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Medical Policy Adoptive Immunotherapy Table of Contents
• Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 455 BCBSA Reference Number: 8.01.01 (For Plan internal use only) NCD/LCD: N/A Related Policies
• Cellular Immunotherapy for Prostate Cancer, #268 • Chimeric Antigen Receptor Therapy for Hematologic Malignancies, #066 • CAR T-Cell Therapy Services for Diffuse Large B-cell Lymphoma (axicabtagene cilleucel or tisagenlecleucel) Prior Authorization Request Form, #924 • CAR T-Cell Therapy Services for B-cell Acute Lymphoblastic Leukemia (tisagenlecleucel) Prior Authorization Request Form, #925 • CAR T-Cell Therapy Services for Mantle Cell Lymphoma (brexucabtagene Autoleucel) Prior Authorization Request Form, #940 • Adoptive Cell Therapies for Melanoma, #089 • Adoptive Cell Therapies for Melanoma (Lifileucel) Prior Authorization Request Form, #096 • Engineered T-Cell Therapy for Synovial Sarcoma (Tecelra®), #213
• Engineered T-Cell Therapy for Synovial Sarcoma (Tecelra®) Prior Authorization Request Form, #222
Policy
Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Adoptive immunotherapy in the form of chimeric antigen receptor T-cell therapy (eg, tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel) for hematologic malignancies is discussed in policy

066, Antigen Receptor Therapy for Hematologic Malignancies.

Adoptive immunotherapy in the form of autologous tumor-infiltrating lymphocytes (e.g. Lifileucel) for advanced melanoma and all other indications is discussed in policy #089, Adoptive Cell Therapies for Melanoma.

All adoptive immunotherapy techniques intended to enhance immunity against cancers re considered INVESTIGATIONAL for the indications included, but not limited to, cancers associated with

2 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.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) This is not a covered service. Commercial PPO and Indemnity This is not a covered service. Medicare HMO BlueSM This is not a covered service. Medicare PPO BlueSM This is not a covered service.

CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The following HCPCS code is considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

HCPCS Codes HCPCS codes: Code Description S2107 Adoptive immunotherapy, i.e., development of specific anti-tumor reactivity (e.g., tumor infiltrating lymphocyte therapy) per course of treatment

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

Based on data from 2016 through 2020, kidney cancer is more common in men than women and occurs more often in non-Hispanic American Indian and Alaskan Native individuals, followed by non- Hispanic Black individuals.2, American Indians and Alaska Natives have higher death rates from kidney cancer than any other racial or ethnic group. A cohort study by Howard et al (2021) included 158,445 patients with localized kidney cancer from the National Cancer Database between 2010 and 2017.3, Investigators found that that female patients were treated more aggressively compared with male patients, with lower adjusted odds of undertreatment and higher adjusted odds of overtreatment. They also found that Black and Hispanic patients had higher adjusted odds of under treatment and overtreatment

3 compared to White patients, and uninsured status was associated with lower adjusted odds of overtreatment and higher adjusted odds of undertreatment. These results suggest that sex, race and ethnicity, and socioeconomic status are associated with disparities in guideline-based treatment for localized kidney cancer, specifically, with increased rates of non-guideline based treatment for women and Black and Hispanic patients.

Adoptive Immunotherapy Adoptive immunotherapy uses “activated” lymphocytes or other immune cells as a treatment modality.4, Both nonspecific and specific lymphocyte activation are used therapeutically. The nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes.

T Lymphocytes and Killer Cells Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T-cell growth factor interleukin (IL)-2 and other cytokines. More recent techniques have yielded select populations of cytotoxic T lymphocytes with specific reactivity to tumor antigens. Peripheral lymphocytes are propagated in vitro with antigen-presenting dendritic cells (DC) that have been pulsed with tumor antigens. Alternatively, innate tumor-infiltrating lymphocytes (TIL) from the tumor biopsy are propagated in vitro with IL-2 and anti-CD3 antibody, a T-cell activator. The expansion of TIL for clinical use is labor-intensive and requires laboratory expertise. Only a few cancers are infiltrated by T cells in significant numbers; of these, TIL can be expanded in only approximately 50% of cases. These factors limit the widespread applicability of TIL treatment. Recently, cytokine-induced killer cells have been recognized as a new type of antitumor effector cells, which can proliferate rapidly in vitro, with stronger antitumor activity and a broader spectrum of targeted tumors than other reported antitumor effector cells.5,

Cellular Therapy and Dendritic Cell Infusions The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing patients. In current trials, 2 methods are studied: adoptive cellular therapy and antigen-loaded DC infusions.

Adoptive cellular therapy is “the administration of a patient’s own (autologous) or donor (allogeneic) antitumor lymphocytes following a lymphodepleting preparative regimen.”6, Protocols vary, but include these common steps: • lymphocyte harvesting (either from peripheral blood or from tumor biopsy) • propagation of tumor-specific lymphocytes in vitro using various immune modulators • selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay • lymphodepletion of the host with immunosuppressive agents • adoptive transfer (ie, transfusion) of lymphocytes back into the tumor-bearing host.

Dendritic cell-based immunotherapy uses autologous DC (ADC) to activate a lymphocyte-mediated cytotoxic response against specific antigens in vivo. Autologous dendritic cells harvested from the patient are either pulsed with antigen or transfected with a viral vector bearing a common cancer antigen. The activated ADCs are then re-transfused into the patient, where they present antigen to effector lymphocytes (CD4-positive T-cells, CD8-positive T-cells, and in some cases, B cells). This initiates a cytotoxic response against the antigen and against any cell expressing the antigen. In cancer immunotherapy, ADCs are pulsed with tumor antigens; effector lymphocytes then mount a cytotoxic response against tumor cells expressing these antigens. (See evidence review 8.01.53 for a discussion of DC-based immunotherapy for prostate cancer.)

In an attempt to regulate the host immune system further, recent protocols have used various cytokines (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.

Summary Description

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

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

Chimeric antigen receptor T-cell therapies for certain hematologic malignancies (eg, tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel) are discussed separately in policy #066

Summary of Evidence

Cytotoxic T Lymphocytes For individuals with Epstein-Barr virus (EBV)-associated cancers who receive cytotoxic T lymphocytes (CTL), the evidence includes 1 RCT and 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 RCT found no significant difference in OS or progression-free survival between patients with EBV-positive nasopharyngeal carcinoma treated with chemotherapy alone versus chemotherapy followed by CTL therapy. The cohort studies have shown a treatment response to infused CTL directed against cancer-associated viral antigens. To establish efficacy, the following are needed: large, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with Cytomegalovirus-associated cancers who receive CTL, the evidence includes a single case series. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. In the absence of a randomized controlled trial (RCT) comparing CTL with the standard of care, no conclusions can be made. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Cytotoxic-Induced Killer Cells For individuals with nasopharyngeal carcinoma who receive cytotoxic-induced killer (CIK) cells, the evidence includes a single RCT. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The RCT reported a numerically favorable but statistically insignificant effect on progression- free survival (PFS) and OS. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with renal cell carcinoma (RCC) who receive CIK cells, the evidence includes multiple RCTs. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The largest of the RCTs reported statistically significant gains in PFS and OS with CIK cell-based immunotherapy compared with interleukin-2 (IL-2) plus interferon-α-2. This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator. The other 2 RCTs have also reported response rates in favor of CIK therapy with an inconsistent effect on survival. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded

5 assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

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

For individuals with colorectal cancer (CRC) who receive CIK cells, the evidence includes a single RCT and 2 meta-analyses. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Results of the RCT showed a statistically significant effect on OS in favor of immunotherapy versus chemotherapy alone. A meta-analysis that included both gastric cancer and CRC found improvements in OS and PFS in favor of CIK or CIK cell/dendritic cell-cytokine-induced killer (DC-CIK) cells compared to chemotherapy alone; another meta-analysis of prospective and randomized studies of CIK or DC-CIK in patients with CRC also showed improvements in survival outcomes compared to non-CIK/DC-CIK treatments. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with hepatocellular carcinoma (HCC) who receive CIK cells, the evidence includes meta- analyses that include RCTs and quasi-randomized trials. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Meta-analyses of these trials have reported improved OS rates when compared to conventional therapies alone, but they are limited by inclusion of studies from Asia only and heterogeneity in comparators. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodological weaknesses. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with non-small cell lung cancer (NSCLC) who receive CIK cells, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. A single systematic review of RCTs reported some benefits in efficacy and disease control. The trials assessed in the systematic review were limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodological weaknesses. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Tumor-Infiltrating Lymphocytes For individuals with 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 patients 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

6 For individuals with glioblastoma multiforme who receive dendritic cells (DC), the evidence includes an RCT and a meta-analysis. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The meta-analysis of phase II and III trials, using open-label designs or external controls, found significant improvements in OS and progression-free survival across both newly diagnosed and recurrent populations, although with substantial heterogeneity in pooled outcomes and non-standardized vaccine manufacturing and administration. A Phase III externally controlled study of DC vaccination plus standard of care also reported longer OS in both newly diagnosed and recurrent disease, without a progression-free survival advantage. Given the reliance on non-propensity-matched external controls for OS estimates, causal inference remains limited. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with NSCLC who receive DC, the evidence includes 2 RCTs, a cohort study, and a meta- analysis. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. The RCTs have generally reported some benefits in response rates and/or survival. A matched-cohort study found improved survival and remission rates, as well as reduced toxicity, compared to chemoradiotherapy alone. The meta-analysis of these trials also reported a statistically significant reduction in the hazard of death. Most trials were from Asia and did not use the standard of care as the control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodological weaknesses. To establish efficacy, the following are needed: larger, well- conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with medullary thyroid cancer (MTC) who receive DC, the evidence includes 1 prospective noncomparative study. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. A small prospective noncomparative study in 10 MTC patients treated with autologous DC has been published. There are no RCTs comparing DC-based adoptive immunotherapy with the standard of care and, therefore, no conclusions can be made. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with pancreatic cancer who receive DC, the evidence includes 2 small prospective noncomparative studies. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. One study reported that it met its prespecified 2-year recurrence-free survival endpoint and observed predominantly low-grade, vaccine-related adverse safety events. The other study reported on treatment outcomes for only 5 patients with pancreatic cancer. Because of the noncomparative nature of the available evidence and small sample base, it is difficult to draw any meaningful conclusions. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. Genetically Engineered T Cells

Peripheral T Lymphocytes For individuals with cancers who receive autologous peripheral T lymphocytes containing tumor antigen- specific T-cell receptors (TCRs), the evidence includes multiple small observational studies. Relevant outcomes are OS, DSS, QOL, and treatment-related mortality and morbidity. Multiple observational studies have examined autologous peripheral T lymphocytes containing tumor antigen-specific TCRs in melanoma, Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma. Because of the noncomparative nature of the available evidence and small sample size, it is difficult to draw any meaningful conclusion. To establish efficacy, the following are needed: larger, well-conducted, multicentric trials with

7 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.

Policy History Date Action 11/2025 Annual policy review. Policy updated with literature review through July 11, 2025; references added. Policy statements unchanged. 6/2025 Related policies section clarified to include MP 213 Engineered T-Cell Therapy for Synovial Sarcoma (Tecelra®).
10/2024 Annual policy review. Policy updated with literature review through June 3, 2024; references added. Indication for TIL in melanoma moved to MP 089. 8/2024 Policy clarified. Reference and link to MP 089 Adoptive Cell Therapies for Melanoma,

089 added.

12/2023 Annual policy review. Policy updated with literature review through August 11, 2023; references added. Indication added (TIL in EBV-associated nasopharyngeal carcinoma). Policy statements unchanged. 12/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 12/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 12/2020 Annual policy review. Policy section clarified to: All adoptive immunotherapy techniques intended to enhance autoimmune effects are considered investigational for the indications included, but not limited to, in this policy.
12/2019 Annual policy review. Sections regarding use of tisagenlecleucel and axicabtagene ciloleucel were removed and added to new policy #066 Chimeric Antigen Receptor Therapy for Hematologic Malignancies), references updated. Policy section clarified to ‘All applications of adoptive immunotherapy evaluated in this policy are considered investigational.’ Clarified coding information. 3/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2019 Clarified coding information. 5/2016 Annual policy review. Section on lymphokine-activated killer cell deleted due to obsolete intervention. Effective 5/1/2016. 5/2015 Annual policy review. Clarified coding information. New investigational indications described. Effective 5/1/2015. 3/2014 New references added from BCBSA National medical policy. 6/2013 The wording of the policy statement under adoptive cellular therapy was changed to include cytokine-induced killer (CIK) cells; however, the intent of both policy statements (i.e., investigational) is unchanged. Effective 6/1/2013. 11/2011- 4/2012 Medical policy ICD 10 remediation: Formatting, editing and coding updates. No changes to policy statements.
1/17/2012 Annual policy review. No changes to policy statements.
1/1/2012 Updated removing information on donor leukocyte infusion which is now addressed in medical policy #338.
7/2011 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements.
9/2010 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements.
4/2010 Annual policy review. No changes to policy statements.
9/2009 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements.
9/2009 Annual policy review. Changes to policy statements.

8 2/2009 Annual policy review. No changes to policy statements.
10/2008 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements.
9/2008 Annual policy review. No changes to policy statements 11/2007 Annual policy review. No changes to policy statements. 9/2007 Reviewed - Medical Policy Group - Hematology and Oncology. No changes to policy statements.
8/2007 Annual policy review. No changes to policy statements.
Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

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