Adoptive Immunotherapy - CAM 80101

Description:
The spontaneous regression of certain cancers (e.g., renal cell carcinoma, melanoma) 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 some period of time, and then infused back into the patient.

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-versus-malignancy effect of donor lymphocytes. In contrast, the adoptive immunotherapy techniques described in this evidence review enhance autoimmune effects primarily. The use of reduced-intensity conditioning in cell transplantation is discussed for specific cancers in individual policies related to cell transplantation.

Chimeric antigen receptor T-cell therapies for certain hematologic malignancies (e.g., tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel) are discussed separately in evidence review 8.01.63.

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

For individuals with Cytomegalovirus-associated cancers who receive CTL, the evidence includes a single case series. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. In the absence of a randomized controlled trial (RCT) comparing CTL with the standard of care, no conclusions can be made. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Cytotoxic-Induced Killer Cells
For individuals with nasopharyngeal carcinoma who receive cytotoxic-induced killer (CIK) cells, the evidence includes a single RCT. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The RCT reported a numerically favorable but statistically insignificant effect on progression-free survival (PFS) and OS. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with renal cell carcinoma who receive CIK cells, the evidence includes multiple RCTs. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The largest of the RCTs reported statistically significant gains in PFS and OS with CIK cell-based immunotherapy compared with interleukin (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 other 2 RCTs have also reported response rates in favor of CIK therapy with an inconsistent effect on survival. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with gastric cancer who receive CIK cells, the evidence includes 2 meta-analyses encompassing non-randomized trials. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Both meta-analyses reported statistically significant effects on OS, disease-free survival (DFS), and PFS in favor of immunotherapy versus no 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with colorectal cancer who receive CIK cells, the evidence includes a single RCT and 1 meta-analysis. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Results of the RCT showed a statistically significant effect on OS in favor of immunotherapy versus chemotherapy alone. A meta-analysis that included both gastric cancer and colorectal cancer found improvements in OS and PFS in favor of CIK/dendritic cells (DC)-CIK compared to chemotherapy alone. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with hepatocellular carcinoma who receive CIK cells, the evidence includes meta-analyses that include RCTs and quasi-randomized trials. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Meta-analyses of these trials have reported improved OS rates when compared to conventional therapies alone, but they are limited by inclusion of studies from Asia only and heterogeneity in comparators. 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. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with non-small-cell lung cancer who receive CIK cells, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, DSS, QOL, 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 trials assessed in the systematic review were limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodological weaknesses. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Tumor-Infiltrating Lymphocytes
For individuals with melanoma who receive tumor-infiltrating lymphocytes (TILs), the evidence includes a meta-analysis of randomized and non-randomized trials. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. A meta-analysis evaluating TIL with IL-2 in patients with cutaneous melanoma reported an objective response rate of 41%. Pooled 1-year OS rates ranged from 46.1% to 56.5% depending on the IL-2 dose level. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Dendritic Cells
For individuals with glioblastoma multiforme who receive DC, the evidence includes a systematic review of observational studies. Relevant outcomes are OS, DSS, QOL, 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 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 1 such RCT have been published but are not informative because the patients were unblinded and results combined for the treatment and placebo arms. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with non-small-cell lung cancer who receive DC, the evidence includes 2 RCTs and a meta-analysis. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The RCTs have generally reported some benefits in response rates and/or survival. The meta-analysis of these trials also reported a statistically significant reduction in the hazard of death. Most trials were from Asia and did not use the 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 methodological weaknesses. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with medullary thyroid cancer (MTC) who receive DC, the evidence includes 1 prospective noncomparative study. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. A small prospective noncomparative study in 10 MTC patients treated with autologous DC has been published. There are no RCTs comparing DC-based adoptive immunotherapy with the standard of care and, therefore, no conclusions can be made. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with pancreatic cancer who receive DC, the evidence includes a small prospective noncomparative study. Relevant outcomes are OS, DSS, QOL, 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 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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 OS, DSS, QOL, 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 and small sample size, it is difficult to draw any meaningful conclusion. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information
Not applicable

Background
Health Disparities in Certain Cancers
Hepatic tumors can arise as primary liver cancer (hepatocellular cancer) or by metastasis to the liver from other tissues. A study from 2016 determined that the incidence of liver cancer was higher among White individuals, Black individuals, and Hispanic individuals born after 1938.¹ The incidence of hepatocellular carcinoma was twice as high for U.S.-born Hispanic men compared to Hispanic men born outside of the US. This may be due to the increased risk of smoking, hepatitis B or C infection, and diabetes among U.S.-born Hispanic individuals.

Based on data from 2015 through 2019, kidney cancer is more common in men than women and occurs more often in American Indian and Alaskan Native individuals, followed by Black individuals.² American Indians and Alaska Natives have higher death rates from kidney cancer than any other racial or ethnic group. A cohort study by Howard et al. (2021) included 158,445 patients with localized kidney cancer from the National Cancer Database between 2010 and 2017.³ Investigators found that that female patients were treated more aggressively compared with male patients, with lower adjusted odds of undertreatment and higher adjusted odds of overtreatment. They also found that Black and Hispanic patients had higher adjusted odds of undertreatment and overtreatment compared to White patients, and uninsured status was associated with lower adjusted odds of overtreatment and higher adjusted odds of undertreatment. These results suggest that sex, race and ethnicity, and socioeconomic status are associated with disparities in guideline-based treatment for localized kidney cancer, specifically, with increased rates of non-guideline based treatment for women and Black and Hispanic patients.

Adoptive Immunotherapy
Adoptive immunotherapy uses “activated” lymphocytes as a treatment modality. Both nonspecific and specific lymphocyte activation are used therapeutically. The nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes.

T Lymphocytes and Killer Cells
Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T-cell growth factor interleukin (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 (DC) 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. The 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.⁴

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 DC infusions.

Adoptive cellular therapy is “the administration of a patient’s own (autologous) or donor (allogeneic) antitumor lymphocytes following a lymphodepleting preparative regimen.”⁵ Protocols vary, but include these common steps:

lymphocyte harvesting (either from peripheral blood or from tumor biopsy)
propagation of tumor-specific lymphocytes in vitro using various immune modulators
selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay
lymphodepletion of the host with immunosuppressive agents
adoptive transfer (i.e., transfusion) of lymphocytes back into the tumor-bearing host.

Dendritic cell-based immunotherapy uses autologous DC (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigens in vivo. Autologous dendritic cells 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 re-transfused 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. (See evidence review 8.01.53 for a discussion of DC-based immunotherapy for prostate cancer.)

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

Regulatory Status
On Aug. 30, 2017, tisagenlecleucel (Kymriah™; Novartis) was approved by the Food and Drug Administration for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

On May 1, 2018, tisagenlecleucel (Kymriah™; Novartis) was approved by the Food and Drug Administration for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

On Oct. 18, 2017, axicabtagene ciloleucel (Yescarta™; Kite Pharma) was approved by the Food and Drug Administration for the treatment of adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

These therapies are discussed separately in evidence review 80163.

Related Policies
80153 Cellular Immunotherapy for Prostate Cancer
80163 Chimeric Antigen Receptor Therapy for Hematologic Malignancies

Policy:
Adoptive immunity in the form of chimeric antigen receptor T-cell therapy (e.g., tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, Idecabtagene vicleucel) for hematologic malignancies is discussed in the new policy 80163 (Chimeric Antigen Receptor Therapy for Hematologic Malignancies).

All applications of adoptive immunotherapy evaluated in this policy are considered investigational/unproven therefore NOT MEDICALLY NECESSARY.

Policy Guidelines
Guidelines for adoptive immunotherapy in the form of chimeric antigen receptor T-cell therapy in certain hematologic malignancies is discussed in evidence review 80163.

See Codes table for details.

Benefit Application
BlueCard/National Account Issues
Adoptive immunotherapy is a specialized service that may require and out-of-network referral.

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

Rationale
This evidence review was created in December 1996 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through Aug. 24, 2022.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and 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 technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Adoptive Immunotherapy 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 (RCC)⁶ and postoperative hepatocellular carcinoma (HCC).^7,8

Cytotoxic T Lymphocytes
Clinical Context and Therapy Purpose
The purpose of cytotoxic T lymphocytes (CTL) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Epstein-Barr virus (EBV)-associated cancers or with Cytomegalovirus-associated cancers.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with EBV-associated or Cytomegalovirus-associated cancers.

Interventions
The therapy being considered is CTL.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), QOL, treatment-related mortality, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.
The version of the therapeutic is described.
Patient/sample clinical characteristics are described.
Patient/sample selection criteria are described.

Epstein-Barr Virus‒Associated Cancers
Review of Evidence
Observational Studies
Bollard et al. (2014) conducted an international prospective cohort study of CTL therapy in patients with EBV‒positive Hodgkin or non-Hodgkin lymphoma.⁹ Patients had either active, relapsed disease (n = 21) or were in remission with a high-risk of relapse (n = 29). Cytotoxic T lymphocytes with activity against EBV antigens were generated by incubating peripheral blood monocytes with EBV antigen-infected dendritic cells (DCs). Eleven (52%) of 21 patients with active disease achieved complete response (CR), and 2 (10%) patients achieved partial response; 2-year event-free survival in this cohort was approximately 50%. Twenty-seven (93%) of 29 patients in remission achieved CR; 2-year event-free survival was 82%. Immediate or delayed toxicity related to CTL infusion was not observed.

Chia et al. (2014) studied 35 patients with EBV-positive nasopharyngeal cancer at a single-center in China.¹⁰ Patients received standard chemotherapy with gemcitabine and carboplatin followed by EBV-specific CTL infusion. Median progression-free survival (PFS) and 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 Japanese series of 7 patients who received CTLs for advanced oral and maxillofacial cancers, Ohtani et al. (2014) reported 1-year survival rates in patients who achieved response (n = 3) and in those with progressive disease (n = 4) of 100% and 25%, respectively, although definitions of response were unclear.¹¹

Subsection Summary: Epstein-Barr Virus-Associated Cancers
Two small, prospective noncomparative cohort studies in patients with relapsed disease have indicated a response to infused CTLs directed against cancer-associated viral antigens. Adverse events were mild or moderate. There are no RCTs comparing CTL with the standard of care and therefore no conclusions can be made about the efficacy of CTL in EBV-associated cancers. To establish efficacy, the following are 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
Review of Evidence
Observational Studies
Schuessler et al. (2014) administered CTLs with or without chemotherapy to 13 patients with recurrent glioblastoma multiforme.¹² Cytotoxic T lymphocytes 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.

Subsection Summary: Cytomegalovirus-Associated Cancers
A single case series in 13 patients with glioblastoma multiforme treated with CTLs has reported mild adverse events. There are no RCTs comparing CTL with the standard of care and therefore no conclusions can be made about the efficacy of CTL in Cytomegalovirus-associated cancers. 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.

Cytokine-Induced Killer Cells
Clinical Context and Therapy Purpose
The purpose of cytokine-induced killer (CIK) cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with various malignancies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with various malignancies, including nasopharyngeal carcinoma, RCC, gastric cancer, colorectal cancer (CRC), HCC, and non-small-cell lung cancer (NSCLC).

Interventions
The therapy being considered is CIK cells.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.
The version of the therapeutic is described.
Patient/sample clinical characteristics are described.
Patient/sample selection criteria are described.

Nasopharyngeal Carcinoma
Review of Evidence
Randomized Controlled Trials
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.¹³ 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 versus 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 = .137). Median PFS was 26 months for the GC plus CIK group and 19 months for the GC group (p = .023). This small, single-center RCT suggests that the combination of CIK cells and GC regimen chemotherapy may be a viable treatment option for patients with advanced nasopharyngeal carcinoma.

Subsection Summary: Nasopharyngeal Carcinoma
A single RCT from China reported a 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 methodological weaknesses (inadequate reporting of randomization, allocation concealment, and power). 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.

Renal Cell Carcinoma
Review of Evidence
Randomized Controlled Trials
Liu et al. (2012) conducted an RCT to evaluate the effects of autologous CIK cell immunotherapy in patients with metastatic RCC followed in another university cancer center in China.¹⁴ From 2005 to 2008, 148 patients were randomized to autologous CIK cell immunotherapy (arm 1, n = 74) or interleukin-2 (IL-2) treatment in combination with human interferon-α-2a (arm 2, n = 74). The primary endpoint was OS, and the secondary endpoint 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, versus 12% and 23%, respectively, in arm 2 (p = .031 and p < .001, respectively). Median PFS and OS in arm 1 were significantly longer than those in arm 2 (PFS, 12 months vs. 8 months, p = .024; OS, 46 months vs. 19 months, p < .001), respectively. Multivariate analyses indicated that the cycle count of CIK cell immunotherapy as a continuous variable was significantly associated with prolonged PFS (HR = 0.88; 95% confidence interval [CI], 0.84 to 0.93; p < .001) and OS (HR = 0.58; 95% CI, 0.48 to 0.69; p < .001) in arm 1. These findings suggest that CIK cell immunotherapy has the potential to improve the prognosis of patients with metastatic RCC.

Zhang et al. (2013) conducted a small RCT in China that assessed 20 patients who had unilateral, locally advanced RCC after nephrectomy.¹⁵ 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% in the CIK group vs. 50% in the control group; p = .175). Mean PFS was significantly longer in the CIK group, but OS was not (mean PFS, 32 months vs. 22 months; p = .032; mean OS, 35 months vs. 34 months; p = .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 RCC.¹⁶ 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. Progression-free survival was also longer in the CIK group (p = .021). Among the 62 inoperable patients, OS was longer in the CIK group (p = .012). No severe adverse reactions were observed.

Subsection Summary: Renal Cell Carcinoma
Three RCTs from China have evaluated the efficacy of CIK cell immunotherapy in RCC. The largest of the 3 RCTs reported statistically significant gains in PFS and OS with CIK cell immunotherapy compared with 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 other 2 RCTs also reported response rates in favor of CIK therapy with inconsistent effects on survival. 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.

Gastric Cancer
Review of Evidence
Systematic Reviews
Two meta-analyses evaluating CIK cell/dendritic cell-cytokine-induced killer (DC-CIK) cell immunotherapy in gastric cancers are summarized in Tables 1 to 3. Wang et al. (2018) evaluated the effect of treatment for gastric cancer after surgery.¹⁷ Compared with the control group, the HR for OS was 0.712 (95% CI, 0.594 to 0.854) and 0.66 (95% CI, 0.546 to 0.797) for overall DFS. No fatal adverse reactions were noted. Fever was the most common adverse event in CIK/DC-CIK treatment. Other effects (such as nausea and headache) could be relieved without medication or by simple treatment. In addition, CIK/DC-CIK therapy reduced bone marrow suppression caused by chemotherapy. The analysis is limited in several ways. First, the difference between the numbers of patients involved in each study may have led to partial differences in outcomes. Secondly, there were differences in the use of immune cells across different studies. Furthermore, different surgical procedures may have led to different outcomes, thus creating a study bias. Patients in stages I to III underwent radical surgery, whereas patients in stage IV underwent palliative surgery. Du et al. (2020) focused their analysis on the combination of CIK/DC-CIK immunotherapy with chemotherapy for the treatment of advanced gastrointestinal cancers, which included both gastric cancers and CRC.¹⁸ Combination therapy was found to be associated with improved OS and PFS compared to chemotherapy alone. Subgroup analyses of the outcomes stratified by gastric cancer and CRC found results were consistent with the overall results. No significant differences in CR, partial response, and overall response rates were noted between the groups. In this analysis, QOL was also assessed using data from 3 of the included trials. Significantly improved QOL was observed in the CIK/DC–CIK immunotherapy group compared with the chemotherapy alone group (n = 245; weighted mean difference = 16.09; 95% CI, 1.66 to 30.52). For safety, no significant differences were noted between groups for adverse events of interest, such as myelosuppression. The analysis was limited by the presence of potential publication bias leading to negative data being omitted.

Table 1. Comparison of Studies Included in Gastric Cancer Meta-analyses

Study	Du et al. (2020)¹⁸	Wang et al. (2018)¹⁷
Jiang (2006)	⚫
Shi (2012)	⚫	⚫
Zhao (2013)	⚫
Lin (2015)	⚫
Mu (2016)	⚫
Zhao (2016)	⚫
Peng (2017)	⚫
Wang (2017)	⚫	⚫
Xie (2017)	⚫
Liu (2013)		⚫
Yu (2015)		⚫
Zhao (2012)		⚫
Li (2017)		⚫
Gao (2013)		⚫
Cu (2015)		⚫

Table 2. Gastric Cancer Meta-analyses Characteristics

Study	Dates	Trials	Participants	Comparison	N (Range)	Design	Duration
Du et al. (2020)¹⁸	2006 – 2017	9	Patients with advanced gastrointestinal cancer (gastric cancer or CRC)	CIK/DC-CIK immunotherapy combined with chemotherapy vs. chemotherapy alone	1,113 (28 to 255)	3 prospective and 6 retrospective studies	At least 24 months
Wang et al. (2018)¹⁷	2010 – 2017	9	Patients with gastric cancer post-surgery	CIK/DC-CIK immunotherapy combined with chemotherapy vs. chemotherapy alone	1,216 (54 to 226)	7 quasi-randomized controlled trials and 2 controlled trials	NR

Table 3. Gastric Cancer Meta-Analyses Results

Study	OS		DFS		PFS
	3-year	5-year	3-year	5-year	3-year	5-year
Du et al. (2020)¹⁸
Total N	727	580			727	580
Pooled effect (95% CI)	1.43 (1.25 to 1.64)	1.84 (1.41 to 2.40)			1.39 (1.20 to 1.62)	1.99 (1.52 to 2.60)
I²(p)	36.3% (.179)	0% (.654)			0% (.664)	0% (.727)
Wang et al. (2018)¹⁷
Total N	627	526	529	370
Pooled effect (95% CI)	1.29 (1.15 to 1.48)	1.73 (1.36 to 2.19)	1.40 (1.19 to 1.65)	2.10 (1.53 to 2.87)
I²(p)	0% (.89)	0% (.62)	9% (.35)	0% (.57)

CI: confidence interval; DFS: disease-free survival; OS: overall survival; PFS: progression-free survival.

Subsection Summary: Gastric Cancer
Two meta-analyses have reported statistically significant improvements in OS, DFS, and PFS with the addition of CIK/DC-CIK immunotherapy to chemotherapy compared to chemotherapy alone. 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.

Colorectal Cancer
Review of Evidence
Systematic Reviews
The systematic review by Du et al. (2020) summarized previously for gastric cancer included both gastric cancers and CRC.¹⁸ Their analysis found significant improvements in OS and PFS in favor of the combination of CIK/DC-CIK immunotherapy with chemotherapy compared to chemotherapy alone for the treatment of advanced gastrointestinal cancers. Subgroup analyses of the outcomes stratified by gastric cancer and CRC found results were consistent with the overall results.

Randomized Controlled Trials
Zhao et al. (2016) reported the results of a controlled trial in which 122 patients with metastatic CRC were randomized to CIK cell immunotherapy plus chemotherapy (n = 61) or chemotherapy alone (n = 61).¹⁹ The primary study endpoint was OS. The median OS was significantly greater with CIK cell immunotherapy plus chemotherapy (36 months) than with chemotherapy alone (16 months; p < .001). The 3-year OS rates for both groups were 48% and 23%, respectively (p < .001).

Subsection Summary: Colorectal Cancer
A single RCT from China has reported a statistically significant effect on OS in favor of immunotherapy with CIK immunotherapy versus chemotherapy alone. A meta-analysis that included both gastric cancer and CRC found improvements in OS and PFS in favor of CIK/DC-CIK compared to chemotherapy alone. 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.

Hepatocellular Carcinoma
Review of Evidence
Systematic Reviews
Two meta-analyses have evaluated the efficacy of CIK, DC, or DC-CIK immunotherapy combined with conventional treatments in HCC, which are summarized in Tables 4 to 6. Cao et al. (2019) evaluated CIK, DC, or DC-CIK immunotherapy in 22 trials.²⁰ Cai et al. (2017) reported on outcomes of conventional treatments plus sequential CIKs compared to conventional treatments alone.²¹ For both studies, all studies evaluating CIK or DC-CIK immunotherapy were conducted in Asia and were limited by the variety of comparators included, some of which do not reflect current practice.

Table 4. Comparison of Studies Included in Hepatocellular Carcinoma Meta-analyses

Study	Cao et al. (2019)²⁰	Cai et al. (2017)²¹
Weng (2007)	⚫	⚫
Dong (2008)	⚫
Hao (2010)	⚫	⚫
Pan (2010)	⚫
Pan (2013)	⚫
Lee (2015)	⚫	⚫
Pan (2015)	⚫
Chen (2016)	⚫
Li (2016)	⚫
Chang (2018)	⚫
Lee (2018)	⚫
Cui (2014)	⚫	⚫
Qian (2016)	⚫
Qui (2011)	⚫	⚫
Niu (2013)	⚫
Takamaya (2000)		⚫
Hui 2009		⚫
Wang (2012)		⚫
Xu (2013)		⚫
Yu (2014)		⚫
Zhang (2014)		⚫
Xu (2016)		⚫

Five studies included in the Cao et al. (2020) analysis evaluated dendritic cell-monotherapy with conventional treatments; these studies are not included in the table summary.

Table 5. Hepatocellular Carcinoma Meta-Analyses Characteristics

Study	Dates	Trials	Participants	Comparison	N (Range)	Design	Duration
Cao et al. (2019)²⁰	2007 – 2018	22	Patients with HCC receiving CIK, DC-CIK, or DC immunotherapy	CIK/DC-CIK/DC immunotherapy combined with conventional therapy vs. conventional therapy alone	3,756 (18 to 1031)	7 RCTs, 15 non-RCTs	NR
Cai et al. (2017)²¹	2000 – 2016	12	Patients with HCC receiving sequential CIKs with conventional treatments	CIK immunotherapy combined with conventional therapy vs. conventional therapy alone	1,387 (18 to 226)	9 RCTs and 3 quasi-RCTs	NR

CIK: cytokine-induced killer cell; DC: dendritic cell; HCC: hepatocellular carcinoma; NR: not reported; RCT: randomized controlled trials.

Table 6. Hepatocellular Carcinoma Meta-analyses Results

Study	OS		PFS
Cao et al. (2019)²⁰	3-year	5-year
Total N	2,582	2,306
Pooled effect (95% CI)	1.23 (1.15 to 1.31)	1.26 (1.15 to 1.37)
I²(p)	0% (.77)	0% (.88)
Cai et al. (2017)²¹	Overall HR (duration not specified)		Overall HR (duration not specified)
Total N	NR		NR
Pooled effect (95% CI)	0.59 (0.46 to 0.77)		0.53 (0.40 to 0.69)
I²( p)	48% (.03)		0% (.85)

CI: confidence interval; HR: hazard ratio; NR, not reported; OS: overall survival; PFS: progression-free survival.

Subsection Summary: Hepatocellular Carcinoma
Several RCTs and quasi-RCTs have evaluated the efficacy of CIK cells in HCC. Meta-analysis of these trials have reported improved OS rates when compared to conventional therapies alone. Included studies in meta-analyses were from Asia and did not use the 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 methodological weaknesses. 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.

Non-Small-Cell Lung Cancer
Review of Evidence
Systematic Reviews
Wang et al. (2014) conducted a systematic review of RCTs of CIK cells for the treatment of NSCLC.²² Overall, 17 RCTs (N = 1,172 ) were included in the analysis. The studies generally had small sample sizes; the largest had 61 CIK-treated patients and 61 control patients. Most studies also incorporated DC therapy. All were conducted in China. A significant effect of CIK was found for the median time to progression and median survival time. The OS at various time points significantly favored CIK.

Subsection Summary: Non-Small-Cell Lung Cancer
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 in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodological weaknesses. 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.

Tumor-Infiltrating Lymphocytes
Clinical Context and Therapy Purpose
The purpose of tumor-infiltrating lymphocytes (TIL) is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with melanoma.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with melanoma.

Interventions
The therapy being considered is TIL.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.
The version of the therapeutic is described.
Patient/sample clinical characteristics are described.
Patient/sample selection criteria are described.

Review of Evidence
Systematic Reviews
Dafni et al. (2019) published a systematic review and meta-analysis that included randomized and non-randomized studies evaluating TIL plus IL-2 in patients with previously treated advanced cutaneous melanoma.²³ Tumor-infiltrating lymphocyte therapy was administered with a full non-myeloablative chemotherapy regimen. Characteristics of the meta-analysis are summarized in Table 7. The primary endpoint was objective response rates (ORR); the pooled overall ORR estimate was 41%. Table 8 summarizes the main results. The analysis additionally compared TIL outcomes with cohorts of patients who were treated with checkpoint blockade immunotherapy. The pooled ORR rates for high-dose IL-2 with TIL (43%) was similar to the ORR rate for nivolumab (44%), but lower than nivolumab/ipilimumab (58%).

Table 7. Cutaneous Melanoma Meta-analyses Characteristics

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Dafni et al. (2019)²³	1988 – 2016	13	Patients with advanced cutaneous melanoma receiving TIL plus IL-2	410 (4 to 69)	Randomized and non-randomized controlled trials (specific n for each type not reported)	NR

IL: interleukin; NR: not reported; TIL: tumor-infiltrating lymphocytes.

Table 8. Cutaneous Melanoma Meta-Analyses Results

Study	OS	ORR	CR rate
Dafni et al. (2019)²³	1-year
Total N	Low-dose IL-2: 54 High-dose IL-2: 332	Low-dose IL-2: 78 High-dose IL-2: 332	Low-dose IL-2: 78 High-dose IL-2: 332
Pooled effect (95% CI)	Low-dose IL-2: 46.1% (27.2 to 63) High-dose IL-2: 56.5% (45 to 66.4)	Low-dose IL-2: 35% (25 to 45) High-dose IL-2: 43% (36 to 50)	Low-dose IL-2: 7% (1 to 12) High-dose IL-2: 14% (7 to 20)
I²(p)	NR	Low-dose IL-2: 41.28% (.15) High-dose IL-2: 45.67% (.075)	Low-dose IL-2: 0% (.52) High-dose IL-2: 68.42% (.0024)

Results were stratified by IL-2 dose level. Low dose: < 720,000 IU/kg; high dose: ≥ 720,000 IU/kg.
CI: confidence interval; CR: complete response; IL: interleukin; NR: not reported; ORR: objective response rate; OS: overall survival.

Section Summary: Tumor-Infiltrating Lymphocytes
A meta-analysis of available randomized and non-randomized trials evaluating TIL with IL-2 in patients with cutaneous melanoma reported an ORR of 41%. Pooled 1-year OS rates ranged from 46.1% to 56.5% depending on the IL-2 dose level. Larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as a control arm showing treatment benefits are needed.

Dendritic Cells
Antigen-loaded autologous dendritic cells (ADCs) have been explored primarily in early-stage trials in various malignancies including lymphoma,²⁴ myeloma,^25,26 subcutaneous tumors,²⁷ melanoma,²⁸ NSCLC,^29,30 RCC,³¹ and cervical cancer.³² A systematic review by Tanyi and Chu (2012) highlighted progress in DC-based immunotherapy in epithelial ovarian cancer.³³

Clinical Context and Therapy Purpose
The purpose of DC is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with various malignancies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with various malignancies, including glioblastoma multiforme, NSCLC, medullary thyroid cancer (MTC), and pancreatic cancer.

Interventions
The therapy being considered is DC.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.
The version of the therapeutic is described.
Patient/sample clinical characteristics are described.
Patient/sample selection criteria are described.

Glioblastoma Multiforme
Review of Evidence
Systematic Reviews
Bregy et al. (2013) published a systematic review of observational studies of active immunotherapy using ADCs in the treatment of glioblastoma multiforme.³⁴ Twenty-one studies published through early 2013 were included in this review (N = 403 patients). Vaccination with DCs loaded with autologous tumor cells resulted in an increased median OS in patients with recurrent disease (72 to 138 weeks across 8 studies), as well as in those newly diagnosed (65 to 230 weeks across 11 studies) compared with an average survival of 58 weeks. Complications and safety of the vaccine were assessed in all studies. No study indicated any sign of an 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%).

Randomized Controlled Trials
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 ADC vaccine or temozolomide plus placebo.³⁵ The interim results reported on a blinded analysis of all patients because sufficient events of disease progression and/or death had not occurred yet. More than 90% of patients in the placebo arm received experimental treatment after documented progression. The blinded median OS of both treatment arms combined (23.1 months) in the RCT was compared with historical controls (15 to 17 months). These results are premature.

Subsection Summary: Glioblastoma Multiforme
A systematic review of observational studies has examined the role of ADC-based adoptive immunotherapy in glioblastoma multiforme. Because of the observational and noncomparative nature of the available evidence, the review was subject to publication and selection bias, which has the potential to lessen or amplify the true effect 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 1 such RCT have been published and are uninformative because patients were unblinded and results combined for treatment and placebo arms.

Non-Small-Cell Lung Cancer
Review of Evidence
Systematic Reviews
Chen et al. (2014) in China conducted a systematic review and meta-analysis of RCTs that compared combination DC plus CIK immunotherapy with any other treatment (placebo, no intervention, conventional treatment, or other complementary and alternative medicines) for any cancer type and stage.³⁶ Two RCTs compared DC plus CIK and chemotherapy with chemotherapy alone in patients with stage III or IV NSCLC and reported OS estimates (N = 150). Pooled relative risk favored DC plus CIK therapy at 2 years but not at 1 year (relative risk for 1-year OS = 1.38; 95% CI, 1.00 to 1.90; p = .05; I2 = 35%; relative risk for 2-year OS = 2.88; 95% CI, 1.38 to 5.99; p = .005; I2 = 0%).

The systematic review by Wang et al. (2014) (discussed previously) also included many studies that used DC in combination with CIK.²²

Randomized Controlled Trials
Shi et al. (2012) conducted an RCT at a university cancer center in China to evaluate the role of combination DC plus CIK immunotherapy as a maintenance treatment of advanced NSCLC.²⁹ From 2008 to 2010, 60 patients with stage IIIB or IV disease after treatment with 4 cycles of a platinum-based chemotherapy regimen were randomized into 2 groups. One group was treated with DC plus CIK cell therapy (n = 30), and the control group - no adoptive immunotherapy (n = 30). Outcome measures were PFS and adverse events of treatment. Progression-free survival was 3.2 months in the DC plus CIK group (95% CI, 2.9 to 3.5 months) versus 2.6 months in the control group (95% CI, 2.39 to 2.73 months; p < .05). No significant toxic reactions were observed in the DC plus CIK group, including bone marrow toxicity and gastrointestinal reactions. The findings of this small single-center RCT would indicate that combination immunotherapy with dendritic and CIK cells may offer a viable option as maintenance therapy for patients with advanced NSCLC.

Subsection Summary: Non-Small-Cell Lung Cancer
Two RCTs and a meta-analysis of these RCTs have evaluated the efficacy of DC plus CIK cells in NSCLC. The RCTs generally reported some benefits in response rates and/or survival. Results of a meta-analysis of these trials also reported a statistically significant reduction in the hazard of death. However, the effect was inconsistent. Most were from Asia and did not use the 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 methodological weaknesses. 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.

Medullary Thyroid Cancer
Review of Evidence
Observational Studies
In a phase 1 pilot study, Bachleitner-Hofman et al. (2009) reported on 10 patients with metastatic MTC treated with ADCs pulsed with allogeneic MTC tumor cell lysate.³⁷ At a 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 the efficacy of ADC therapy for MTC using allogeneic tumor lysate, an unlimited source of tumor material may be available for lysate preparation.

Subsection Summary: Medullary Thyroid Cancer
A small prospective noncomparative study in 10 MTC patients treated with ADCs has been published. There are no RCTs comparing DC-based adoptive immunotherapy with the standard of care and therefore no conclusions can be made. 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.

Pancreatic Cancer
Review of Evidence
Non-Randomized Controlled Trials
In a phase 1 study, Hirooka et al. (2009) assessed 5 patients with inoperable pancreatic cancer given 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.³⁸ One patient had a partial response, 2 had stable disease for more than 6 months, and 2 had disease progression. Toxicities included grade 1 anemia and grade 2 leukocytopenia, nausea, and constipation.

Subsection Summary: Pancreatic Cancer
A small prospective noncomparative study in 5 patients with pancreatic cancer treated with ADCs and the lymphokine-activated killer has been published. There are no RCTs comparing DC-based adoptive immunotherapy with the standard of care and therefore no conclusions can be made. 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.

Genetically Engineered T Cells
Engineered T-cell‒based antitumor immunotherapy uses gene transfer of tumor antigen-specific T-cell receptors (TCR) or synthetic chimeric antigen receptors. Review articles have highlighted recent progress in this field for solid and hematologic malignancies.^39,40,41

T-Cell Receptor Therapy
Clinical Context and Therapy Purpose
The purpose of autologous peripheral T lymphocytes containing tumor antigen-specific TCRs is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with cancer.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with cancer.

Interventions
The therapy being considered is autologous peripheral T lymphocytes containing tumor antigen-specific TCRs.

Comparators
Comparators of interest include standard of care.

Outcomes
The general outcomes of interest are OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
Studies with duplicative or overlapping populations were excluded.
The version of the therapeutic is described.
Patient/sample clinical characteristics are described.
Patient/sample selection criteria are described.

Review of Evidence
Observational Studies
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).⁴² 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 CR 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 in normal adult tissues (e.g., cancer-testes antigens).

Additional studies have examined TCR gene therapy in Hodgkin⁴³ and non-Hodgkin lymphoma,⁴⁴ prostate tumors,⁴⁵ and neuroblastoma.⁴⁶

Subsection Summary: T-Cell Receptor Therapy
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 benefits with genetically engineered T cells in patients with metastatic melanoma.

Summary of Evidence
Cytotoxic T Lymphocytes
For individuals with EBV-associated cancers who receive CTL, the evidence includes 2 small, prospective noncomparative cohort studies. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The cohort studies have shown a treatment response to infused CTL directed against cancer-associated viral antigens. To establish efficacy, the following are needed: large, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with Cytomegalovirus-associated cancers who receive CTL, the evidence includes a single case series. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. In the absence of an RCT comparing CTL with the standard of care, no conclusions can be made. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Cytotoxic-Induced Killer Cells
For individuals with nasopharyngeal carcinoma who receive CIK cells, the evidence includes a single RCT. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The RCT reported a numerically favorable but statistically insignificant effect on PFS and OS. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with RCC who receive CIK cells, the evidence includes multiple RCTs. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The largest of the RCTs reported statistically significant gains in PFS and OS 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 an inconsistent effect on survival. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with gastric cancer who receive CIK cells, the evidence includes 2 meta-analyses encompassing non-randomized trials. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Both meta-analyses reported statistically significant effects on OS, DFS, and PFS in favor of immunotherapy versus no 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with CRC who receive CIK cells, the evidence includes a single RCT and 1 meta-analysis. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Results of the RCT showed a statistically significant effect on OS in favor of immunotherapy versus chemotherapy alone. A meta-analysis that included both gastric cancer and CRC found improvements in OS and PFS in favor of CIK/DC-CIK compared to chemotherapy alone. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with HCC who receive CIK cells, the evidence includes meta-analyses that include RCTs and quasi-randomized trials. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Meta-analyses of these trials have reported improved OS rates when compared to conventional therapies alone, but they are limited by inclusion of studies from Asia only and heterogeneity in comparators. 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. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with NSCLC who receive CIK cells, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, DSS, QOL, 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 trials assessed in the systematic review were limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodological weaknesses. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Tumor-Infiltrating Lymphocytes
For individuals with melanoma who receive TILs, the evidence includes a meta-analysis of randomized and non-randomized trials. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The meta-analysis evaluating TIL with IL-2 in patients with cutaneous melanoma reported an ORR of 41%. Pooled 1-year OS rates ranged from 46.1% to 56.5% depending on the IL-2 dose level. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Dendritic Cells
For individuals with glioblastoma multiforme who receive DC, the evidence includes a systematic review of observational studies. Relevant outcomes are OS, DSS, QOL, 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 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 1 such RCT have been published but are not informative because the patients were unblinded and results were combined for the treatment and placebo arms. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with NSCLC who receive DC, the evidence includes 2 RCTs and a meta-analysis. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The RCTs have generally reported some benefits in response rates and/or survival. The meta-analysis of these trials also reported a statistically significant reduction in the hazard of death. Most trials were from Asia and did not use the 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 methodological weaknesses. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with MTC who receive DC, the evidence includes 1 prospective noncomparative study. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. A small prospective noncomparative study in 10 MTC patients treated with autologous DC has been published. There are no RCTs comparing DC-based adoptive immunotherapy with the standard of care and, therefore, no conclusions can be made. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Genetically Engineered T Cells
Peripheral T Lymphocytes
For individuals with cancers who receive autologous peripheral T lymphocytes containing tumor antigen-specific TCRs, the evidence includes multiple small observational studies. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Multiple observational studies have examined autologous peripheral T lymphocytes containing tumor antigen-specific TCRs in melanoma, Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma. Because of the noncomparative nature of the available evidence and small sample size, it is difficult to draw any meaningful conclusion. 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. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
Current guidelines from the National Comprehensive Cancer Network do not include recommendations for adoptive immunotherapy to treat cancers of the bladder,⁴⁷ central nervous system,⁴⁸ head and neck,⁴⁹ hepatobiliary system,⁵⁰ kidney,⁴⁸ pancreatic,⁵¹ stomach,⁵² thyroid,⁵³ melanoma,⁵⁴ or non-small-cell lung cancer.⁵⁵

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 9.

Table 9. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
Tumor-infiltrating lymphocytes
NCT01174121	A Phase II Study Using Short-Term Cultured, Autologous Tumor-Infiltrating Lymphocytes Following a Lymphodepleting Regimen in Metastatic Cancers Plus the Administration of Pembrolizumab	332	Dec 2024
NCT01319565	A Prospective Randomized Study of Cell Transfer 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 With 12Gy Total Body Irradiation (TBI)	102	Jun 2025
NCT02278887	Randomized Phase III Study Comparing a Non-myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Tumor-Infiltrating Lymphocytes and Interleukin-2 to Standard Ipilimumab Treatment in Metastatic Melanoma	168	Sep 2023
Autologous dendritic cells
NCT00338377^a	Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization in Patients With Metastatic Melanoma	1230	Feb 2030
NCT01204684	A Phase II Clinical Trial Evaluating Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen +/- Toll-like Receptor Agonists for the Treatment of Malignant Glioma	60	Jan 2025
Dendritic cells/cytokine-induced killer cells
NCT01691625^a	Concurrent Chemoradiation With or Without DC-CIK Immunotherapy in Treating Locally Advanced Esophageal Cancer	50	Dec 2021
NCT02487992	The Randomized, Controlled, Multicenter Clinical Trial of CIK Plus S-1 and Bevacizumab as Maintenance Treatment for Patients With Advanced Colorectal Cancer	1200	Jul 2045
Unpublished
Tumor-infiltrating lymphocytes
NCT01993719	A Phase II Study for Metastatic Melanoma Using High-Dose Chemotherapy Preparative Regimen Followed by Cell Transfer Therapy Using Tumor-Infiltrating Lymphocytes Plus IL-2 With the Administration of Pembrolizumab in the Retreatment Arm	33	Jul 2022

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

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Coding Section

Codes	Number	Description
CPT	36511	Therapeutic apheresis; for white blood cells
HCPCS	S2107	Adoptive immunotherapy, i.e., development of specific antitumor reactivity (e.g., tumor-infiltrating lymphocyte therapy) per course of treatment
ICD-10-CM	B97.32	Oncovirus as the cause of diseases classified elsewhere
	B25.9	Cytomegaloviral disease, unspecified
	C11.0-C11.9	Malignant neoplasm of the nasopharynx code range
	C16.0-C16.9	Malignant neoplasm of the stomach code range
	C18..0-C20	Colorectal neoplasm code range
	C22.0-C22.9	Malignant neoplasm of the liver code range
	C25.0-C25.9	Malignant neoplasm of the pancreas code range
	C34.90-C34.92	Non-small cell lung cancer code range
	C43.0-C43.9	Melanoma code range
	C64.1-C65.9	Malignant neoplasm of the kidney code range
	C71.9	Glioblastoma
	C73	Malignant neoplasm of thyroid gland
ICD-10-PCS	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/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

History From 2013 Forward

11/16/2023	Annual review, no change to policy intent.
11/16/2022	Annual review, no change to policy intent. Updating description, background, rationale and references
11/18/2021	Annual review, no change to policy intent. Adding brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vidleucel. Also updating rationale and references.
11/16/2020	Annual review, no change to policy intent.
11/03/2019	Annual review. Major rewrite of policy as language regarding hematologic malignancies is being relocated to a new CAM policy. Please see CAM 80163 Chimeric Antigen Receptor Therapy for Hematologic Malignancies. This policy will address all other uses of adoptive immunotherapy.
04/10/2019	Corrected a typographical error.
12/20/2018	Updating with 2019 codes.
12/06/2018	Annual review, medical necessity statement for Axicabtagene cileucel or tisangenlecleucel has been updated. Also updating decription, background, guidelines, rationale and references.
01/30/2018	Updating coding with Q2041. No change to policy intent.
01/11/2018	Interim review to add verbiage related to precertification requirement.
01/02/2018	Interim review, policy updated to include medical necessity criteria for axicabtagene ciloleucel. Also updating background, description, policy, guidelines, regulatory status, rationale and references.
12/04/2017	Returned to in progress from the proof reader. Policy being updated to include medical necessity criteria. Also updating background, description, regulatory status, guidelines, rationale, references and coding.
11/21/2017	Annual review, no change to policy intent.
11/01/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
11/04/2015	Annual review, cytotoxic T lymphocytes added as investigational. Updated background, description, rationale and references.
11/11/2014	Annual review, no change to policy intent. Updated rationale and references. Added coding.
11/07/2013	Updated Description, Policy verbiage, Rationale and References. Added Benefit Application section.

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Adoptive Immunotherapy - CAM 80101