Coverage Policy Manual
Policy #: 2020001
Category: Pharmacy
Initiated: January 2020
Last Review: November 2023
  Adoptive Immunotherapy
Description:
The spontaneous regression of certain cancers (e.g., renal cell carcinoma, melanoma) supports the idea that an individual’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 an individual’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 individual, processed for some period of time, and then infused back into the individual.
 
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 (Singh, 2020). The incidence of hepatocellular carcinoma was twice as high for US-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 US-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 (NCI, 2022). 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 included 158,445 individuals with localized kidney cancer from the National Cancer Database between 2010 and 2017 (Howard, 2021). Investigators found that that female individuals were treated more aggressively compared with male individuals, with lower adjusted odds of undertreatment and higher adjusted odds of overtreatment. They also found that Black and Hispanic individuals had higher adjusted odds of undertreatment and overtreatment compared to White individuals, 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 individuals.
 
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-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 interleukin-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.
 
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 individuals. In current trials, two methods are studied: adoptive cellular therapy and antigen-loaded DC infusions.
 
Adoptive cellular therapy is “the administration of an individual’s own (autologous) or donor (allogeneic) antitumor 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 (i.e., transfusion) of lymphocytes back into the tumor-bearing host.
 
DC-based immunotherapy uses autologous DC (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigensin vivo. ADCs harvested from the individual is either pulsed with antigen or transfected with a viral vector bearing a common cancer antigen. The activated ADCs are then re-transfused into the individual, 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 (eg, IL-7 and IL-15 instead of interleukin-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 for specific cancers in individual policies related to cell transplantation.
 
Policy/
Coverage:
Effective January 2020
 
Adoptive immunity in the form of chimeric antigen receptor T-cell therapy (e.g., tisagenlecleucel, axicabtagene ciloleucel) for hematologic malignancies is discussed in policy number 1998109 Chimeric Antigen Receptor Therapy for Hematologic Malignancies.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Adoptive immunotherapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, adoptive immunotherapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
 
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, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one 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. RCTs 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 has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when RCTs show efficacy. Selected studies include only new RCTs.
 
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 T Lymphocytes
 
Epstein-Barr Virus‒Associated Cancers
 
Clinical Context and Therapy Purpose
 
The purpose of CTL is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with EBV-associated cancers.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with EBV-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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
Bollard et al (2014) conducted an international prospective cohort study of CTL therapy in patients with 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 (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. 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 three 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 survey although definitions of response were unclear.
 
Subsection Summary: EBV‒Associated Cancers
Two small, prospective noncomparative cohort studies in patients with the 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
 
Clinical Context and Therapy Purpose
The purpose of CTL is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with Cytomegalovirus-associated cancers.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with 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 OS, DSS, QOL, treatment-related mortality, and treatment-related morbidity.
 
Study Selection Criteria
Methodologically credible studies were selected using the following principles:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
Schuessler et al (2014) administered CTLs with or without chemotherapy to 13 patients with recurrent glioblastoma multiforme. CTLs with activity against Cytomegaloviruswere 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 CTL 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
 
Nasopharyngeal Carcinoma
 
Clinical Context and Therapy Purpose
The purpose of CIK cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with nasopharyngeal carcinoma.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with nasopharyngeal carcinoma.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
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. 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 suggests that the combination of CIK cells and GC regime
 
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 methodologic 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
 
Clinical Context and Therapy Purpose
The purpose of CIK cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with RCC.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with RCC.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
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. From 2005 to 2008, 148 patients were randomized to autologous CIK cell immunotherapy (arm 1, n=74) or interleukin-2 (IL-2) treatment 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, vs 12% and 23%, respectively, in arm 2 (p=0.031 and p<0.001, respectively). Median PFS and OS in arm 1 were significantly longer than those in arm 2 (PFS, 12 months vs 8 months, p=0.024; OS, 46 months vs 19 months, p<0.001), 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<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 that assessed 20 patients who had unilateral, locally advanced RCC 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% in the CIK group and vs 50% the control group; 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 three 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. 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 longer in the CIK group (p=0.021). Among the 62 inoperable patients, OS was longer in the CIK group (p=0.012). No severe adverse reactions were observed.
 
Subsection Summary: RCC
Three RCTs from China have evaluated the efficacy of CIK cell immunotherapy in RCC. The largest of the three 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 two 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
 
Clinical Context and Therapy Purpose
The purpose of CIK cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with GC.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with GC.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
Shi et al (2012) 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 GC. 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.
 
Wang et al (2018) published the results of their systematic review and meta-analysis of CIK cell/dendritic cell-cytokine-induced killer (DC-CIK) cell immunotherapy for the postoperative treatment of GC. The study assessed the effect of CIK/DC-CIK treatment for GC after surgery. In total, 9 trials that included 1216 patients were eligible for inclusion in the meta-analysis. Compared with the control group, the HR for OS was 0.712 (95% CI 0.594-0.854) and 0.66 (95% CI 0.546-0.797) for overall DFS. The risk ratio of the 3 and 5-year OS rate was 1.29 (95% CI 1.15-1.46) and 1.73 (95% CI 1.36-2.19), respectively. The risk ratio for the 3- and 5-year DFS rate was 1.40 (95% CI 1.19-1.65) and 2.10 (95% CI1.53-2.87), respectively. The proportion of patients who were CD3+, CD4+, and CD4+/CD8+ increased in cellular therapy groups. 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 bysi
 
Subsection Summary: GC
A single nonrandomized prospective study from China, as well as one meta-analysis, have reported statistically significant effects on DFS and OS in favor of immunotherapy with autologous CIK vs 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.
 
Colorectal Cancer
 
Clinical Context and Therapy Purpose
The purpose of CIK cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with CRC.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with CRC.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
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). 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<0.001). The 3-year OS rates for both groups were 48% and 23%, respectively (p<0.001).
 
Subsection Summary: CRC
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 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
 
Clinical Context and Therapy Purpose
The purpose of CIK cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with HCC.
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with HCC.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
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 a meta-analysis reported a statistically 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 HCC. 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, favoring CIK therapy. 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, the three-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.
 
Lee et al (2015) conducted an RCT in Korea of 230 patients being treated for HCC 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 endpoint was recurrence-free survival; secondary endpoints 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.
 
Subsection Summary: HCC
Several RCTs and quasi-RCTs have evaluated the efficacy of CIK cells in HCC. These studies have 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 by 41%, but there was considerable heterogeneity among the included studies. 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 methodologic 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
 
Clinical Context and Therapy Purpose
The purpose of CIK cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with NSCLC.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with 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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
Wang et al (2014) conducted a systematic review of RCTs of CIK cells for the treatment of 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 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: NSCLC
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 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 TIL is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with melanoma.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are 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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
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 nonmyeloablative 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 a 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 nonmyeloablative, 200-cGy, and 1200-cGy groups, respectively). Of these 20 patients (22% of the original cohort), 19 (95%) had ongoing complete regression for long
 
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.
 
Section Summary: TIL
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 most of the patients who achieved CR were observed beyond three years. Toxicities appeared primarily associated with the myeloablative regimen. 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 to establish.
 
Dendritic Cells
Antigen-loaded autologous dendritic cells (ADCs) have been explored primarily in early-stage trials in various malignancies including lymphoma, myeloma, subcutaneous tumors, melanoma, NSCLC, RCC, and cervical cancer. A systematic review by Tanyi and Chu (2012) highlighted progress in DC-based immunotherapy in epithelial ovarian cancer.
 
Glioblastoma Multiforme
 
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 glioblastoma multiforme.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with glioblastoma multiforme.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
Bregy et al (2013) 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 DCs loaded with autologous tumor cells resulted in increased median OSin 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 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%).
 
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. 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 (15-17 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 one 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
 
Clinical Context and Therapy Purpose
The purpose of dendritic cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with NSCLC.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with NSCLC.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
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. 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. PFS was 3.2 months in the DC plus 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 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.
 
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. Two RCTs compared DC plus CIK and chemotherapy with chemotherapy alone in patients with stage III or IV NSCLC and reported OS estimates (total 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=0.05; I2=35%; relative risk for 2-year OS=2.88; 95% CI, 1.38 to 5.99; p=0.005; I2=0%).
 
The systematic review by Wang et al (2014) (discussed previously) also included many studies that used DC in combination with CIK.
 
Subsection Summary: NSCLC
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 methodologic 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
 
Clinical Context and Therapy Purpose
The purpose of dendritic cells is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with MTC.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with MTC.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
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. 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: MTC
A small prospective noncomparative study in ten 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
 
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 pancreatic cancer.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with 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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
In a phase 1 study, Hirooka et al (2009) assessed 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 six months, and two 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 five 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.
 
TCR Therapy
 
Clinical Context and Therapy Purpose
The purpose of autologous peripheral T lymphocytes containing tumor antigen-specific TCR is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with cancer.
 
The question addressed in this evidence review is: Does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?
 
The following PICOs were used to select literature to inform this review.
 
Patients
The relevant population of interest are individuals with cancer.
 
Interventions
The therapy being considered is autologous peripheral T lymphocytes containing tumor antigen-specific TCR.
 
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:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
e. The version of the therapeutic is described.
f. Patient/sample clinical characteristics are described.
g. Patient/sample selection criteria are described.
 
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). 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 (eg, 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 Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma.
 
Subsection Summary: TCR 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 two small, prospective noncomparative cohort studies. The 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 the effects of the technology on health outcomes.
 
For individuals with Cytomegalovirus-associated cancers who receive CTL, the evidence includes a single case series. The 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 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. The 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 the effects of the technology on health outcomes.
 
For individuals with RCC who receive CIK cells, the evidence includes multiple RCTs. The 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 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 two 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 the effects of the technology on health outcomes.
 
For individuals with GC who receive CIK cells, the evidence includes a single nonrandomized prospective study and one systematic review and meta-analysis. The relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The prospective cohort study reported statistically significant effects on DFS and OS in favor of immunotherapy vs 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 the effects of the technology on health outcomes.
 
For individuals with CRC who receive CIK cells, the evidence includes a single RCT and one cohort study. The 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 vs 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 the effects of the technology on health outcomes.
 
For individuals with HCC who receive CIK cells, the evidence includes several RCTs. The relevant outcomes are OS, DSS, QOL, 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 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 the effects of the technology on health outcomes.
 
For individuals with NSCLC who receive CIK cells, the evidence includes multiple RCTs and a systematic review. The 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 methodologic 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 the effects of the technology on health outcomes.
 
Tumor-Infiltrating Lymphocytes
For individuals with melanoma who receive TIL, the evidence includes a single RCT. The relevant outcomes are OS, DSS, QOL, 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 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 the effects of the technology on health outcomes.
 
Dendritic Cells
For individuals with glioblastoma multiforme who receive DC, the evidence includes a systematic review of observational studies. The 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 one 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 the effects of the technology on health outcomes.
 
For individuals with NSCLC who receive DC, the evidence includes two RCTs and a meta-analysis. The 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 methodologic 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 the effects of the technology on health outcomes.
 
For individuals with MTC who receive DC, the evidence includes one prospective noncomparative study. The relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. A small prospective noncomparative study in ten MTC patients treated with ADC 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 the effects of the technology on health outcomes.
 
For individuals with pancreatic cancer who receive DC, the evidence includes a small prospective noncomparative study. The relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The study reported on treatment outcomes for five 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 the effects of the technology on health outcomes.
 
Genetically Engineered T Cells
 
Peripheral T Lymphocytes
For individuals with cancers who receive autologous peripheral T lymphocytes containing tumor antigen-specific TCR, the evidence includes multiple small observational studies. The 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 TCR in melanoma, Hodgkin and NHL, 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 the effects of the technology on health outcomes.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
36511Therapeutic apheresis; for white blood cells
S2107Adoptive immunotherapy i.e. development of specific anti tumor reactivity (e.g., tumor infiltrating lymphocyte therapy) per course of treatment
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