferred CD8 T cells in patients with metastatic melanoma. PLoS One. 2009;4(3):e Wu C, Jiang J, Shi L, Xu N. Prospective study of chemotherapy in combination with cytokine-induced killer cells in patients suffering from advanced non-small cell lung cancer. Anticancer Res Nov-Dec;28(6B): References Update May Dossett ML, Teague RM, Schmitt RM, et al. Adoptive Immunotherapy of Disseminated Leukemia With TCR-transduced, CD8+ T Cells Expressing a Known Endogenous TCR. Molecular Therapy (2009) 17 4, Thistlethwaite FC, Elkord E, Griffiths RW, et al. Adoptive transfer of T(reg) depleted autologous T cells in advanced renal cell carcinoma. Cancer Immunol Immunother. 2008;57(5): 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 Nov 10;26(32): Epub 2008 Sep Kimura H, Iizasa T, Ishikawa A, et al. Prospective phase II study of post-surgical 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. 2008;28(2B): Bernhard H, Neudorfer J, Gebhard K, et al. Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2- overexpressing breast cancer. Cancer Immunol Immunother. 2008;57(2): Motohashi S, Nakayama T. Clinical applications of natural killer T cell-based immunotherapy for cancer. Cancer Sci. 2008;99(4): Lange JR, Fecher LA, Sharfman WH, et al. Clinical oncology. New York, NY: Churchill Livingstone; American Cancer Society. Other active specific immunotherapies. Mar 18, American Cancer Society. What is immunotherapy? Mar 18, Accessed Sep 23, Available at: py.asp?sitearea=eto References Update May 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; 28(1B): Heemskerk B, Liu K, Dudley ME, et al. Adoptive Cell Therapy for Patients with Melanoma, Using Tumor-Infiltrating Lymphocytes Genetically Engineered to Secrete Interleukin-2. Hum Gene Ther Apr Chu CS, Kim SH, June CH, et al. Immunotherapy opportunities in ovarian cancer. Expert Rev Anticancer Ther Feb;8(2): Weng DS, Zhou J, Zhou QM, et al. Minimally invasive treatment combined with cytokine-induced killer cells therapy lower the short-term recurrence rates of hepatocellular carcinomas. J Immunother Jan; 31(1): Muul LM, Candotti F. Immune responses to gene-modified T cells. Curr Gene Ther Oct; 7(5): Adoptive Immunotherapy for Cancer May 15 19

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