Adoptive Immunotherapy

 Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts)  Are up to 25 years old at the time of infusion  Have not received prior treatment with tisagenlecleucel or any other gene therapy or are being considered for treatment with any other gene therapy  Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis  Do not have any of the following: o Burkitt lymphoma o Active hepatitis B, C, or any uncontrolled infection o Grade 2 to 4 graft-versus-host disease o Concomitant genetic syndrome with the exception of Down syndrome o Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to tisagenlecleucel infusion o Patient has active central nervous system 3 acute lymphoblastic leukemia (ie, white blood cell count ≥5 cells/μL in cerebrospinal fluid with presence of lymphoblasts).


Services Are Considered Investigational
Coverage is not available for investigational medical treatments or procedures, drugs, devices or biological products.
Based on review of available data, the Company considers all adoptive immunotherapy techniques intended to enhance autoimmune effects for the indications including, but not limited to, cancers associated with Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), nasopharyngeal cancer, renal cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC), melanoma, glioblastoma multiforme, medullary thyroid cancer, pancreatic cancer, and cancers treated with autologous peripheral T lymphocytes containing tumor antigen-specific T cell receptors to be investigational.*

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

Cellular Therapy and Dendritic Cell Infusions
The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing patients.In current trials, 2 methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions.
Adoptive cellular therapy is "the administration of a patient's own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lymphodepleting preparative regimen."Protocols vary, but include these common steps: 1.
Lymphocyte harvesting (either from peripheral blood or from tumor biopsy) 2.
Propagation of tumor-specific lymphocytes in vitro using various immune modulators 3.
Selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay 4.
Lymphodepletion of the host with immunosuppressive agents 5.
Adoptive transfer (ie, transfusion) of lymphocytes back into the tumor-bearing host Dendritic cell-based immunotherapy uses autologous dendritic cells (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigens in vivo.ADCs harvested from the patient are either pulsed with antigen or transfected with a viral vector bearing a common cancer antigen.The activated ADCs are then retransfused into the patient, where they present antigen to effector lymphocytes (CD4-positive T-cells, CD8-positive T-cells, and in some cases, B cells).This initiates a cytotoxic response against the antigen and against any cell expressing the antigen.In cancer immunotherapy, ADCs are pulsed with tumor antigens; effector lymphocytes then mount a cytotoxic response against tumor cells expressing these antigens.
In an attempt to regulate the host immune system further, recent protocols use various cytokines (eg, IL-7 and IL-15 instead of IL-2) to propagate lymphocytes.Protocols also differ in the extent of host lymphodepletion induced prior to transfusing lymphocytes to the tumor-bearing host.
Note: Allogeneic cell transplantation following nonmyeloablative conditioning of the recipient (known as reduced-intensity conditioning) also may be referred to as "adoptive immunotherapy" in the literature.However, reduced-intensity conditioning cell transplantation relies on a donor-vsmalignancy effect of donor lymphocytes.In contrast, the adoptive immunotherapy techniques described in this evidence review enhance autoimmune effects primarily.The use of reducedintensity conditioning in cell transplantation is discussed for specific cancers in individual policies related to cell transplantation.

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

Rationale/Source
This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. Food and Drug Administration approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.
Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when randomized controlled trials show efficacy.The selected studies included only new randomized controlled trials.

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
Bollard et al (2014) conducted an international prospective cohort study of cytotoxic T lymphocytes (CTL) therapy in patients with Epstein-Barr virus (EBV)-positive Hodgkin or non-Hodgkin lymphoma.Patients had either active, relapsed disease (n=21) or were in remission with a high risk of relapse (n=29).CTLs with activity against EBV antigens were generated by incubating peripheral blood monocytes with EBV antigen-infected dendritic cells (DCs).Eleven (52%) of 21 patients with active disease achieved complete response (CR), and 2 (10%) patients achieved partial response; 2year event-free survival in this cohort was approximately 50%.Twenty-seven (93%) of 29 patients in remission achieved CR; 2-year event-free survival was 82%.Immediate or delayed toxicity related to CTL infusion was not observed.
Chia et al (2014) studied 35 patients with EBV-positive nasopharyngeal cancer at a single center in China.Patients received standard chemotherapy with gemcitabine and carboplatin followed by EBV-specific CTL infusion.Median progression-free survival (PFS) and overall survival (OS) were 8 months and 30 months, respectively.One-, 2-, and 3-year OS rates were 77%, 63%, and 37%, respectively.In comparison, median OS in a group of similar historical controls treated at the same institution with chemotherapy only was 18 to 21 months, and 2-and 3-year OS rates were 30% to 43% and 16% to 25%, respectively.The most common adverse events associated with CTL infusion were grade 1 and 2 fatigue and grade 1 myalgia.Two patients developed transient fever, and 3 patients developed grade 1 skin rash.Grade 3 or higher hematologic or nonhematologic toxicities were not observed during CTL therapy.In a 2014 Japanese series of 7 patients who received CTLs for advanced oral and maxillofacial cancers, 1-year survival in patients who achieved response (n=3) and in those with progressive disease (n=4) were 100% and 25%, respectively, although definitions of response were unclear.

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

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

Subsection Summary: Cytomegalovirus-Associated Cancers
A single case series in 13 patients with glioblastoma multiforme treated with CTL has been published.Adverse events were mild.There are no RCTs comparing CTL with standard of care and therefore no conclusions can be made about the efficacy of CTL in Cytomegalovirus-associated cancers.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

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

Gastric Cancer
In 2012, Shi et al in China published a nonrandomized, comparative study to determine the longterm efficacy of adjuvant immunotherapy with autologous CIK cells in 151 patients with locally advanced gastric cancer.Five-year OS and 5-year DFS rates for immunotherapy vs no immunotherapy (control group) were 32% vs 23% (p=0.07) and 28% vs 10% (p=0.04),respectively.For patients with intestinal-type tumors, 5-year OS (47% vs 31%; p=0.045) and DFS (42% vs 16%; p=0.02) rates were significantly higher for immunotherapy.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

Subsection Summary: Gastric Cancer
randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

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

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

Hepatocellular Carcinoma
Cai et al (2017) reported the results of a meta-analysis of 9 RCTs and 3 quasi-RCTs that compared outcomes of conventional treatments plus sequential CIKs with conventional treatments alone (total N=1387 patients).None of the 12 studies were rated as low risk of bias in all 7 domains as assessed by the Cochrane risk of bias tool.Of the 12 RCTs and quasi-RCTs, 5 reported a statistically significant favorable survival benefit for patients receiving conventional treatments plus sequential CIKs.All 12 studies were from Asia (1 Japan, 1 Korea, 10 China).Results of meta-analysis reported a statistical significant reduction in the hazard of death by 41% (HR=0.59;95% CI, 0.46 to 0.77; p<0.005).However, the heterogeneity among the included studies was statistically significant (p=0.03,I 2 =48).No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

Subsection Summary: Non-Small-Cell Lung Cancer
A single systematic review of RCTs of CIK cells for the treatment of NSCLC that included trials conducted in China reported some benefits in median time to progression and median survival time.
The included body of evidence trials in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

TUMOR-INFILTRATING LYMPHOCYTES
original cohort), 19 (95%) had ongoing complete regression longer than 3 years.Actuarial 3-and 5year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders, 100% and 93%, respectively.Likelihood of achieving a CR was similar regardless of prior therapy.
Dreno et al ( 2002) conducted an RCT of 88 patients with malignant melanoma without detectable metastases who were randomized to TIL plus IL-2 or to IL-2 alone.There was no significant difference in the duration of relapse-free interval or OS.Figlin et al (1999) randomized 178 patients with metastatic renal cell carcinoma or resectable renal tumors to adjuvant continuous low-dose IL-2 therapy, with or without additional TIL.TILs were harvested from surgical specimens.Outcomes were similar in both groups and, for this reason, the trial was terminated early.

Subsection Summary: Melanoma
One small RCT compared TILs plus IL-2 with IL-2 alone in patients with nonmetastatic melanoma and reported no difference between treatment groups in relapse or survival outcomes.Cohort studies in patients with refractory metastatic melanoma demonstrated response rates of 49% and 52% to 72% with TIL plus nonmyeloablative or myeloablative regimens, respectively.Durable responses in the majority of patients who achieved CR were observed beyond 3 years.Toxicities appeared primarily associated with myeloablative regimen.Larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and use of appropriate standard of care as control arm showing treatment benefit are needed to establish.

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

Glioblastoma Multiforme
In No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

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 is subject to publication and selection bias, which has the potential to lessen or amplify the true potential of adoptive immunotherapy.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

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

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

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

Subsection Summary: Medullary Thyroid Cancer
A small prospective noncomparative study in 10 MTC patients with treated with ADCs has been published.There are no RCTs comparing DC-based adoptive immunotherapy with standard of care and therefore no conclusions can be made.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

Pancreatic Cancer
A 2009 phase 1 study of 5 patients with inoperable pancreatic cancer reinfused ADCs and lymphokine-activated killer cells with gemcitabine; antigen priming of the ADCs was presumed to occur in vivo from apoptosis of gemcitabine-exposed tumor cells.One patient had a partial response, two had stable disease for more than 6 months, and 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 5 patients with pancreatic cancer treated with ADCs and lymphokine-activated killer has been published.There are no RCTs comparing DC-based adoptive immunotherapy with standard of care and therefore no conclusions can be made.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight and the use of an appropriate standard of care as the control arm showing treatment benefit.

GENETICALLY ENGINEERED T CELLS
Engineered T cell-based antitumor immunotherapy uses gene transfer of tumor antigen-specific Tcell receptors (TCR) or synthetic chimeric antigen receptors.Review articles have highlighted recent progress in this field for solid and hematologic malignancies.

TCR Therapy
In a phase 2 study, Johnson et al (2009) transfected autologous peripheral lymphocytes of 36 patients who had metastatic melanoma with genes encoding TCRs highly reactive to melanoma/melanocyte antigens (MART-1:27-35 and gp100:154-162).Nine (25%) patients experienced an objective response; 8 patients had a partial response lasting 3 months to more than 17 months; and 1 patient (in the gp100 group) had a complete response lasting more than 14 months.Treatment toxicities included erythematous rash, anterior uveitis, hearing loss, and dizziness, suggesting that these were attributable to recognition by the genetically modified lymphocytes of normally quiescent cells expressing the targeted cancer antigens; melanocytic cells exist in the skin, eye, and the inner ear.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.

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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 benefit with genetically engineered T cells in patients with metastatic melanoma.

SUMMARY OF EVIDENCE Cytotoxic T Lymphocytes
For individuals with Epstein-Barr virus−associated cancers who receive cytotoxic T lymphocytes, the evidence includes 2 small, prospective noncomparative cohort studies.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.The cohort studies have shown a treatment response to infused cytotoxic T lymphocytes directed against cancer-associated viral antigens.To establish efficacy, the following is needed: large, well-conducted, 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 cytotoxic T lymphocytes, the evidence includes a single case series.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.In the absence of an RCT comparing cytotoxic T lymphocytes with standard of care, no conclusions can be made.To establish efficacy, the following is needed: larger, well-conducted, 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.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.The RCT reported a numerically favorable but statistically insignificant effect on progression-free survival and overall survival.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.
efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with renal cell carcinoma who receive CIK cells, the evidence includes multiple RCTs.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.The largest of the RCTs reported statistically significant gains in progression-free survival and overall survival with CIK cell−based immunotherapy compared with interleukin-2 plus interferon-α-2.This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator.The other 2 RCTs have also reported response rates in favor of CIK therapy with inconsistent effect on survival.To establish efficacy, the following is needed: larger, well-conducted, 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 gastric cancer who receive CIK cells, the evidence includes a single nonrandomized prospective study.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.The prospective cohort study reported statistically significant effect on disease-free survival and overall survival in favor of immunotherapy vs no immunotherapy.To establish efficacy, the following is needed: larger, wellconducted, 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 colorectal cancer who receive CIK cells, the evidence includes a single RCT.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatmentrelated mortality and morbidity.Results of the RCT showed a statistically significant effect on overall survival in favor of immunotherapy vs chemotherapy alone.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.
care as the control arm showing treatment benefit.The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with hepatocellular carcinoma who receive CIK cells, the evidence includes several RCTs.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.Several RCTs from Asia have generally reported some benefits in response rates and/or survival.The results of a meta-analysis of these trials have also shown a statistically significant 41% reduction in the hazard of death, but there was considerable heterogeneity across the included studies.This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses.To establish efficacy, the following is needed: larger, well-conducted, 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 non-small-cell lung cancer who receive CIK cells, the evidence includes multiple RCTs and a systematic review.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.A single systematic review of RCTs reported some benefits in median time to progression and median survival time.The included body of evidence trials in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses.To establish efficacy, the following is needed: larger, well-conducted, 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 tumor-infiltrating lymphocytes, the evidence includes a single RCT.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.Results of a small RCT have reported no difference in relapse or survival outcomes.Cohort studies in patients with refractory metastatic melanoma have demonstrated response rates of 49% with immunotherapy and 52% to 72% with no immunotherapy.
To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an

Dendritic Cells
For individuals with glioblastoma multiforme who receive dendritic cells, the evidence includes a systematic review of observational studies.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.Because of the observational and noncomparative nature of the available evidence, it is difficult to draw any meaningful conclusions.To establish efficacy, the following is needed: larger, well-conducted, 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 non-small-cell lung cancer who receive dendritic cells, the evidence includes 2 RCTs and a meta-analysis.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.The RCTs have generally reported some benefits in response rates and/or survival.The results of a meta-analysis of these trials also reported a statistical significant reduction in the hazard of death.Most trials were from Asia and did not use standard of care as the control arm.This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with medullary thyroid cancer who receive dendritic cells, the evidence includes one prospective noncomparative study.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.A small prospective noncomparative study in 10 medullary thyroid cancer patients treated with autologous dendritic cells has been published.There are no RCTs comparing dendritic cell−based adoptive immunotherapy with standard of care and, therefore, no conclusions can be made.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the For individuals with pancreatic cancer who receive dendritic cells, the evidence includes a small prospective noncomparative study.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity.The study reported on treatment outcomes for 5 patients with pancreatic cancer.Because of the noncomparative nature of the available evidence and small sample base, it is difficult to draw any meaningful conclusions.To establish efficacy, the following is needed: larger, well-conducted, 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 T-cell receptors, the evidence includes multiple small observational studies.Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatmentrelated mortality and morbidity.Multiple observational studies have examined autologous peripheral T lymphocytes containing tumor antigen-specific T-cell receptors in melanoma, Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma.Because of the noncomparative nature of the available evidence with a small sample size, it is difficult to draw any meaningful conclusion.
To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.The evidence is insufficient to determine the effects of the technology on health outcomes.CPT is a registered trademark of the American Medical Association.
Codes used to identify services associated with this policy may include (but may not be limited to) the following: Code Type Code CPT 38999 Add codes effective 1/1/2022: 0708T, 0709T HCPCS M0075, S2107 ICD-10 Diagnosis All related diagnoses *Investigational -A medical treatment, procedure, drug, device, or biological product is Investigational if the effectiveness has not been clearly tested and it has not been incorporated into standard medical practice.Any determination we make that a medical treatment, procedure, drug, device, or biological product is Investigational will be based on a consideration of the following: A. Whether the medical treatment, procedure, drug, device, or biological product can be lawfully marketed without approval of the U.S. Food and Drug Administration (FDA) and whether such approval has been granted at the time the medical treatment, procedure, drug, device, or biological product is sought to be furnished; or B. Whether the medical treatment, procedure, drug, device, or biological product requires further studies or clinical trials to determine its maximum tolerated dose, toxicity, safety,  **Medically Necessary (or "Medical Necessity") -Health care services, treatment, procedures, equipment, drugs, devices, items or supplies that a Provider, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury, disease or its symptoms, and that are: A. In accordance with nationally accepted standards of medical practice; B. Clinically appropriate, in terms of type, frequency, extent, level of care, site and duration, and considered effective for the patient's illness, injury or disease; and C.Not primarily for the personal comfort or convenience of the patient, physician or other health care provider, and not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient's illness, injury or disease.For these purposes, "nationally accepted standards of medical practice" means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, Physician Specialty Society recommendations and the views of Physicians practicing in relevant clinical areas and any other relevant factors.‡ Indicated trademarks are the registered trademarks of their respective owners.

NOTICE:
If the Patient's health insurance contract contains language that differs from the BCBSLA Medical Policy definition noted above, the definition in the health insurance contract will be relied upon for specific coverage determinations.NOTICE: Medical Policies are scientific based opinions, provided solely for coverage and informational purposes.Medical Policies should not be construed to suggest that the Company recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service, or any particular course of treatment, procedure, or service.
Policy # 00248 Original Effective Date: 02/17/2010 Current Effective Date: 03/13/2023 Non-Small-Cell Lung CancerWang et al (2014) conducted a systematic review of RCTs of CIK cells for the treatment of nonsmall-cell lung cancer (NSCLC).Overall, 17 RCTs (total N=1172 patients) were included in the analysis.The studies generally had small sample sizes; the largest had 61 CIK-treated patients and 61 control patients.Most studies also incorporated DC therapy.All were conducted in China.A significant effect of CIK was found for median time to progression and median survival time.OS at various time points significantly favored CIK.
Policy # 00248 Original Effective Date: 02/17/2010 Current Effective Date: 03/13/2023 ©2023 Blue Cross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.
Policy # 00248 Original Effective Date: 02/17/2010 Current Effective Date: 03/13/2023 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.
Policy # 00248 Original Effective Date: 02/17/2010 Current Effective Date: 03/13/2023 control arm showing treatment benefit.The evidence is insufficient to determine the effects of the technology on health outcomes.
effectiveness, or effectiveness as compared with the standard means of treatment or diagnosis, must improve health outcomes, according to the consensus of opinion among experts as shown by reliable evidence, including:1.Consultation with technology evaluation center(s); 2. Credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community; or 3. Reference to federal regulations.
Results of meta-analysis of these trials also reported a statistical significant reduction in the hazard of death by 41%, but there was considerable heterogeneity among the included studies.Most trials were from Asia and did not use standard of care as the control arm.This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses.To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.
Common adverse events attributed to CIK therapy were grade 1 or 2 fever, allergy, and headache.Grade 3 or 4 adverse events were not observed.A 2014 nonrandomized study from China reported improved PFS in 30 patients who received radiofrequency ablation plus CIK/natural killer cell/gamma delta T-cell (a type of tumorinfiltrating lymphocytes [TIL]) infusion (median PFS, not reached) compared with 32 patients who received radiofrequency ablation alone (median PFS, 12.0 months).Lee et al (2015) conducted an RCT in Korea of 230 patients being treated for hepatocellular carcinoma by surgical resection, radiofrequency ablation, or percutaneous ethanol injection.Patients were randomized 1:1 to adjuvant CIK cell injections 16 times during 60 weeks or to no adjuvant therapy.The primary end point was recurrence-free survival; secondary end points included OS and cancer-specific survival.The median recurrence-free survival was 44 months in the CIK group and 30 months in the control group (p=0.010).OS was longer in the CIK group than in the control group (HR=0.21,p=0.008).Cancer-specific survival was longer in the CIK group than in the control group (HR=0.19,p=0.02).Adverse events occurred more frequently in the CIK group than in the control group, but grade 3 or 4 adverse events did not differ significantly between groups.Adverse events associated with CIK included pyrexia, chills, myalgia, and fatigue.Subsection Summary: Hepatocellular CarcinomaSeveral RCTs and quasi-RCTs have evaluated the efficacy of CIK cells in hepatocellular cancers.These studies have generally reported some benefits in response rates and/or survival.©2023BlueCrossandBlue Shield of LouisianaBlue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.Page 10 of 27 Objective response rates by Response Evaluation Criteria in Solid Tumors were 49%, 52%, and 72%, respectively, and did not differ significantly among groups.Responses occurred at multiple metastatic sites, including the brain, and many were durable; 10 patients who achieved CR had no relapse at a median follow-up of 31 months.Toxicities of treatment occurred primarily in the 1200-cGy group and included a delay in marrow recovery of 1 to 2 days compared with the other treatment groups, somnolence requiring intubation, renal insufficiency, and posterior uveitis.Rosenberg et al (2011)reported updated results of these patients with median follow-up of 62 months.Ten patients who previously had been classified as partial responders were reclassified as complete responders by Response Evaluation Criteria in Solid Tumors (1, 3, and 6 patients in the nonmyeloablative, 200-cGy, and 1200-cGy groups, respectively).Of these 20 patients (22% of the MelanomaDudley 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) totalbody irradiation.Ninety-five percent of patients had progressive disease after prior systemic treatment.©2023BlueCross and Blue Shield of LouisianaBlue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.
2013, Bregy et al published a systematic review of observational studies of active immunotherapy using ADCs in the treatment of glioblastoma multiforme.Twenty-one studies published through early 2013 were included in this review (total N=403 patients).Vaccination with DCs loaded with autologous tumor cells resulted in an increased median OS in patients with recurrent disease (72-138 weeks across 8 studies), as well as in those newly diagnosed (65-230 weeks across 11 studies) ©2023 Blue Cross and Blue Shield of LouisianaBlue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.
The responsibility for the content of Blue Cross Blue Shield of Louisiana Medical Policy Coverage Guidelines is with Blue Cross and Blue Shield of Louisiana and no endorsement by the AMA is intended or should be implied.The AMA disclaims responsibility for any consequences or liability attributable or related to any use, nonuse or interpretation of information contained in Blue Cross Blue Shield of Louisiana Medical Policy Coverage Guidelines.Fee schedules, relative value units, conversion factors and/or related components are not assigned by the AMA, are not part of CPT, and the AMA is not recommending their use.The AMA does not directly or indirectly practice medicine or dispense medical services.The AMA assumes no liability for data contained or not contained herein.Any use of CPT outside of Blue Cross Blue Shield of Louisiana Medical Policy Coverage Guidelines should refer to the most current Current Procedural Terminology which contains the complete and most current listing of CPT codes and descriptive terms.Applicable FARS/DFARS apply.
©2023 Blue Cross and Blue Shield of LouisianaBlue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.©2023BlueCross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.©2023BlueCross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.©2023BlueCross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.©2023BlueCross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.©2023BlueCross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.©2023BlueCross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.©2023BlueCross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.Page 26 of 27 # 00248 Original Effective Date: 02/17/2010 Current Effective Date: 03/13/2023 ©2023 Blue Cross and Blue Shield of Louisiana Blue Cross and Blue Shield of Louisiana is an independent licensee of the Blue Cross and Blue Shield Association and incorporated as Louisiana Health Service & Indemnity Company.No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from Blue Cross and Blue Shield of Louisiana.