Latest Review Date: August 2024

Category:  Medical                                                              

POLICY:

All adoptive immunotherapy techniques intended to enhance autoimmune effects are considered investigational for the indications included, but not limited to, cancers associated with Epstein-Barr virus, Cytomegalovirus-associated cancers, nasopharyngeal cancer, renal cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, non-small-cell lung cancer, melanoma, glioblastoma multiforme, medullary thyroid cancer, pancreatic cancer, and cancers treated with autologous peripheral T lymphocytes containing tumor antigen-specific T cell receptors.

Note: CAR-T Therapy and Amtagvi® are addressed separately in each of the medical policies noted below:

 VP-0319 Kymriah™ (tisagenlecleucel), VP-0333 Yescarta™ (axicabtagene ciloleucel), VP-0558 Tecartus™ (brexucabtagene autoleucel), VP-0590 Breyanzi® (lisocabtagene maraleucel), and VP-0598 Abecma® (idecabtagene vicleucel), VP-0663 Carvykti™ (ciltacabtagene autoleucel), VP-0748 Amtagvi® (lifileucel)

DESCRIPTION OF PROCEDURE OR SERVICE:

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

Allogeneic cell transplantation following non-myeloablative conditioning of the recipient (known as reduced-intensity conditioning or RIC) may also be referred to as “adoptive immunotherapy” in the literature. However, RIC cell transplantation relies on a donor-versus-malignancy effect of donor lymphocytes. In contrast, the adoptive immunotherapy techniques described in this policy enhance autoimmune effects primarily. The use of RIC in stem-cell transplantation is discussed for specific cancers in individual policies related to cell transplantation.

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 auto lymphocyte therapy, increases the number of activated lymphocytes.

T Lymphocytes and Killer Cells

Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer (LAK) cells and activating them in vitro with the T-cell growth factor interleukin-2 (IL-2) and other cytokines. More recent techniques 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. The expansion of TIL for clinical use is labor-intensive and requires laboratory expertise. Only a few cancers are infiltrated by T cells in significant numbers; of these, TIL can be expanded in only approximately 50% of cases. These factors limit the widespread applicability of TIL treatment.  Recently, cytokine-induced killer (CIK) cells have been recognized as a new type of anti-tumor effector cells, which can proliferate rapidly in vitro, with stronger anti-tumor activity and broader spectrum of targeted tumor than other reported anti-tumor effector cells.

Cellular Therapy and Dendritic Cell Infusions

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

ACT 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 (ELISA)

4) lymphodepletion of the host with immunosuppressive agents

5) adoptive transfer (i.e., 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 individual are either pulsed with antigen or transfected with a viral vector bearing a common cancer antigen. The activated ADCs are then transfused back into the individual, where they present antigen to effector lymphocytes (CD4+ T cells, CD8+ 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 further regulate the host immune system, recent protocols use various cytokines (e.g., IL-7 and IL-15 instead of IL-2) to propagate lymphocytes. Protocols also differ in the extent of host lymphodepletion induced prior to transfusing the lymphocytes to the tumor-bearing host.

KEY POINTS:

The most recent literature search was performed through June 3, 2024.

Summary of Evidence

Cytotoxic T Lymphocytes

For individuals with Epstein-Barr virus-associated cancers who receive cytotoxic T lymphocytes (CTL), the evidence includes 2 small, prospective noncomparative cohort studies. Relevant outcomes are overall survival (OS), disease-specific survival (DSS), quality of life (QOL), and treatment-related mortality and morbidity. The cohort studies have shown a treatment response to infused 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 that the technology results in an improvement in the net health outcome.

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 a randomized controlled trial (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 that the technology results in an improvement in the net health outcome.

Cytotoxic-Induced Killer Cells

For individuals with nasopharyngeal carcinoma who receive CIK cells, the evidence includes a single RCT. Relevant outcomes are 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 (PFS) and overall survival (OS). 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 that the technology results in an improvement in the net health outcome.

For individuals with renal cell carcinoma (RCC) 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 (IL-2) plus interferon-α-2. This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator. The other 2 RCTs have also reported response rates in favor of CIK therapy with 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 that the technology results in an improvement in the net health outcome.

For individuals with gastric cancer who receive CIK cells, the evidence includes 2 meta-analyses encompassing non-randomized trials. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Both meta-analyses reported statistically significant effect on disease-free survival, overall survival, quality of life, and progression free survival in favor of immunotherapy vs no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with colorectal cancer (CRC) who receive CIK cells, the evidence includes a single RCT and 2 meta-analyses. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Results of the RCT showed a statistically significant effect on overall survival in favor of immunotherapy vs chemotherapy alone. A meta-analysis that included both gastric cancer and CRC found improvements in OS and PFS in favor of CIK or CIK cell/dendritic cell-cytokine-induced killer compared to chemotherapy alone; another meta-analysis of prospective and randomized studies of CIK or DC-CIK in individuals with CRC also showed improvements in survival outcomes compared to non-CIK/DC-CIK treatments. 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 that the technology results in an improvement in the net health outcome.

For individuals with hepatocellular carcinoma (HCC) who receive CIK cells, the evidence includes meta-analyses that include RCTs and quasi-randomized trials. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Meta-analyses of these trials have reported improved overall survival rates when compared to conventional therapies alone, but they are limited by inclusion of studies from Asia only and heterogeneity in comparators. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other 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 that the technology results in an improvement in the net health outcome.

For individuals with non-small-cell lung cancer (NSCLC) 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 that the technology results in an improvement in the net health outcome.

Tumor-Infiltrating Lymphocytes

For individuals with EBV-associated nasopharyngeal carcinoma who receive tumor infiltrating lymphocytes (TILs), the evidence includes an RCT evaluating TILs as adjuvant therapy. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The RCT evaluating TILs as adjuvant therapy following standard chemoradiation in individuals with EBV-associated nasopharyngeal carcinoma found no difference in PFS or other clinical outcomes compared to individuals who received standard chemoradiation alone. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Dendritic Cells

For individuals with glioblastoma multiforme who receive dendritic cells (DC), 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 that the technology results in an improvement in the net health outcome.

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 that the technology results in an improvement in the net health outcome.

For individuals with medullary thyroid cancer (MTC) 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 individuals 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 control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with pancreatic cancer who receive 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 individuals 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 that the technology results in an improvement in the net health outcome.

Genetically Engineered T Cells

Peripheral T Lymphocytes

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

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

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

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Adoptive immunotherapy (AI), lymphokine-activated killer (LAK) cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, autolymphocyte therapy (ALT), leukophoresis, and interleukin-2 (IL-2), cytotoxic T-lymphocytes, genetically engineered T-cells, cytokine-induced killer cells, T-Cell Receptor Therapy, TCR, adoptive cellular therapy, ACT, CIK, antigen-loaded autologous dendritic cells, ADC

APPROVED BY GOVERNING BODIES:

There are currently no adoptive immunotherapy products within the scope of this review that are U.S. Food and Drug Administration (FDA)-approved.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply. Refer to member’s benefit plan

CURRENT CODING: 

CPT codes:

HCPCS codes:

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POLICY HISTORY:

Medical Policy Group, April 2003 (1)

Medical Policy Administration Committee, August 2003

Available for comment August 11-September 25, 2003

Medical Policy Group, April 2005 (1)

Medical Policy Group, April 2007 (1)

Medical Policy Group, January 2009 (1)

Medical Policy Group, June 2011 (1): Update to Key Points and References

Medical Policy Group, March, 2012 (1): Update to Key Points and References related to MPP update; no change in policy statement

Medical Policy Group, September 2013 (1): Update to the policy statement under adoptive cellular therapy was changed to include cytokine-induced killer (CIK) cells; however, the intent of both policy statement (i.e., investigational) is unchanged; update to Description, Key Points and References

Medical Policy Administration Committee, September 2013

Medical Policy Panel, December 2013

Medical Policy Group, January 2014 (1): Update to Key Points and References; no change in policy statement

Medical Policy Panel, December 2014

Medical Policy Group, December 2014 (4): Updates to Description, Key Points, Approved Governing Bodies, Key Words and References.  Update to policy statement adding “cytotoxic T-lymphocytes”, “autologous” dendritic cells and “genetically engineered T-cells”. Also updated Policy section to include other applications of adoptive immunotherapy are considered investigational

Medical Policy Panel, December 2015

Medical Policy Group, January 2016 (3): Updates to Description, Key Points & References; no change in policy statement.

Medical Policy Group, March 2016 (3): Update to Key Words. No change in policy statement.

Medical Policy Group, August 2017 (2): Updates to Key Words, Approved by Governing Bodies, Current Coding, and References; no change in policy statement.

Medical Policy Group, October 2017 (2): Updates to Key Words, Approved by Governing Bodies, Current Coding, and References; no change in policy section.

Medical Policy Group, November 2017 (2): Updates to Key Points and References; No change in policy statement.

Medical Policy Group, December 2017: Annual Coding Update 2018.  Added new HCPCS code Q2040 to the Current Coding section.

Medical Policy Group, December 2017 (2): Removed all CAR-T related content and made a note to refer to medical policies #675 Kymriah and #676 Yescarta.

Medical Policy Panel, July 2018

Medical Policy Group, August 2018 (2): Updates to Key Points and References; no change in policy statement.

Medical Policy Group, March 2019 (2): Updates to Key Points and References; no change in policy statement.

Medical Policy Panel, October 2019

Medical Policy Group, November 2019 (2): Updates to Key Points; no change in policy statement.

Medical Policy Panel, October 2020

Medical Policy Group, October 2020 (2): Updates to Key Points and Reference; no change in Policy Statement; note added for allogeneic cell transplantation is not adoptive immunotherapy.

Medical Policy Panel, October 2021

Medical Policy Group, October 2021 (2): Updates to Key Points and References; Policy statement updated to remove “not medically necessary,” no change to intent.

Medical Policy Group, December 2021 (2): 2022 Annual Coding Update, new codes 0708T and 0709T added to the Current Coding section.           

Medical Policy Panel, October 2022

Medical Policy Group, October 2022 (2): Updates to Key Points and References; no change in policy statement.

Medical Policy Panel, October 2023

Medical Policy Group, October (2): Updates to Key Points, Approved by Governing Bodies, Benefit Application, and References; no change in Policy statement.

Medical Policy Group, May 2024 (2): Added note to refer to VP-0748 Amtagvi for coverage criteria; policy is managed through pharmacy drug benefit.

Medical Policy Panel, August 2024

Medical Policy Group, August 2024 (9): Updates to Key Points, Approved by Governing Bodies, and References; no change in policy statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. 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.