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MP 8.01.01 Adoptive Immunotherapy

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/12:2014
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.



Adoptive immunotherapy uses “activated” lymphocytes as a treatment modality. Both nonspecific and specific lymphocyte activation are used therapeutically. Nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes. Initially, this was done by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T cell growth factor interleukin-2 (IL-2) and other cytokines. More recent techniques yield select populations of 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 cells have recently been recognized as a new type of antitumor effector cells, which can proliferate rapidly in vitro, with stronger antitumor activity and broader spectrum of targeted tumor than other reported antitumor effector cells.(1)

The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing patients. In current trials, 2 methods are studied: adoptive cellular therapy (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.”(2) 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 (ie, transfusion) of lymphocytes back into the tumor-bearing host

Dendritic cell-based immunotherapy uses autologous dendritic cells (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigensin 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 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. (See Related Policies section for dendritic cell-based immunotherapy for prostate cancer.)

In an attempt to further regulate the host immune system, recent protocols use various cytokines (eg, IL-7 and IL-15 instead of IL-2) to propagate lymphocytes. Protocols also differ in the extent of host lymphodepletion induced prior to transfusing the lymphocytes to the tumor-bearing host.

Note: Allogeneic stem-cell transplantation following nonmyeloablative conditioning of the recipient (known as reduced-intensity conditioning [RIC]) may also be referred to as “adoptive immunotherapy” in the literature. However, RIC stem-cell transplantation relies on a donor-versus-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.

Regulatory Status

Adoptive immunotherapy is not a US Food and Drug Administration-regulated procedure.


Adoptive immunotherapy, using adoptive cellular therapy for the administration of cytotoxic T lymphocytes, cytokine-induced killer cells, lymphokine-activated killer cells, tumor-infiltrating lymphocytes, antigen-loaded autologous dendritic cells, or genetically engineered T cells is considered investigational.

Other applications of adoptive immunotherapy are considered investigational.

Policy Guidelines

Autologous lymphocytes used as part of adoptive immunotherapy may be harvested in a pheresis procedure, or may be isolated from resected tumor tissue.

Benefit Application
BlueCard/National Account Issues

Adoptive immunotherapy is a specialized service that may require out-of-network referral.

Some plans may participate in voluntary programs offering coverage for patients participating in National Institutes of Health-approved clinical trials of cancer chemotherapies, including adoptive immunotherapy.


This policy was originally created in 1996 and has been updated regularly with searches of the MEDLINE database. The most recent literature search was performed for the period through November 2, 2014. Following is the summary of key literature to date.

Mixed Adoptive Immunotherapy Modalities

Three systematic reviews on adoptive immunotherapy using different adoptive immunotherapy methods have been published. Conditions treated in these reviews were renal cell carcinoma,(3) and postoperative hepatocellular carcinoma.(4,5)

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.(3) Four RCTs (3 studies published between 1990 and 1999, a fourth study by Liu et al published in 2012 [discussed below]) met inclusion criteria (total N=469); 3 RCTs were conducted in the United States and one was conducted in China. Interventions included cytokine-induced killer (CIK) cells, lymphokine-activated killer (LAK) cells, and tumor-infiltrating lymphocytes (TIL). Most adoptive immunotherapy-related adverse reactions were grade 1 or 2 and reversible. In meta-analysis, outcomes were superior for patients treated with adoptive immunotherapy compared with no adoptive immunotherapy, including rates of objective
response (pooled risk ratio [RR], 1.65; 95% confidence interval [CI], 1.15 to 2.38; p=0.007; =49%), 1-year survival (pooled RR=1.30; 95% CI, 1.12 to 1.52; p<0.001; =0%), 3-year survival (RR=2.76; 95% CI, 1.85 to 4.14; p<0.001; =46%), and 5-year survival (RR=2.42; 95% CI, 1.21 to 4.83; p=0.01; =28%).Heterogeneity across studies was acceptable.(3) However, limitations of the review included varying adoptive immunotherapy protocols and lack of clear descriptions of randomization methods, allocation concealment, blinding, and withdrawals, which may lead to distribution and implementation bias in this meta-analysis.

Hepatocellular Carcinoma

Xie et al (2012) performed a meta-analysis of RCTs comparing adoptive immunotherapy with no adjuvant treatment in patients with hepatocellular carcinoma who had undergone curative resection.(4) Six RCTs (published between 1995 and 2009; total N=494) met inclusion criteria. All 6 trials were conducted in Asia (4 in China, 2 in Japan), with 2 studies published in the Chinese language. Two trials used CIK cells as adoptive immunotherapy, 1 used CIK cells plus interleukin-2 (IL-2), and the remaining 3 used LAK plus IL-2. Outcome measures were 1- and 3-year recurrence and survival rates. Meta-analysis revealed a significantly reduced risk of both 1-year recurrence (odds ratio [OR], 0.35; 95% CI, 0.17 to 0.71; p=0.003), and 3-year recurrence (OR=0.31; 95% CI, 0.16 to 0.61; p=0.001) in patients receiving adoptive
immunotherapy. However, no statistically significant difference was observed in 3-year survival rates between the 2 study groups (OR=0.91; 95% CI, 0.45 to 1.84; 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 low-to-moderate methodological quality of the included trials.(4)

Zhong et al (2012) also performed a systematic review of RCTs to evaluate the clinical efficacy of adjuvant adoptive immunotherapy for postoperative patients with hepatocellular carcinoma.(5) Four RCTs (published between 1995 and 2009; total N=423) met inclusion criteria. As with the Xie meta-analysis discussed above,(4)
all 4 trials were conducted in Asia. Three (of 4) trials in this review also were included in the Xie meta-analysis. Primary outcomes evaluated in this review were overall survival (OS), diseasefree survival (DFS), and recurrence rates. The secondary outcome was adverse effects of treatment/toxicity. Owing to clinical heterogeneity (including operation methods, dose, and type of cytokines) across studies, meta-analysis was not performed. All RCTs reported significantly improved DFS or reduced recurrence rate after treatment with adjuvant adoptive immunotherapy (p<0.05). However, no statistically significant differences were observed in OS between study groups across the 3
trials reporting this outcome. The main adverse effect of adoptive immunotherapy was fever (persistent or transient), reported in 3 (of 4) trials. Conclusions of this systematic review5 are subject to similar limitations as with the above meta-analysis by Xie et al.

Section Summary

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 OS. In renal cell carcinoma, objective response and 1-, 3-,and 5-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 (2014) conducted an international prospective cohort study of CTL therapy in patients with Epstein-Barr virus (EBV)‒positive Hodgkin or non-Hodgkin lymphoma.(6) 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 2 patients (10%) achieved partial response; 2-year event-free survival in this cohort was approximately 50%. Twenty-seven (93%) of 29 patients in remission achieved complete response; 2-year event-free survival was 82%. Immediate or delayed toxicity related to CTL infusion was not observed.

Chia et al (2014) studied 35 patients with EBV-positive nasopharyngeal cancer at a single center in China.(7) Patients received standard chemotherapy with gemcitabine and carboplatin followed by EBVspecific CTL infusion. Median progression-free and OS were 8 months and 30 months, respectively. One-, 2-, and 3-year OS was 77%, 63%, and 37%, respectively. In comparison, median OS in a group of similar historical controls treated at the same institution with chemotherapy only was 18 to 21 months, and 2- and 3-year OS was 30% to 43% and 16% to 25%, respectively. The most common adverse events associated with CTL infusion were grade 1 and 2 fatigue and grade 1 myalgia. Two patients developed transient fever, and 3 patients developed grade 1 skin rash. Grade 3 or higher hematological or nonhematological
toxicities were not observed during CTL therapy. In a Japanese series of 7 patients who received CTLs for advanced oral and maxillofacial cancers, 1-year survival in patients who achieved response (n=3) and in those with progressive disease (n=4) were 100% and 25%, respectively, although definitions of response were unclear.(8)

Cytomegalovirus-Associated Cancers

Schuessler et al (2014) administered CTLs with or without chemotherapy to 13 patients with recurrent glioblastoma multiforme.(9) CTLs with activity against cytomegalovirus (CMV) were generated by incubating peripheral blood monocytes with synthetic peptide epitopes. Median OS was 1.1 years (range,4.4 months to 6.6 years). Adverse events were minor.

Section Summary

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 a 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 Cells

Nasopharyngeal Carcinoma

Li et al (2012) conducted an RCT to evaluate the efficacy of autologous CIK transfusion in combination with gemcitabine and cisplatin (GC) chemotherapy to treat nasopharyngeal carcinoma in patients with distant metastasis after radiotherapy.(10) From September 2007 to August 2008, 60 patients with distant metastasis after radiotherapy were followed up in a university cancer center in China. Patients were randomly divided into 2 groups; 30 patients in the GC+CIK group received adoptive autologous CIK cell transfusion in combination with GC chemotherapy, and 30 patients in the GC group received chemotherapy alone. One- and 2-year OS were 90% (27/30) and 70% (21/30), respectively, in the GC+CIK group versus 83% (25/30) and 50% (15/30), respectively, in the GC group. Mean OS was 31 months for the GC+CIK group and 26 months for the GC group (log-rank test, p=0.137). Median progression-free survival (PFS) was 26 months for the GC+CIK group and 19 months for the GC group (log-rank test, p=0.023). This small, single-center RCT indicates that the combination of CIK cells and GC regimen chemotherapy may be a viable treatment option for patients with advanced nasopharyngeal carcinoma.(10)

Renal Cell Carcinoma

Liu et al (2012) conducted an RCT to evaluate the effects of autologous CIK cell immunotherapy in patients with metastatic renal cell carcinoma followed up in another university cancer center in China.(11) 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)--2a (arm 2, n=74). The primary end point was OS, and the secondary end point was PFS evaluated by Kaplan-Meier analyses and hazard ratios (HRs) with Cox proportional hazards models. Three-year PFS and OS in arm 1 were 18% and 61%, respectively, versus 12% and 23%, respectively, in arm 2 (p=0.031 and <0.001, respectively). Median PFS and OS in arm 1 were significantly longer than those in arm 2 (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, 0.84 to 0.93; p<0.001) and OS (HR=0.58; 95% CI, 0.48 to 0.69; p<0.001) in arm 1. These findings suggest that CIK cell immunotherapy has the potential to improve the prognosis of patients with metastatic renal cell carcinoma, and increased frequency of this immunotherapy could result in additional benefits.(11)

Zhang et al (2013) conducted a small RCT in China with 20 patients who had unilateral, locally advanced renal cell carcinoma after nephrectomy.(12) 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 a median follow-up of 44 months, 6 patients in the CIK group and 5 controls achieved complete response; 2 patients in the CIK group and no controls achieved partial response (overall objective response, 80% vs 50% in the CIK and control groups, respectively; 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 3 patients. Grade 3 or higher adverse events were not observed.

Gastric Cancer

In 2012, Shi et al in China published a nonrandomized, comparative study to determine the long-term efficacy of adjuvant immunotherapy with autologous CIK cells in 151 patients with locally advanced gastric cancer.(13) Five-year OS and 5-year DFS 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, 5-year OS and DFS were significantly higher for immunotherapy (OS, 47% vs
31%; p= 0.045; DFS, 42% vs 16%; p=0.02).(13) Larger and well-designed multicenter studies are needed to confirm these findings.

Pancreatic Cancer

Chung et al (2014) administered CIKs in Korea to 20 patients who had gemcitabine-refractory pancreatic cancer.(14) Four patients withdrew before the first response evaluation at 8 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 2 patients and thrombocytopenia in 1 patient. No grade 4 adverse events were observed.

Hepatocellular Carcinoma

Yu et al (2014) conducted an RCT in China of 132 patients who had previously untreated hepatocellular carcinoma.(15) 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 a median follow-up of 19 months, median PFS was 14 months in the CIK group versus 7 months in the control group (log-rank test for all comparisons, p=0.019). Estimated 1-, 2-, and 3-year PFS was 56% versus 35% (p=0.004), 36% versus 18% (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 1-, 2-, and 3-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).(16)

Non-Small-Cell Lung Cancer

Zhang et al (2014) conducted a retrospective study of patients with stage I-IV non-small-cell lung cancer (NSCLC) who were treated at a single institution in China.(17)
Fifty-four patients who had received CIK therapy in addition to standard treatments (surgery, chemotherapy, and/or radiotherapy) were compared with 54 patients who had received standard treatments only. Median OS was 31 months in the CIK group versus 18 months in the control group (HR for death, 0.56; 95% CI, 0.36 to 0.86; log-rank test, p=0.008). Two-year OS was 63% versus 35%, respectively (p<0.05); 1-, 3-, 4-, and 5-year OS did not differ statistically between groups. Adverse events included transient chills and fever in 5 patients and moderate pruritic papular rash in 2 patients.

Section Summary

Several RCTs from Asia have evaluated the efficacy of CIK cells in different cancer types. These studies have generally reported some benefits in recurrence rates and/or DFS. One RCT in patients with hepatocellular carcinoma and 1 retrospective study in patients with NSCLC reported improved OS. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodological weaknesses. This evidence is insufficient to determine
whether use of CIK cells in any specific cancer type leads to net health benefits.

Lymphokine-Activated Killer Cells

Hepatocellular Carcinoma

Takayama et al (2000) conducted a study that randomized 150 patients who had undergone curative resection for hepatocellular carcinoma to receive either adjuvant adoptive immunotherapy or no additional treatment.(18) Immunotherapy comprised 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 OS, the final health outcome, did not differ significantly between the 2 groups.

Renal Cell Carcinoma

A 1993 randomized trial of lymphokine-activated killer (LAK) cell therapy in patients with metastatic renal cell cancer or melanoma unresponsive to standard therapy failed to show that LAK cells provided any health benefit beyond that associated with IL-2 alone.(19) A 2007 post hoc analysis of this study found survival benefit in stage 3 melanoma patients with 1 tumor-invaded lymph node; however, this study has not been reproduced.

Chang et al (2003) conducted a phase 2 study in patients with stage 4 renal cell carcinoma who received irradiated autologous tumor cells admixed with Calmette-Guérin bacillus.(20) Seven days later, vaccineprimed lymph nodes were harvested, and lymphoid cells secondarily activated and then infused back into the patient. Of 39 patients who participated in the study, 4 had a complete response and 5 had a partial response.


Khammari et al (2009) studied tumor-specific T cells derived from peripheral blood in a phase 2 study.(21) Lymphocytes were harvested from 14 melanoma patients with regional or distant metastases. Cells were propagated with Melan-A/MART-1, the antigen most commonly expressed by melanoma tumors, and then reinfused with IL-2 and IFN-α. Six patients (43%) experienced an objective response: 2 patients with regional metastases had complete responses, 1 lasting 20 months and the other lasting more than 60 months; 4 patients with regional metastases had partial responses; and 1 patient with distant metastases had a partial response. Significant toxicities of treatment included asthenia, flu-like syndrome, and lymphopenia, which were attributed mainly to treatment with IL-2 and IFN-α.

Pancreatic Cancer

Kobari et al (2000) described the use of intraportal injections of LAK cells after tumor resection in 12 patients with advanced pancreatic cancer and compared their outcomes with a group of 17 patients who did not receive LAK cells postresection.(22) OS between the 2 groups did not differ.

Other Cancers

LAK cells also have been investigated as a treatment for malignant glioma and bladder cancer, but no controlled trials have been published.(23-25)

Section Summary

Evidence on the use of LAK cells for adoptive immunotherapy is limited. Small RCTs have reported benefit for some outcomes, but not for others, and a survival benefit has not been demonstrated. This body of evidence is insufficient to determine whether LAK cells improve outcomes for any specific cancer type.

Tumor-Infiltrating Lymphocytes


Dudley et al (2008) conducted a series of nonrandomized phase 2 studies examining TIL plus IL-2 in patients with metastatic melanoma under various conditions of preinfusion lymphodepletion.(26) A nonmyeloablative 7-day chemotherapy regimen (n=43) was compared with ablative regimens comprising 5-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 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 followup of 31 months. Toxicities of treatment occurred primarily in the 1200 cGy group and included a delay in marrow recovery of 1 to 2 days compared with the other treatment groups, somnolence requiring intubation, renal insufficiency, and posterior uveitis. Rosenberg et al (2011) reported updated results of these patients with median follow-up of 62 months.(27) Ten patients who previously had been classified as partial responders were reclassified as complete responders by RECIST (1, 3, and 6 patients in the
nonmyeloablative, 200 cGy, and 1200 cGy groups, respectively). Of these 20 patients (22% of the original cohort), 19 (95%) had ongoing complete regression longer than 3 years. Actuarial 3- and 5-year survival 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 et al (2002) conducted an RCT of 88 patients with malignant melanoma without detectable metastases who were randomized to receive TIL plus IL-2 versus IL-2 alone.(28) There was no significant difference in the duration of relapse-free interval or OS. Figlin et al (1999) randomized 178 patients with metastatic renal cell carcinoma or resectable renal tumors to adjuvant continuous low-dose IL-2 therapy, with or without additional TIL.(29) TILs were harvested from surgical specimens. Outcomes were similar in both groups, and for this reason the trial was terminated early.

Section Summary

One small RCT compared TILs plus IL-2 with IL-2 alone in patients with nonmetastatic melanoma and reported no difference between treatment groups in relapse or survival outcomes. Cohort studies in patients with refractory metastatic melanoma demonstrated response rates of 49% and 52% to 72% with TIL plus nonmyeloablative or myeloablative regimens, respectively. Durable responses in the majority of patients who achieved complete response were observed beyond 3 years. Toxicities appeared primarily associated with myeloablative regimen.

Dendritic Cells

Antigen-loaded autologous dendritic cells (ADCs) have been explored primarily in early-stage trials in various malignancies including lymphoma,(30) myeloma,(31,32)
subcutaneous tumors,(33) melanoma,(34) NSCLC,(35,36) renal cell cancer,(37) and cervical cancer.(38) A 2012 review article highlighted progress in dendritic cell-based immunotherapy in epithelial ovarian cancer.(39)

Glioblastoma Multiforme

In 2013, Bregy et al published a systematic review of observational studies of active immunotherapy using ADCs in the treatment of glioblastoma multiforme.(40) Twenty-one studies published through early 2013 were included in this review (total N=403). Vaccination with dendritic cells loaded with autologous tumor cells resulted in increased median OS in patients with recurrent disease (72-138 weeks across 8 studies), as well as in those newly diagnosed (65-230 weeks across 11 studies) compared with average survival of 58 weeks. Complications and safety of the vaccine were assessed in all studies. No study indicated any sign of autoimmune reaction. The majority of adverse events were injection site reactions (22%). Other adverse events included fatigue (19.5%), constipation/diarrhea (1.6%), myalgia/malaise (1.6%), shivering (1.4%), and vomiting (0.5%). Because of the nature of the current literature available (ie, case reports, phase 1 and phase 2 clinical trials, prospective studies), the review is subject to publication and selection bias, which has the potential to lessen or amplify the true potential of adoptive immunotherapy.(40) Larger controlled trials are required to assess survival and effect on quality of life of adoptive immunotherapy in this patient population.

Non-Small-Cell Lung Cancer

Shi et al (2012) conducted an RCT at a university cancer center in China to evaluate the role of dendritic cell (DC)/CIK combination immunotherapy as maintenance treatment of advanced NSCLC.(35) From October 2008 to June 2010, 60 patients with stage IIIB/IV disease after treatment with 4 cycles of a platinum-based chemotherapy regimen were randomly divided into 2 groups. One group was treated with DC/CIK cell therapy (n=30), and the other was a control group who received no adoptive immunotherapy (n=30). Outcome measures were PFS and adverse effects of treatment/toxicity. PFS was 3.2 months in the DC/CIK group (95% CI, 2.9 to 3.5) versus 2.6 months control group (95% CI, 2.39 to 2.73; 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 NSCLC.(35)

Chen et al (2014) in China conducted a systematic review and meta-analysis of RCTs that compared DC/CIK combination immunotherapy with any other treatment (placebo, no intervention, conventional treatment, or other complementary and alternative medicines) for any cancer type and stage.(41) Two included RCTs that compared DC/CIK plus chemotherapy with chemotherapy alone in patients with stage III/IV NSCLC reported OS estimates (total N=150). Pooled risk ratios (RR) favored DC/CIK therapy at 2 years but not at 1 year (RR for 1-year OS, 1.38; 95% CI, 1.00 to 1.90; p=0.05; =35%; RR for 2-year OS, 2.88; 95% CI, 1.38 to 5.99; p=0.005; =0%).

Medullary Thyroid Cancer

In a 2009 phase 1 pilot study, 10 patients with metastatic medullary thyroid cancer (MTC) were treated with ADCs pulsed with allogeneic MTC tumor cell lysate.(42) At median follow-up of 11 months, 3 patients (30%) had stable disease and 7 patients (70%) progressed. No World Health Organization grade 3 or 4 toxicities or autoimmune reactions were observed. Of note, human leukocyte antigen match between patients and tumor cell lines did not predict disease stabilization or progression, suggesting that, should future studies demonstrate efficacy of ADC therapy for MTC using allogeneic tumor lysate, an unlimited source of tumor material may be available for lysate preparation.

Pancreatic Cancer

A 2009 phase 1 study of 5 patients with inoperable pancreatic cancer reinfused ADCs and LAK cells with gemcitabine; antigen priming of the ADCs was presumed to occur in vivo from apoptosis of gemcitabineexposed tumor cells.(43) One patient had a partial response, 2 had stable disease for more than 6 months, and 2 patients had disease progression. Toxicities included grade 1 anemia and grade 2 leukocytopenia, nausea, and constipation.

Section Summary

Observational studies and small RCTs have examined the role of adoptive immunotherapy with ADCs in glioblastoma multiforme, NSCLC, medullary thyroid cancer, and pancreatic cancer. All patients had advanced disease; however, treatment protocols varied across studies (eg, coadministration 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 NSCLC showed increased PFS with ADC/CIK adoptive immunotherapy compared with controls. Although results of this RCT and of some observational studies (eg, 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 antitumor immunotherapy uses gene transfer of tumor antigen-specific T-cell receptors (TCR) or synthetic chimeric antigen receptors (CAR). Review articles have highlighted recent progress in this field for solid and hematologic malignancies.(44-46)

TCR Therapy

In a phase 2 study, Johnson et al (2009) transfected autologous peripheral lymphocytes of 36 patients who had metastatic melanoma with genes encoding TCRs highly reactive to melanoma/melanocyte antigens (MART-1:27-35 and gp100:154-162).(47) Nine patients (25%) experienced an objective response; 8 patients had a partial response lasting 3 months to more than 17 months; and 1 patient (in the gp100 group) had a complete response lasting more than 14 months. Treatment toxicities included erythematous rash, anterior uveitis, hearing loss, and dizziness, suggesting that these were attributable to recognition by the genetically modified lymphocytes of normally quiescent cells expressing the targeted cancer antigens; melanocytic cells exist in the skin, eye, and the inner ear. Ideal targets for TCR gene therapy may be antigens that arise in cancers of nonessential organs (eg, prostate, ovary, breast, thyroid) or are not expressed on normal adult tissues (eg, cancer-testes antigens).

Additional studies have examined TCR gene therapy in Hodgkin48 and non-Hodgkin lymphoma,(49) prostate tumors,(50) and neuroblastoma.(51)

CAR Therapy

CAR therapy generates T cells that express artificial TCRs that bind tumor cell surface antigens but do not need to match the patient’s immune type.(46) Preliminary U.S. studies have investigated add-on CAR therapy in 8 patients with relapsed chronic lymphocytic leukemia.(52,53) Four (50%) of 8 patients achieved complete remission. Adverse events included significant cytokine-mediated toxicities (fever, hypotension, and mental status changes) requiring high-dose, lymphotoxic steroid therapy in 3 patients who had high tumor burden at the time of CAR therapy.

Section Summary

One small cohort study in patients with metastatic melanoma reported a 25% response rate with TCR gene therapy and broad treatment-related toxicities. This evidence does not demonstrate net health benefit with genetically engineered T cells in patients with metastatic melanoma. CAR therapy is in a preliminary stage of development.

Ongoing and Unpublished Clinical Trials

A search of identified 25 active trials of adoptive immunotherapies in various cancers. Randomized trials are listed in Table 1. Additionally, the European Union Clinical Trials Registry currently lists an RCT conducted in Belgium that aims compare treatment for glioblastoma multiforme with or without ADCs (EudraCT 2009–018228-14). Expected enrollment is 146 patients. Estimated completion date is unknown.

Table 1. Ongoing Adoptive Immunotherapy Randomized Controlled Trials Listed at

NCT Number




Completion Dateb

Cytotoxic T lymphocytes


Evaluation of Recovery From Drug-Induced Lymphopenia Using Cytomegalovirus-specific T-cell Adoptive Transfer (ERaDICATe)



Jun 2016


Preventative/Preemptive Adoptive Transfer of Peptide Stimulated CMV/EBV Specific T-cells in Patients After Allogeneic Stem Cell Transplantation



Oct 2016

Cytokine-induced killer cells


Adoptive Cellular Therapy and Radiation Therapy After Surgery in Treating Patients With Esophageal Cancer



Sep 2016

Lymphokine-activated killer cells


Targeted Natural Killer (NK) Cell Based Adoptive Immunotherapy for the Treatment of Patients With Non-Small Cell Lung Cancer (NSCLC) After Radiochemotherapy (RCT)



Feb 2018


Randomised Controlled Phase-2 Trial to Determine the Efficacy of Adoptive Immunotherapy With NK Cells in High-risk AML(HINKL)



Sep 2019

Tumor-infiltrating lymphocytes


Prospective Randomized Study of Cell Therapy for Metastatic Melanoma Using Short-Term Cultured Tumor Infiltrating

Lymphocytes Plus IL-2 Following Either a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Alone or in Conjunction w/1200 TBI



Jun 2015


SGI-110 in Combination With an Allogeneic Colon Cancer Cell Vaccine (GVAX) and Cyclophosphamide (CY) in Metastatic

Colorectal Cancer (mCRC)



Dec 2017


A Phase II Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating

Lymphocytes Plus IL-2 Comparing Two Different Chemotherapy Preparative Regimens



Sep 2019


TIL Therapy in Metastatic Melanoma and IL2 Dose Assessment (METILDA)



Dec 2018


Study Comparing TIL to Standard Ipilimumab in Patients With Metastatic Melanoma (TIL)



Sep 2020

Autologous dendritic cells


Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer



Sep 2015


Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization



Feb 2016


Dendritic Cell Vaccine for Patients With Brain Tumors



Sep 2014


A Study of ICT-107 Immunotherapy in Glioblastoma Multiforme (GBM)



Dec 2015


T Cell Transfer With or Without Dendritic Cell Vaccination in Patients With Melanoma



Dec 2015

Dendritic cells/cytokine-induced killer cells


Concurrent Chemoradiation With or Without DC-CIK Immunotherapy in Treating Locally Advanced Esophageal Cancer



Sep 2017


Adoptive Cell Therapy Plus Chemotherapy and Radiation After Surgery in Treating Patients With Colorectal Cancer



Oct 2017

NR: not reported
aExpected enrollment

Summary of Evidence

Clinical studies using adoptive immunotherapy are primarily small, early-stage investigations of novel immunologic treatments for a variety of cancers. Although there is some evidence of benefit with cytokine-induced killer cells for end points such as recurrence rate, improvement in overall survival has not been demonstrated. Additionally, available studies are from non-U.S. centers in heterogeneous patient populations, and have methodological 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 (eg, autologous dendritic cells) may improve outcomes in some cancer types (eg, glioblastoma multiforme). However, impact of adoptive immunotherapy on patient outcomes (eg, increased survival, improved quality of life) has yet to be clarified in large, randomized, controlled trials. Specifically, high-quality trials with adequate follow-up are needed to show that there is an advantage for adoptive immunotherapy strategies in important end points for a significant cohort of cancer patients compared with standard treatments. Therefore, adoptive immunotherapy remains investigational.

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,(54) central nervous system,(55) head and neck,(56) hepatobiliary system,(57) kidney,(58) pancreas,(59) stomach,(60) or thyroid,(61) melanoma,(62)
Hodgkin(63) or non-Hodgkin lymphomas,(64) or non-small-cell lung cancer.(65)

U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force has not addressed the treatment of adoptive immunotherapy.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.


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CPT 36511 Therapeutic apheresis; for white blood cells
  37799 Unlisted procedure, vascular surgery (therapeutic leukopheresis)
  96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to one hour
ICD-9 Procedure 99.28 Injection or infusion of biological response modifier as an antineoplastic agent
  99.71-99.79 Therapeutic apheresis code range
ICD-9 Diagnosis   No specific codes; various malignancies may be treated with adoptive immunotherapy
HCPCS S2107 Adoptive immunotherapy, i.e., development of specific anti-tumor reactivity (e.g., tumor infiltrating lymphocyte therapy) per course of treatment
ICD-10-CM (effective 10/1/15)   Investigational for all diagnoses
  C00.0-C96.9 Malignant neoplasms code range
ICD-10-PCS (effective 10/1/15)   ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this therapy.
  6A550Z1 Extracorporeal therapies physiological systems, pheresis, circulatory, single, leukocytes
  6A551Z1 Extracorporeal therapies physiological systems, pheresis, circulatory, multiple, leukocytes
Type of Service Therapy  
Place of Service Inpatient

Adoptive Immunotherapy
Antigen Loaded Dendritic Cells
Autolymphocyte Therapy
Dendritic Cells, Adoptive Immunotherapy
Immunotherapy, Adoptive
Lymphokine Activated Killer Cells
Tumor Infiltrating Lymphocytes

Policy History


Date Action Reason
12/01/96 Add to Therapy section New policy
04/01/98 Replace policy Policy updated; new indications discussed, but policy statement unchanged
12/18/02 Replace policy Policy updated, new references added. No change in policy statement
12/17/03 Replace policy Policy updated with literature search; no change in policy statement. Additional discussion of dendritic cell therapy. Policy returned to regular review cycle due to research interest in dendritic cell therapy
03/15/05 Replace policy Policy updated with literature search; no change in policy statement
03/7/06 Replace policy Policy updated with literature search; no change in policy statement
11/13/08 Replace policy Policy updated with literature search; reference numbers 21-31 added. The policy statement on autolymphocyte therapy (ALT) using peripheral T-cells stimulated in vitro by OKT3 monoclonal antibody in conjunction with IL-2 was deleted as the statement was felt to be redundant (included in the “other applications” policy statement) . The wording of the remaining policy statements was changed slightly; however, the intent of the remaining policy statements is unchanged
12/11/08 Replace policy - correction only Policy history from 11/13/08 revised to state that the policy statement on autolymphocyte therapy was deleted as redundant
01/14/10   Policy updated with literature search; reference numbers 33–48 added; no change in policy statements
12/9/10 Replace policy - coding update only ICD-10 codes added to policy.
12/08/11 Replace policy Policy updated with literature search; references 23 and 24 added and other references renumbered or removed. No change in policy statements.
12/13/12 Replace Policy
Policy updated with literature search; Two systematic reviews added; Primary studies added on cytokine-induced killer (CIK) cells; references 1, 3-6, 24, and 27 added and other references renumbered. The wording of the policy statement under adoptive cellular therapy was changed to include cytokine-induced killer (CIK) cells; however, the intent of both policy statements (i.e., investigational) is unchanged.
12/12/13 Replace policy Policy updated with literature search through November 8, 2013; references 3, 8, 27, and 31 added. No change in policy statements.
12/11/14 Replace policy Policy updated with literature review through November 2, 2014; references 6-9, 12, 14-17, 41, 46, 52-53, and 56-65 added; reference 55 updated. Rationale reorganized and references renumbered. Cytotoxic Tlymphocytes and genetically engineered T cells added to investigational policy statements; “autologous” added to clarify antigen-loaded dendritic cells.