Medical Policy: 08.01.26 

Original Effective Date: October 2017 

Reviewed: October 2018 

Revised: October 2018 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Adoptive Immunotherapy

The spontaneous regression of certain cancers supports the idea that a patient’s immune system can delay tumor progression and, on rare occasions, can eliminate tumors altogether. These observations have led to research into various immunologic therapies designed to stimulate a patient’s own immune system. Adoptive immunotherapy is a method of activating lymphocytes and/or other types of cells for the treatment of cancer and other diseases. Cells are removed from the patient, processed for a period of time, and then infused back into the patient.

 

T Lymphocytes and Killer Cells

Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T-cell growth factor interleukin-2 (IL-2) and other cytokines. More recent techniques have yielded select populations of cytotoxic T lymphocytes with specific reactivity to tumor antigens. Peripheral lymphocytes are propagated in vitro with antigen-presenting dendritic cells that have been pulsed with tumor antigens. Alternatively, innate tumor-infiltrating lymphocytes (TIL) from the tumor biopsy are propagated in vitro with IL-2 and anti-CD3 antibody, a T-cell activator. Expansion of TIL for clinical use is labor intensive and requires laboratory expertise. Only a few cancers are infiltrated by T cells in significant numbers; of these, TIL can be expanded in only approximately 50% of cases. These factors limit the widespread applicability of TIL treatment. Recently, cytokine-induced killer cells have been recognized as a new type of antitumor effector cells, which can proliferate rapidly in vitro, with stronger antitumor activity and a broader spectrum of targeted tumors than other reported antitumor effector cells.

 

Cellular Therapy and Dendritic Cell Infusions

The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing patients. In current trials, 2 methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions.

 

Adoptive cellular therapy is “the administration of a patient’s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lymphodepleting preparative regimen. Protocols vary, but include these common steps:

  1. Lymphocyte harvesting (either from peripheral blood or from tumor biopsy)
  2. Propagation of tumor-specific lymphocytes in vitro using various immune modulators
  3. Selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay
  4. Lymphodepletion of the host with immunosuppressive agents
  5. Adoptive transfer (ie, transfusion) of lymphocytes back into the tumor-bearing host

 

Dendritic cell-based immunotherapy uses autologous dendritic cells (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigens in vivo. ADCs harvested from the patient are either pulsed with antigen presenting cells or transfected with a viral vector bearing a common cancer antigen. The activated ADCs are then retransfused into the patient, where they present antigen to effector lymphocytes (CD4-positive T-cells, CD8-positive T-cells, and in some cases, B cells). This initiates a cytotoxic response against the antigen and against any cell expressing the antigen. In cancer immunotherapy, ADCs are pulsed with tumor antigens; effector lymphocytes then mount a cytotoxic response against tumor cells expressing these antigens.

 

For the evidence review of dendritic cell based immunotherapy therapy (antigen presenting cells APCs – to include T-cells, B-cells, natural killer (NK) cells and other cells) for prostate cancer, see medical policy 08.01.27.

 

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

 

Note: Allogeneic cell transplantation following nonmyeloablative conditioning of the recipient (known as reduced-intensity conditioning) also may be referred to as “adoptive immunotherapy” in the literature. However, reduced-intensity conditioning cell transplantation relies on a donor-vs-malignancy effect of donor lymphocytes. In contrast, the adoptive immunotherapy techniques described in this evidence review enhance autoimmune effects primarily. The use of reduced-intensity conditioning in cell transplantation is discussed in medical policy 07.03.11 Hematopoietic Stem Cell Transplantation (Bone Marrow Transplant) Autologous and Allogeneic*.

 

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-T cell therapy). For CAR-T cell therapy see medical policies 08.01.30 Kymriah (Tisgenlecleucel)* and 08.01.29 Yescarta (Axicabtagene Ciloleucel)*.

 

Rationale

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcomes. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant studies must represent one or more intended use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. The quality and credibility of the evidence depend on the study design and conduct, minimizing bias and confounding that can generate incorrect findings. Randomized controlled trial (RCT) is preferred to assess efficacy.

 

Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when RTCs show efficacy.

 

Adoptive Immunotherapy Modalities

Three systematic reviews on adoptive immunotherapy combining studies using different adoptive immunotherapy methods have been published. Conditions treated in these reviews were renal cell carcinoma, and postoperative hepatocellular carcinoma.

Cytotoxic Lymphocytes

Epstein-Barr Virus-Associated Cancers

Bollard et al (2014) conducted an international prospective cohort study of cytotoxic T lymphocytes (CTL) therapy in patients with Epstein-Barr virus (EBV)-positive Hodgkin or non-Hodgkin lymphoma. Patients had either active, relapsed disease (n=21) or were in remission with a high risk of relapse (n=29). CTLs with activity against EBV antigens were generated by incubating peripheral blood monocytes with EBV antigen-infected dendritic cells. Eleven (52%) of 21 patients with active disease achieved complete response (CR), and 2 (10%) patients achieved partial response; 2-year event-free survival in this cohort was approximately 50%. Twenty-seven (93%) of 29 patients in remission achieved CR; 2-year event-free survival was 82%. Immediate or delayed toxicity related to CTL infusion was not observed.

 

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

 

Summary

Two small, prospective noncomparative cohort studies in patients with relapsed disease indicated response to infused CTLs directed against cancer-associated viral antigens. Adverse events were mild or moderate. There are no RCTs comparing CTL with standard of care and therefore no conclusions can be made about the efficacy of CTL in EBV-associated cancers. To establish efficacy, the following is needed: large, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Cytomegalovirus-Associated Cancers

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

 

Summary

A single case series in 13 patients with glioblastoma multiforme treated with CTL has been published. Adverse events were mild. There are no RCTs comparing CTL with standard of care and therefore no conclusions can be made about the efficacy of CTL in Cytomegalovirus-associated cancers. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Cytokine-Induced Killer Cells

Nasopharyngeal Carcinoma

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

 

Summary

A single RCT from China reported numerically favorable but statistically insignificant effect on PFS and OS. This body of evidence is limited by the context of the studies (non-U.S.), small sample size, and other methodologic weaknesses (inadequate reporting of randomization, allocation concealment, and power). To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Renal Cell Carcinoma

Liu et al (2012) conducted an RCT to evaluate the effects of autologous CIK cell immunotherapy in patients with metastatic renal cell carcinoma followed up in another university cancer center in China. From 2005 to 2008, 148 patients were randomized to autologous CIK cell immunotherapy (arm 1, n=74) or IL-2 treatment combination with human interferon- α-2a (arm 2, n=74). The primary end point was OS, and the secondary end point was PFS evaluated by Kaplan-Meier analyses and hazard ratios (HRs) with Cox proportional hazards models. Three-year PFS and OS rates in arm 1 were 18% and 61%, respectively, vs 12% and 23%, respectively, in arm 2 (p=0.031 and <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.

 

Zhang et al (2013) conducted a small RCT in China with 20 patients who had unilateral, locally advanced renal cell carcinoma after nephrectomy. Patients were randomized 1:1 to postoperative CIK therapy or usual care (chemotherapy with or without radiotherapy, additional surgery, or no further treatment). Method of randomization was not described. At a median follow-up of 44 months, 6 patients in the CIK group and 5 controls achieved CR; 2 patients in the CIK group and no controls achieved partial response (overall objective response, 80% vs 50% in the CIK and control groups, respectively; p=0.175). Mean PFS was significantly longer in the CIK group, but OS was not (mean PFS, 32 months vs 22 months; p=0.032; mean OS, 35 months vs 34 months; p=0.214). Adverse events included mild arthralgia, laryngeal edema, fatigue, and low-grade fever in 3 patients. Grade 3 or higher adverse events were not observed.

 

Zhao et al (2015) conducted an RCT in China among operable and inoperable patients with renal cell carcinoma. Dendritic cells were also incorporated into treatment. Among the 60 operable patients, the 3-year disease-free survival (DFS) rate was 96.7% compared with 57.7% in the control group. PFS was also better in the CIK group (p=0.021). Among the 62 inoperable patients, OS was better in the CIK group (p=0.012). No severe adverse reactions were observed.

 

Summary

Three RCTs from China have evaluated the efficacy of CIK cell immunotherapy in renal cell carcinoma. The largest of the 3 RCTs reported statistically significant gain in PFS and OS with CIK cell immunotherapy compared with interleukin-2 (IL-2) plus interferon-α-2. This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator. The remaining 2 RCTs also reported response rate in favor of CIK therapy with inconsistent effect on survival. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Gastric Cancer

In 2012, Shi et al in China published a nonrandomized, comparative study to determine the long-term efficacy of adjuvant immunotherapy with autologous CIK cells in 151 patients with locally advanced gastric cancer. Five-year OS and 5-year DFS rates for immunotherapy vs no immunotherapy (control group) were 32% vs 23% (p=0.07) and 28% vs 10% (p=0.04), respectively. For patients with intestinal-type tumors, 5-year OS (47% vs 31%; p=0.045) and DFS (42% vs 16%; p=0.02) rates were significantly higher for immunotherapy.

 

Summary

A single nonrandomized prospective study from China has reported statistically significant effects on DFS and OS in favor of immunotherapy with autologous CIK vs no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Colorectal Cancer

Zhao et al (2016) reported the results of a controlled trial in which 122 patients with metastatic colorectal cancer were randomized to CIK cell immunotherapy plus chemotherapy (n=61) or chemotherapy alone (n=61). The primary study end point was OS. The median OS was significantly greater with CIK cell immunotherapy plus chemotherapy (36 months) than with chemotherapy alone (16 months; p<0.001). The 3-year OS rates for both groups were 48% and 23%, respectively (p<0.001).

 

Summary

A single RCT from China has reported a statistically significant effect on OS in favor of immunotherapy with CIK immunotherapy vs chemotherapy alone. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Hepatocellular Carcinoma

Cai et al (2017) reported the results of a meta-analysis of 9 RCTs and 3 quasi-RCTs that compared outcomes of conventional treatments plus sequential CIKs with conventional treatments alone (total N=1387 patients). None of the 12 studies were rated as low risk of bias in all 7 domains as assessed by the Cochrane risk of bias tool. Of the 12 RCTs and quasi-RCTs, 5 reported a statistically significant favorable survival benefit for patients receiving conventional treatments plus sequential CIKs. All 12 studies were from Asia (1 Japan, 1 Korea, 10 China). Results of meta-analysis reported a statistical significant reduction in the hazard of death by 41% (HR=0.59; 95% CI, 0.46 to 0.77; p<0.005). However, the heterogeneity among the included studies was statistically significant (p=0.03, I2=48).

 

Yu et al (2014) conducted an RCT in China of 132 patients who had previously untreated hepatocellular carcinoma. Patients were randomized 1:1 to CIK therapy plus standard treatment (surgical resection in eligible patients, local treatment, or best supportive care) or standard treatment only. At a median follow-up of 19 months, median PFS was 14 months in the CIK group and 7 months in the control group (p=0.019). Estimated 1-, 2-, and 3-year PFS rates were 56% vs 35% (p=0.004), 36% vs 18% (p=0.004), and 27% vs 18% (p=0.017), respectively. Median OS was 25 months in the CIK group vs 11 months in the control group (p=0.008). Estimated 1-, 2-, and 3-year OS rates were significantly higher for immunotherapy: 74% vs 50% (p=0.002), 53% vs 30% (p=0.002), and 42% vs 24% (p=0.005), respectively. In the subgroup of operable patients, 3-year and median OS did not differ statistically between groups. Common adverse events attributed to CIK therapy were grade 1 or 2 fever, allergy, and headache. Grade 3 or 4 adverse events were not observed. A 2014 nonrandomized study from China reported improved PFS in 30 patients who received radiofrequency ablation plus CIK/natural killer cell/gamma delta T-cell (a type of tumor-infiltrating lymphocytes [TIL]) infusion (median PFS, not reached) compared with 32 patients who received radiofrequency ablation alone (median PFS, 12.0 months).

 

Lee et al (2015) conducted an RCT in Korea of 230 patients being treated for hepatocellular carcinoma by surgical resection, radiofrequency ablation, or percutaneous ethanol injection. Patients were randomized 1:1 to adjuvant CIK cell injections 16 times during 60 weeks or to no adjuvant therapy. The primary end point was recurrence-free survival; secondary end points included OS and cancer-specific survival. The median recurrence-free survival was 44 months in the CIK group and 30 months in the control group (p=0.010). OS was longer in the CIK group than in the control group (HR=0.21, p=0.008). Cancer-specific survival was longer in the CIK group than in the control group (HR=0.19, p=0.02). Adverse events occurred more frequently in the CIK group than in the control group, but grade 3 or 4 adverse events did not differ significantly between groups. Adverse events associated with CIK included pyrexia, chills, myalgia, and fatigue.

 

Summary

Several RCTs and quasi-RCTs have evaluated the efficacy of CIK cells in hepatocellular cancers. These studies have generally reported some benefits in response rates and/or survival. Results of meta-analysis of these trials also reported a statistical significant reduction in the hazard of death by 41%, but there was considerable heterogeneity among the included studies. Most trials were from Asia and did not use standard of care as the control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Non-Small-Cell Lung Cancer

Wang et al (2014) conducted a systematic review of RCTs of CIK cells for the treatment of non-small-cell lung cancer (NSCLC). Overall, 17 RCTs (total N=1172 patients) were included in the analysis. The studies generally had small sample sizes; the largest had 61 CIK-treated patients and 61 control patients. Most studies also incorporated dendritic cell therapy. All were conducted in China. A significant effect of CIK was found for median time to progression and median survival time. OS at various time points significantly favored CIK.

 

Summary

A single systematic review of RCTs of CIK cells for the treatment of NSCLC that included trials conducted in China reported some benefits in median time to progression and median survival time. The included body of evidence trials in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Tumor-Infiltrating Lymphocytes

Melanoma

Dudley et al (2008) conducted a series of nonrandomized phase 2 studies examining TIL plus IL-2 in patients with metastatic melanoma under various conditions of preinfusion lymphodepletion. A non-myeloablative 7-day chemotherapy regimen (n=43) was compared with ablative regimens comprising 5-day chemotherapy plus either 200 centigray (cGy; n=25) or 1200 cGy (n=25) total-body irradiation. Ninety-five percent of patients had progressive disease after prior systemic treatment. Objective response rates by Response Evaluation Criteria in Solid Tumors were 49%, 52%, and 72%, respectively, and did not differ significantly among groups. Responses occurred at multiple metastatic sites, including the brain, and many were durable; 10 patients who achieved CR had no relapse at a median follow-up of 31 months. Toxicities of treatment occurred primarily in the 1200-cGy group and included a delay in marrow recovery of 1 to 2 days compared with the other treatment groups, somnolence requiring intubation, renal insufficiency, and posterior uveitis. Rosenberg et al (2011) reported updated results of these patients with median follow-up of 62 months. Ten patients who previously had been classified as partial responders were reclassified as complete responders by Response Evaluation Criteria in Solid Tumors (1, 3, and 6 patients in the non-myeloablative, 200-cGy, and 1200-cGy groups, respectively). Of these 20 patients (22% of the original cohort), 19 (95%) had ongoing complete regression longer than 3 years. Actuarial 3- and 5-year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders, 100% and 93%, respectively. Likelihood of achieving a CR was similar regardless of prior therapy.

 

Dreno et al (2002) conducted an RCT of 88 patients with malignant melanoma without detectable metastases who were randomized to TIL plus IL-2 or to IL-2 alone. 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. TILs were harvested from surgical specimens. Outcomes were similar in both groups and, for this reason, the trial was terminated early.

 

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 CR were observed beyond 3 years. Toxicities appeared primarily associated with myeloablative regimen. Larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and use of appropriate standard of care as control arm showing treatment benefit are needed to establish.

 

Dendritic Cells

For the evidence review of dendritic cell based immunotherapy therapy (antigen presenting cells APCs – to include T-cells, B-cells, natural killer (NK) cells and other cells) for prostate cancer, see medical policy 08.01.27.

 

Antigen-loaded autologous dendritic cells (ADCs) have been explored primarily in early-stage trials in various malignancies including lymphoma, myeloma, subcutaneous tumors, melanoma, NSCLC, renal cell cancer, and cervical cancer. A 2012 systematic review highlighted progress in dendritic cellbased immunotherapy in epithelial ovarian cancer.

 

Glioblastoma Multiforme

In 2013, Bregy et al published a systematic review of observational studies of active immunotherapy using ADCs in the treatment of glioblastoma multiforme. Twenty-one studies published through early 2013 were included in this review (total N=403 patients). Vaccination with dendritic cells loaded with autologous tumor cells resulted in an increased median OS in patients with recurrent disease (72-138 weeks across 8 studies), as well as in those newly diagnosed (65-230 weeks across 11 studies) compared with average survival of 58 weeks. Complications and safety of the vaccine were assessed in all studies. No study indicated any sign of autoimmune reaction. Most adverse events were injection-site reactions (22%). Other adverse events included fatigue (19.5%), constipation/diarrhea (1.6%), myalgia/malaise (1.6%), shivering (1.4%), and vomiting (0.5%).

 

Liau et. al. (2018) reported on interim results of an RCT of 331 newly diagnosed glioblastoma patients initially treated with surgery and chemoradiotherapy who were randomized to temozolomide plus DCVax-L vaccine (autologous tumor lysate-pulsed dendritic cell vaccine) (n=232) or temozolomide plus placebo (n=99). The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. The authors concluded the addition of DCVax-L autologous dendritic cell vaccine to standard of care (SOC) is feasible and safe. Collectively, the blinded interim survival data suggest that he patients in this phase 3 trial are living longer than expected. These findings warrant further follow-up and analyses.

 

Summary

A systematic review of observational studies has examined the role of antigen-loaded autologous dendritic cells (ADC)-based adoptive immunotherapy in glioblastoma multiforme. Because of the observational and noncomparative nature of the available evidence, the review is subject to publication and selection bias, which has the potential to lessen or amplify the true potential of adoptive immunotherapy. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. Interim results from one such RCT (Liau et. al. 2018) have been published and may show promise, however, these findings warrant further follow up and analyses.

 

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. From 2008 to 2010, 60 patients with stage IIIB or 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 events of treatment/toxicity. PFS was 3.2 months in the DC/CIK group (95% CI, 2.9 to 3.5 months) vs 2.6 months control group (95% CI, 2.39 to 2.73 months; p<0.05). No significant toxic reactions were observed in the DC/CIK group, including bone marrow toxicity and gastrointestinal reactions. The findings of this small single-center RCT indicate that combination immunotherapy with dendritic cells and CIK cells may offer a viable option as maintenance therapy for patients with advanced NSCLC.

 

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. Two included RCTs that compared DC/CIK plus chemotherapy with chemotherapy alone in patients with stage III or IV NSCLC reported OS estimates (total N=150). Pooled relative risk (RRs) favored DC/CIK therapy at 2 years but not at 1 year (RR for 1-year OS=1.38; 95% CI, 1.00 to 1.90; p=0.05; I2=35%; RR for 2-year OS=2.88; 95% CI, 1.38 to 5.99; p=0.005; I2=0%).

 

The 2014 systematic review by Wang (discussed previously) also included many studies that used DC in combination with CIK.

 

Summary

Two RCTs and a meta-analysis of these RCTs have evaluated the efficacy of DC/CIK cells in NSCLC. The RCTs have generally reported some benefits in response rates and/or survival. Results of meta-analysis of these trials also reported a statistical significant reduction in the hazard of death. However, the effect was inconsistent. Most were from Asia and did not use standard of care as control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Medullary Thyroid Cancer

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

 

Summary

A small prospective noncomparative study in 10 MTC patients with treated with ADCs has been published. There are no RCTs comparing dendritic cell based adoptive immunotherapy with standard of care and therefore no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Pancreatic Cancer

A 2009 phase 1 study of 5 patients with inoperable pancreatic cancer reinfused ADCs and lymphokine-activated killer cells with gemcitabine; antigen priming of the ADCs was presumed to occur in vivo from apoptosis of gemcitabine-exposed tumor cells. One patient had a partial response, two 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.

 

Summary

A small prospective noncomparative study in 5 patients with pancreatic cancer treated with ADCs and lymphokine-activated killer has been published. There are no RCTs comparing dendritic cell based adoptive immunotherapy with standard of care and therefore no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

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-T cell therapy). For CAR-T cell therapy see medical policies 08.01.30 Kymriah (Tisgenlecleucel)* and 08.01.29 Yescarta (Axicabtagene Ciloleucel)*.

 

Review articles have highlighted recent progress in this field for solid and hematologic malignancies.

 

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

 

Additional studies have examined TCR gene therapy in Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma.

 

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.

 

Summary Of Evidence

Cytotoxic T Lymphocytes

For individuals with Epstein-Barr virus associated cancers who receive cytotoxic T lymphocytes, the evidence includes 2 small, prospective noncomparative cohort studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The cohort studies have shown a treatment response to infused cytotoxic T lymphocytes directed against cancer-associated viral antigens. To establish efficacy, the following is needed: large, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with Cytomegalovirus-associated cancers who receive cytotoxic T lymphocytes, the evidence includes a single case series. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. In the absence of an RCT comparing cytotoxic T lymphocytes with standard of care, no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Cytotoxic-Induced Killer Cells

For individuals with nasopharyngeal carcinoma who receive CIK cells, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The RCT reported a numerically favorable but statistically insignificant effect on progression-free survival and overall survival. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with renal cell carcinoma who receive CIK cells, the evidence includes multiple RCTs. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The largest of the RCTs reported statistically significant gains in progression-free survival and overall survival with CIK cell-based immunotherapy compared with interleukin-2 plus interferon-α-2. This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator. The other 2 RCTs have also reported response rates in favor of CIK therapy with inconsistent effect on survival. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with gastric cancer who receive CIK cells, the evidence includes a single nonrandomized prospective study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The prospective cohort study reported statistically significant effect on disease-free survival and overall survival in favor of immunotherapy vs no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with colorectal cancer who receive CIK cells, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Results of the RCT showed a statistically significant effect on overall survival in favor of immunotherapy vs chemotherapy alone. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with hepatocellular carcinoma who receive CIK cells, the evidence includes several RCTs. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Several RCTs from Asia have generally reported some benefits in response rates and/or survival. The results of a meta-analysis of these trials have also shown a statistically significant 41% reduction in the hazard of death, but there was considerable heterogeneity across the included studies. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with non-small-cell lung cancer who receive CIK cells, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. A single systematic review of RCTs reported some benefits in median time to progression and median survival time. The included body of evidence trials in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Tumor-Infiltrating Lymphocytes

For individuals with melanoma who receive tumor-infiltrating lymphocytes, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Results of a small RCT have reported no difference in relapse or survival outcomes. Cohort studies in patients with refractory metastatic melanoma have demonstrated response rates of 49% with immunotherapy and 52% to 72% with no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Dendritic Cells

For individuals with glioblastoma multiforme who receive dendritic cells, the evidence includes a systematic review of observational studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Because of the observational and noncomparative nature of the available evidence, it is difficult to draw any meaningful conclusions. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with non-small-cell lung cancer who receive dendritic cells, the evidence includes 2 RCTs and a meta-analysis. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The RCTs have generally reported some benefits in response rates and/or survival. The results of a meta-analysis of these trials also reported a statistical significant reduction in the hazard of death. Most trials were from Asia and did not use standard of care as the control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with medullary thyroid cancer who receive dendritic cells, the evidence includes one prospective noncomparative study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. A small prospective noncomparative study in 10 medullary thyroid cancer patients treated with autologous dendritic cells has been published. There are no RCTs comparing dendritic cellbased adoptive immunotherapy with standard of care and, therefore, no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with pancreatic cancer who receive dendritic cells, the evidence includes a small prospective noncomparative study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The study reported on treatment outcomes for 5 patients with pancreatic cancer. Because of the noncomparative nature of the available evidence and small sample base, it is difficult to draw any meaningful conclusions. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For the evidence review of dendritic cell based immunotherapy therapy (antigen presenting cells APCs – to include T-cells, B-cells, natural killer (NK) cells and other cells) for prostate cancer, see medical policy 08.01.27.

 

Genetically Engineered T Cells

Peripheral T Lymphocytes

For individuals with cancers who receive autologous peripheral T lymphocytes containing tumor antigen-specific T-cell receptors, the evidence includes multiple small observational studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Multiple observational studies have examined autologous peripheral T lymphocytes containing tumor antigen-specific T-cell receptors in melanoma, Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma. Because of the noncomparative nature of the available evidence with a small sample size, it is difficult to draw any meaningful conclusion. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

Head and Neck Cancers Version 2.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Kidney Cancer (Renal Cell Carcinoma) Version 2.2019

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Gastric Cancer Version 2.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Colon Cancer Version 3.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Rectal Cancer Version 3.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Hepatobiliary Cancers Version 3.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option for hepatocellular carcinoma.

 

Non-Small Cell Lung Cancer Version 6.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Melanoma (Cutaneous) Version 3.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Central Nervous System Cancers Version 1.2018
Glioblastoma Multiforme

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Thyroid Carcinoma Version 1.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Pancreatic Adenocarcinoma 2.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Bladder Cancer Version 5.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Hodgkin Lymphoma Version 3.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Uterine Neoplasms Version 1.2019

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option

 

Regulatory Status

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

 

Prior Approval:

Not applicable

 

Policy:

See related medical policies

  • 08.01.27 Cellular Immunotherapy for Prostate Cancer – Provenge (Sipuleucel-T)
  • 08.01.30 Kymriah (Tisgenlecleucel)*
  • 08.01.29 Yescarta (Axicabtagene Ciloleucel)*

 

Adoptive Immunotherapy

Adoptive immunotherapy using any one of the following is considered investigational for all indications as the evidence is insufficient to determine the effects of this technology on net health outcomes:

  • Adoptive cellular therapy for the administration of cytotoxic T-lymphocytes
  • Cytokine-induced killer cells
  • Tumor-infiltrating lymphocytes
  • Antigen-loaded autologous dendritic cells (ADCs) (except for prostate cancer, see medical policy 08.01.27)
  • Genetically engineered T-cell receptors (TCRs) such as peripheral T-lymphocytes, (this does not include CAR-T cell therapy, see medical policies 08.01.30 Kymriah (Tisgenlecleucel)* and 08.01.29 Yescarta (Axicabtagene Ciloleucel)* 

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • S2107 Adoptive immunotherapy i.e. development of specific antitumor reactivity (e.g. tumor-infiltrating lymphocyte therapy) per course of treatment

 

Selected References:

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  • Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. Apr 2008;8(4):299-308. PMID 18354418
  • Tang X, Liu T, Zang X, et al. Adoptive cellular immunotherapy in metastatic renal cell carcinoma: a systematic review and meta-analysis. PLoS One. May 2013;8(5):e62847. PMID 23667530
  • Xie F, Zhang X, Li H, et al. Adoptive immunotherapy in postoperative hepatocellular carcinoma: a systemic review. PLoS One. Aug 2012;7(8):e42879. PMID 22916174
  • Zhong JH, Ma L, Wu LC, et al. Adoptive immunotherapy for postoperative hepatocellular carcinoma: a systematic review. Int J Clin Pract. Jan 2012;66(1):21-27. PMID 22171902
  • Bollard CM, Gottschalk S, Torrano V, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol. Mar 10 2014;32(8):798-808. PMID 24344220
  • Chia WK, Teo M, Wang WW, et al. Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther. Jan 2014;22(1):132-139. PMID 24297049
  • Ohtani T, Yamada Y, Furuhashi A, et al. Activated cytotoxic T-lymphocyte immunotherapy is effective for advanced oral and maxillofacial cancers. Int J Oncol. Nov 2014;45(5):2051-2057. PMID 25120101
  • Schuessler A, Smith C, Beagley L, et al. Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res. Jul 1 2014;74(13):3466-3476. PMID 24795429
  • Li JJ, Gu MF, Pan K, et al. Autologous cytokine-induced killer cell transfusion in combination with gemcitabine plus cisplatin regimen chemotherapy for metastatic nasopharyngeal carcinoma. J Immunother. Feb-Mar 2012;35(2):189-195. PMID 22306907
  • Liu L, Zhang W, Qi X, et al. Randomized study of autologous cytokine-induced killer cell immunotherapin metastatic renal carcinoma. Clin Cancer Res. Mar 15 2012;18(6):1751-1759. PMID 22275504
  • Zhang Y, Wang J, Wang Y, et al. Autologous CIK cell immunotherapy in patients with renal cell carcinoma after radical nephrectomy. Clin Dev Immunol. Jan 2013;2013:195691. PMID 24382970
  • Zhao X, Zhang Z, Li H, et al. Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma. Cancer Lett. Jul 1 2015;362(2):192-198. PMID 25843292
  • Shi L, Zhou Q, Wu J, et al. Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol Immunother. Dec 2012;61(12):2251-2259. PMID 22674056
  • Zhao H, Wang Y, Yu J, et al. Autologous cytokine-induced killer cells improves overall survival of metastatic colorectal cancer patients: results from a phase II clinical trial. Clin Colorectal Cancer. Sep 2016;15(3):228-235. PMID 27052743
  • Cai XR, Li X, Lin JX, et al. Autologous transplantation of cytokine-induced killer cells as an adjuvant therapy for hepatocellular carcinoma in Asia: an update meta-analysis and systematic review. Oncotarget. May 09 2017;8(19):31318-31328. PMID 28412743
  • Yu X, Zhao H, Liu L, et al. A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J Clin Immunol. Feb 2014;34(2):194-203. PMID 24337625
  • Cui J, Wang N, Zhao H, et al. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int J Cancer. Jan 15 2014;134(2):342-351. PMID 23825037
  • Lee JH, Lee JH, Lim YS, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. Jun 2015;148(7):1383-1391 e1386. PMID 25747273
  • Wang M, Cao JX, Pan JH, et al. Adoptive immunotherapy of cytokine-induced killer cell therapy in the treatment of non-small cell lung cancer. PLoS One. Nov 2014;9(11):e112662. PMID 25412106
  • 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 2008;26(32):5233-5239. PMID 18809613
  • Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. Jul 01 2011;17(13):4550-4557. PMID 21498393
  • Dreno B, Nguyen JM, Khammari A, et al. Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother. Nov 2002;51(10):539-546. PMID 12384805
  • Figlin RA, Thompson JA, Bukowski RM, et al. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. Aug 1999;17(8):2521-2529. PMID 10561318
  • Motta MR, Castellani S, Rizzi S, et al. Generation of dendritic cells from CD14+ monocytes positively selected by immunomagnetic adsorption for multiple myeloma patients enrolled in a clinical trial of anti-idiotype vaccination. Br J Haematol. Apr 2003;121(2):240-250. PMID 12694245
  • Triozzi PL, Khurram R, Aldrich WA, et al. Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer. Dec 15 2000;89(12):2646-2654. PMID 11135227
  • Bedrosian I, Mick R, Xu S, et al. Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol. Oct 15 2003;21(20):3826-3835. PMID 14551301
  • Shi SB, Ma TH, Li CH, et al. Effect of maintenance therapy with dendritic cells: cytokine-induced killer cells in patients with advanced non-small cell lung cancer. Tumori. May-Jun 2012;98(3):314-319. PMID 22825506
  • Yang L, Ren B, Li H, et al. Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients. Cancer Immunol Immunother. Jan 2013;62(1):65-73. PMID 22744010
  • Su Z, Dannull J, Heiser A, et al. Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res. May 01 2003;63(9):2127-2133. PMID 12727829
  • Santin AD, Bellone S, Palmieri M, et al. Induction of tumor-specific cytotoxicity in tumor infiltrating lymphocytes by HPV16 and HPV18 E7-pulsed autologous dendritic cells in patients with cancer of the uterine cervix. Gynecol Oncol. May 2003;89(2):271-280. PMID 12713991
  • Tanyi JL, Chu CS. Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: a systematic review. Immunotherapy. Oct 2012;4(10):995-1009. PMID 23148752
  • Bregy A, Wong TM, Shah AH, et al. Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme. Cancer Treat Rev. Dec 2013;39(8):891-907. PMID 23790634
  • Chen R, Deng X, Wu H, et al. Combined immunotherapy with dendritic cells and cytokine-induced killer cells for malignant tumors: a systematic review and meta-analysis. Int Immunopharmacol. Oct 2014;22(2):451-464. PMID 25073120
  • 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 2009;21(6):1585-1592. PMID 19424640
  • 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 2009;38(3):e69-74. PMID 19276867
  • Ngo MC, Rooney CM, Howard JM, et al. Ex vivo gene transfer for improved adoptive immunotherapy of cancer. Hum Mol Genet. Apr 15 2011;20(R1):R93-99. PMID 21415041
  • Ochi T, Fujiwara H, Yasukawa M. Requisite considerations for successful adoptive immunotherapy with engineered T-lymphocytes using tumor antigen-specific T-cell receptor gene transfer. Expert Opin Biol Ther. Jun 2011;11(6):699-713. PMID 21413911
  • Humphries C. Adoptive cell therapy: Honing that killer instinct. Nature. Dec 19 2013;504(7480):S13-15. PMID 24352359
  • Johnson LA, Morgan RA, Dudley ME, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. Jul 16 2009;114(3):535-546. PMID 19451549
  • Savoldo B, Rooney CM, Di Stasi A, et al. Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood. Oct 01 2007;110(7):2620-2630. PMID 17507664
  • Pinthus JH, Waks T, Malina V, et al. Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes. J Clin Invest. Dec 2004;114(12):1774-1781. PMID 15599402
  • Pule MA, Savoldo B, Myers GD, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. Nov 2008;14(11):1264-1270. PMID 18978797 
  • National Comprehensive Cancer Network (NCCN) Head and Neck Cancers Version 2.2018.
  • National Comprehensive Cancer Network (NCCN) Kidney Cancer Version 2.2019.
  • National Comprehensive Cancer Network (NCCN) Gastric Cancer Version 2.2018.
  • National Comprehensive Cancer Network (NCCN) Colon Cancer Version 3.2018.
  • National Comprehensive Cancer Network (NCCN) Rectal Cancer Version 3.2018.
  • National Comprehensive Cancer Network (NCCN) Hepatobiliary Cancer Version 3.2018.
  • National Comprehensive Cancer Network (NCCN) Non-Small Cell Lung Cancer Version 6.2018.
  • National Comprehensive Cancer Network (NCCN) Melanoma Version 3.2018.
  • National Comprehensive Cancer Network (NCCN) Central Nervous System Cancers Version 1.2018.
  • National Comprehensive Cancer Network  (NCCN) Thyroid Carcinoma Version 1.2018.
  • National Comprehensive Cancer Network  (NCCN) Pancreatic Adenocarcinoma Version 2.2018.
  • National Comprehensive Cancer Network (NCCN) Bladder Cancer Version 5.2018.
  • National Comprehensive Cancer Network (NCCN) Hogkin Lymphoma Version 3.2018.
  • National Comprehensive Cancer Network (NCCN) Uterine Neoplasms Version 1.2019.
  • Cheson B, Pfistner B, Juweid M, et. al. Revised response criteria for malignant melanoma. Journal of Clinical Oncology Volume 25 Number 5 February 2007
  • Liau LM, Ashkan K, Tran DD, et. al. First results on survival from a large phase 3 clinical trial of autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 2018 May 29;16(1):142. PMID 29843811 

 

Policy History:

  • October 2018 - Annual Review, Policy Revised
  • August 2018 - Interim Review, Policy Revised
  • May 2018 - Interim Review, Policy Revised
  • February 2018 - Interim Review, Policy Revised
  • December 2017 - Interim Review, Policy Revised
  • October 2017 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

*CPT® is a registered trademark of the American Medical Association.