Acute Lymphoblastic Leukemia

ALL is a malignancy (clonal) of the bone marrow in which the early lymphoid precursors of the white blood cells (called lymphoblasts) proliferate and replace the normal hematopoietic cells of the marrow. This results in overcrowding of the bone marrow, as well as the peripheral organs (particularly the liver, spleen, and lymph nodes) by the lymphoblasts. As a consequence, the leukemic blasts displace the normal hematopoietic bone marrow and cause cytopenias in all three cell lineages (anemia, thrombocytopenia, granulocytopenia). Leukostasis affecting brain and lung may also occur. Death occurs commonly due to severe pancytopenia and resulting infections. Refractory (resistant) disease is defined as those patients who fail to obtain a complete response with induction therapy, ie, failure to eradicate all detectable leukemia cells (<5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (>25% marrow cellularity and normal peripheral blood counts).Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of complete remission. Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. MRD positivity is defined as the presence of 0.01% or more ALL cells and has been shown to be a strongest prognostic factor to predict the risk of relapse and death when measured during and after induction therapy in both newly diagnosed and relapsed ALL. In a meta-analysis of 20 studies of 11249 pediatric ALL, Berry et al (2017) reported a hazard ratio for event-free survival in MRD-negative patients compared with MRD-positive patients of 0.23 (95% confidence interval, 0.18 to 0.28).^1,

Approximately 5000 cases of B-cell ALL are diagnosed every year in the United States,² and approximately 620 pediatric and young adult patients with B-cell ALL will relapse each year in the United States.^3, B-cell ALL is largely a disease of the young, with approximately 60% of cases occurring in patients younger than 20 years old with a median age at diagnosis of 15 years.^2,

Treatment

While treatable in 85% cases, approximately 15% of children and young adults with ALL will relapse and 2% to 3% of ALL patients are primary refractory.^4, Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate.^5, The 2-year survival rate among patients with ALL who relapse after hematopoietic cell transplantation is 15%.^6, The Food and Drug Administration (FDA) approved clofarabine (as a single agent or in combination) in 2004 and blinatumomab in 2014 for relapsed and refractory ALL. Reported median objective response rates in the pivotal trials of the 2 agents were 19.7% and 33%, the mediandurations of response were 2.5 months and 6 months, and median overall survival durations were 3 months and 7.5 months, respectively.^7,8, Note that the percentages of patients treated with 3 or more prior treatments of clofarabine and blinatumomab trial were 62% and 7%, respectively. Nevertheless, treatment options for patients with relapsed or refractory ALL are limited, associated with poor outcomes and high toxicity and the disease remains incurable.

Diffuse Large B-Cell Lymphoma

DLBCL is the most common histologic subtype of non-Hodgkin lymphoma and accounts for approximately 25% of non-Hodgkin lymphoma cases.^9, DLBCL exhibits large heterogeneity in morphologic, genetic, and clinical aspects and multiple clinicopathologic entities are defined by the 2016 World Health Organization classification, which are sufficiently distinct to be considered separate diagnostic categories. Teras et al (2016) has estimated that 27650 new cases of DLBCL were diagnosed in the United States in 2016.^10,

Treatment

Treatment in the first-line setting (particularly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is associated with a 5-year survival rate ranging from 60% to 70%.^11, However, based on a number of prognostic factors, 20% to 50% of DLBCL cases are refractory or relapse after first-line chemotherapy.^12,13, The response to subsequent salvage chemotherapy and consolidation with autologous cell transplantation is suboptimal. A retrospective analysis of the SCHOLAR-1 study by Crump et al (2017), which pooled data from 2, phase 3 clinical trials and 2 observational cohorts, included 636 patients with refractory DLBCL.^14, The objective response rate to the next line of therapy was 26%, with 7% achieving a complete response. Median overall survival was 6.3 months and 2-year survival 20%. Refractory DLBCL was defined as progressive disease or stable disease as best response at any point during chemotherapy (>4 cycles of first-line or 2 cycles of later-line therapy) or as relapse 12 or fewer months after autologous cell transplantation.

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. 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.^15,

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, two 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.”^16, Protocols vary, but include these common steps:

1.     lymphocyte harvesting (either from peripheral blood or from tumor biopsy)

2.     propagation of tumor-specific lymphocytes in vitro using various immune modulators

3.     selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay

4.     lymphodepletion of the host with immunosuppressive agents

5.     adoptive transfer (ie, transfusion) of lymphocytes back into the tumor-bearing host.

DC-based immunotherapy uses autologous DC (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigensin vivo. ADCs harvested from the patient are either pulsed with antigen or transfected with a viral vector bearing a common cancer antigen. The activated ADCs are then 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 policy on 'Sipuleucel-T (Provenge®) - Policy #078 in the Drugs Section 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 policy 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.

Regulatory Status

On August 30, 2017, tisagenlecleucel (Kymriah™; Novartis) was approved by the FDA 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 FDA 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 October 18, 2017, axicabtagene ciloleucel (Yescarta™; Kite Pharma) was approved by the FDA 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.

Related Policies

• Sipuleucel-T (Provenge®) (Policy #078 in the Drugs Section)
• Tisagenlecleucel (Kymriah) (Policy #158 in the Drugs Section)
• Axicabtagene Ciloleucel (Yescarta) (Policy #164 in the Drugs Section)

Medicare Coverage:
There is no National Coverage Determination (NCD) specific to Adoptive immunotherapy. Per National Coverage Determination (NCD) for Autologous Cellular Immunotherapy Treatment 110.22, CMS has determined that autologous cellular immunotherapy treatment - sipuleucel-T; PROVENGE® will be covered for individuals with asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancer.

For additional information and eligibility, refer to National Coverage Determination (NCD) for Autologous Cellular Immunotherapy Treatment 110.22. Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx

Per NCD 110.22, coverage of all off-label uses of autologous cellular immunotherapy treatment – sipuleucel-T; PROVENGE® for the treatment of prostate cancer is left to the discretion of the local Medicare Administrative Contractors. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not announced a position on off-label uses of autologous cellular immunotherapy treatment – sipuleucel-T; PROVENGE® for the treatment of prostate cancer.

Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE-SNP Coverage:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2010 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through October 29, 2018.

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, and ability to function¾including 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^19, and postoperative hepatocellular carcinoma.^20,21,

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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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), quality of life (QOL), treatment-related mortality, and treatment-related morbidity.

Timing

Though not completely standardized, follow-up for EBV-associated cancers symptoms would typically occur in the months after starting treatment.

Setting

Patients with EBV-associated cancers are actively managed by oncologists in an outpatient clinical setting.

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.

Bollard et al (2014) conducted an international prospective cohort study of CTL therapy in patients with EBV‒positive Hodgkin or non-Hodgkin lymphoma.^22, 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.^23, 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 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.^24,

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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Though not completely standardized, follow-up for Cytomegalovirus-associated cancers symptoms would typically occur in the months after starting treatment.

Setting

Patients with Cytomegalovirus-associated cancers are actively managed by oncologists in an outpatient clinical setting.

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.

Schuessler et al (2014) administered CTLs with or without chemotherapy to 13 patients with recurrent glioblastoma multiforme.^25, 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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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, DSS, treatment-related mortality, and treatment-related morbidity.

Timing

Though not completely standardized, follow-up for nasopharyngeal carcinoma symptoms would typically occur in the months after starting treatment.

Setting

Patients with nasopharyngeal carcinoma are actively managed by oncologists in an outpatient clinical setting.

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.

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.^26, 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 regimen chemotherapy may be a viable treatment option for patients with advanced nasopharyngeal carcinoma.

Subsection Summary: Nasopharyngeal Carcinoma

A single RCT from China reported the 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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Follow-up at 44 months is of interest for CIK cells to monitor relevant outcomes.

Setting

Patients with RCC are actively managed by oncologists in an outpatient clinical setting.

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.

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.^27, 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.^28, 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.^29, 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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Though not completely standardized, follow-up for GC symptoms would typically occur in the months after starting treatment.

Setting

Patients with GC are actively managed by oncologists in an outpatient clinical setting.

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.

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.^30,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.^31, 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 the 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 by a 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. 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.

Subsection Summary: GC

A single nonrandomized prospective study from China, as well as one meta-analysis, has 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 cytotoxic-induced killer 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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Though not completely standardized, follow-up for CRC symptoms would typically occur in the months after starting treatment.

Setting

Patients with CRC are actively managed by oncologists in an outpatient clinical setting.

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.

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).^32, 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.^33,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 question addressed in this policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Follow-up at 19 months is of interest for CIK cells to monitor relevant outcomes.

Setting

Patients with HCC are actively managed by oncologists in an outpatient clinical setting.

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.

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).^34, 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 significantreduction 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.^35, 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, 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. Grade 3 or 4 adverse events were not observed. A nonrandomized study from China by Cui et al (2014) reported improved PFS in 30 patients who received radiofrequency ablation plus CIK/natural killer cell/gamma delta T-cell (a type of tumor-infiltrating lymphocytes [TIL]) infusion (median PFS, not reached) compared with 32 patients who received radiofrequency ablation alone (median PFS, 12.0 months).^36,

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.^37, 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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Though not completely standardized, follow-up for NSCLC symptoms would typically occur in the months after starting treatment.

Setting

Patients with NSCLC are actively managed by oncologists in an outpatient clinical setting.

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 lonr-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.

Wang et al (2014) conducted a systematic review of RCTs of CIK cells for the treatment of NSCLC.^38, 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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Follow-up at 31 and 62 months is of interest for TIL to monitor relevant outcomes.

Setting

Patients with melanoma are actively managed by dermatologists in an outpatient clinical setting.

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.

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.^39, 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 (ORRs) 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.^40, 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 completeregression for longer than 3 years. Actutimes 3- and 5-year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders, 100% and 93%, respectively. Likelihood of achieving a CR was similar regardless of prior therapy.

Dreno et al (2002) conducted an RCT of 88 patients with malignant melanoma without detectable metastases who were randomized to TIL plus IL-2 or to IL-2 alone.^41, 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.^42, 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 use of an appropriate standard of care as control arm showing treatment benefit 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,^43, myeloma,^44,45, subcutaneous tumors,^46, melanoma,^47, NSCLC,^48,49, RCC,^50, and cervical cancer.^51, A systematic review by Tanyi and Chu (2012) highlighted progress in DC-based immunotherapy in epithelial ovarian cancer.^52,

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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Though not completely standardized, follow-up for glioblastoma multiforme symptoms would typically occur in the months after starting treatment.

Setting

Patients with glioblastoma multiforme are actively managed by oncologists in an outpatient clinical setting.

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.

Bregy et al (2013) published a systematic review of observational studies of active immunotherapy using ADCs in the treatment of glioblastoma multiforme.^53, 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 an 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 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.^54, 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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Though not completely standardized, follow-up for NSCLC symptoms would typically occur in the months after starting treatment.

Setting

Patients with NSCLC are actively managed by oncologists in an outpatient clinical setting.

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.

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.^48,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.^55, 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.^38,

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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Follow-up at 11 months is of interest for DC to monitor relevant outcomes.

Setting

Patients with MTC are actively managed by oncologists in an outpatient clinical setting.

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.

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.^56, 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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Though not completely standardized, follow-up for pancreatic cancer symptoms would typically occur in the months after starting treatment.

Setting

Patients with pancreatic cancer are actively managed by oncologists in an outpatient clinical setting.

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.

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.^57, 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 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.^58,59,60,

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 policy is: does the use of adoptive immunotherapy in patients with various malignancies improve the net health outcome?

The following PICOTS 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.

Timing

Though not completely standardized, follow-up for cancer symptoms would typically occur in the monthsafter starting treatment.

Setting

Patients with cancer are actively managed by oncologists in an outpatient clinical setting.

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.

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).^61, 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 on normal adult tissues (eg, cancer-testes antigens).

Additional studies have examined TCR gene therapy in Hodgkin^62, and non-Hodgkin lymphoma,^63, prostate tumors,^64, and neuroblastoma.^65,

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 benefit 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 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 NSCLCwho 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 NSCLCwho 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.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

Current guidelines from the National Comprehensive Cancer Network do not include recommendations for adoptive immunotherapy to treat cancers of the bladder,^74, central nervous system,^75, head and neck,^76, hepatobiliary system,^77, kidney,^78, pancreatic,^79, stomach,^80, or thyroid,^81, melanoma,^82, Hodgkin lymphoma,^83, or non-small-cell lung cancer.^84,

Current National Comprehensive Cancer Network guidelines for acute lymphoblastic leukemia recommend (category 2A) tisagenlecleucel as a treatment option for^85,:

·         Philadelphia chromosome-positive patients 26 years or less in age with refractory disease or 2 or more relapses and failure of 2 tyrosine kinase inhibitors.

·         Philadelphia chromosome-negative patients 26 years or less in age with refractory disease or 2 or more relapses.

Current Network guidelines for B-cell lymphomas recommend (category 2A) axicabtagene ciloleucel or tisagenlecleucel as a treatment option^86,

·         For histological transformation to diffuse large B-cell lymphoma after multiple lines of prior therapies which include ≥2 chemo-immunotherapy regimens for the indolent or transformed disease.

·         For relapsed or refractory disease diffuse large B-cell lymphoma after multiple lines of prior therapies which include ≥2 chemo-immunotherapy regimens for the indolent or transformed disease.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently 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
Cytotoxic-induced killer cells
NCT02118415	Targeted Natural Killer (NK) Cell Based Adoptive Immunotherapy for the Treatment of Patients With Non-Small Cell Lung Cancer (NSCLC) After Radiochemotherapy (RCT)	90	Feb 2018 (ongoing)
NCT02229266	Randomised Controlled Phase-2 Trial to Determine the Efficacy of Adoptive Immunotherapy With NK Cells in High-risk AML (HINKL)	56	Sep 2020
Tumor-infiltrating lymphocytes
NCT01993719	A Phase II Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Comparing Two Different Chemotherapy Preparative Regimens	64	Sep 2029
NCT01966289	A Pilot Study of SGI-110 in Combination With an Allogeneic Colon Cancer Cell Vaccine (GVAX) and Cyclophosphamide (CY) in Metastatic Colorectal Cancer (mCRC) as Maintenance Therapy	18	Dec 2019
NCT01319565	Prospective Randomized Study of Cell Therapy for Metastatic Melanoma Using Short-Term Cultured Tumor Infiltrating Lymphocytes Plus IL-2 Following Either a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Alone or in Conjunction w/1200 TBI	102	Jun 2020
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 2020
Autologous dendritic cells
NCT00338377a	Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization	189	Feb 2019
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	Oct 2019
Dendritic cells/cytokine-induced killer cells
NCT01691625a	Concurrent Chemoradiation With or Without DC-CIK Immunotherapy in Treating Locally Advanced Esophageal Cancer	50	Sep 2019

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

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Adoptive Immunotherapy
Immunotherapy, Adoptive
Adoptive Cellular Therapy

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77. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: hepatobiliary cancers. Version 2.2018.http://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed June 19, 2018.

78. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: kidney cancer. Version 4.2018.https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed June 19, 2018.

79. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: pancreatic adenocarcinoma. Version 1.2018.http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed June 19, 2018.

80. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: gastric cancer.Version 2.2018.http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed June 19, 2018.

81. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: thyroid carcinoma. Version 1.2018.http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Accessed June 19, 2018.

82. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: melanoma. Version 2.2018.https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed June 19, 2018.

83. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Hodgkin lymphoma. Version 3.2018.http://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed June 19, 2018.

84. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Version 4.2018.http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed June 19, 2018.

85. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: acute lymphoblastic leukemia. Version 1.2018.https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed June 19, 2018.

86. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: B-Cell lymphomas. Version 4.2018.https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed June 19, 2018.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

S2107