CurrentPremera BluecrossPolicy 8.01.01

Adoptive Immunotherapy

Defines coverage stance and evidence assessment for adoptive immunotherapy techniques (e.g., tumor-infiltrating lymphocytes, cytotoxic T lymphocytes, cytokine-induced killer cells, dendritic cell infusions) for cancer treatment and indicates investigational status for many applications; intended for providers and payers.

Policy Summary

PayerPremera Bluecross

PolicyAdoptive Immunotherapy

Policy CodePolicy 8.01.01

Change TypeNo material changes

Effective DateMay 1, 2026

Next Review Date

Key ActionObtain and document prior authorization and clinical rationale when requesting coverage for investigational adoptive immunotherapy procedures.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

no FDA-approved productsregulatory status within scope of review

S2107Listed adoptive immunotherapy HCPCS code

36511Listed therapeutic apheresis CPT code

small trialsprimary evidence base size

Annualpolicy review frequency

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Coverage Criteria and Evidence Conclusions

inv-01: Investigational Applications — other applications considered investigational

Other applications considered investigational

Investigational adoptive immunotherapy: 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.

Treatments are subject to the product's US Food and Drug Administration (FDA) dosage and administration prescribing information.

inv-02: Not established / Insufficient evidence (by therapy and indication)

Coverage conclusions based on available evidence in this section:

Dendritic cells for non-small-cell lung cancer: Evidence includes two randomized controlled trials, a cohort study, and a meta-analysis reporting some benefits in response rates and/or survival; however, most trials were non‑US, had small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. The evidence is insufficient to determine that dendritic cell therapy improves net health outcome.insufficient evidence

See source evidence summary.

Dendritic cells for medullary thyroid cancer: Only a small prospective noncomparative study (n=10) is available and there are no RCTs comparing dendritic cell–based adoptive immunotherapy to standard of care; evidence is insufficient to determine improvement in net health outcome.insufficient evidence

See source evidence summary.

Dendritic cells for pancreatic cancer: Available evidence consists of two small prospective noncomparative studies (one reporting outcomes for as few as five individuals); because of noncomparative design and very small sample sizes, evidence is insufficient to determine improvement in net health outcome.insufficient evidence

See source evidence summary.

Peripheral T lymphocytes with tumor-specific TCRs for various cancers: Multiple small observational studies in melanoma, Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma are noncomparative and limited by small sample sizes; evidence is insufficient to determine improvement in net health outcome.insufficient evidence

See source evidence summary.

Regulatory and guideline context: No adoptive immunotherapy products within the scope of this review are FDA‑approved, and current NCCN guidelines do not include recommendations for adoptive immunotherapy for many tumor types; these factors support an investigational/insufficient evidence conclusion.regulatory/guideline absence

See regulatory and guideline statements.

inv-03: Overall coverage stance — general coverage stance from history and scope statements

General coverage stance (from history and scope statements)

Policy stance: Adoptive immunotherapy techniques not addressed in the related CAR T policy are considered investigational for the indications included; CAR T for hematologic malignancies is addressed under related policy 8.01.63.

Derived from policy history and scope statements.

Adoptive immunotherapy techniques that are intended to enhance immune-mediated anti-tumor effects are designated investigational for the indications listed in this policy. This includes, but is not limited to, therapies for cancers associated with Epstein-Barr virus (EBV), Cytomegalovirus (CMV)-associated cancers, nasopharyngeal carcinoma, renal cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, non–small-cell lung cancer, melanoma, glioblastoma multiforme, medullary thyroid cancer, pancreatic cancer, and treatments using autologous peripheral T lymphocytes with tumor antigen–specific T-cell receptors. Treatments described in this policy remain subject to the product's FDA dosage and administration prescribing information when applicable.

Current National Comprehensive Cancer Network (NCCN) guidelines do not include recommendations for adoptive immunotherapy for many tumor types referenced in this policy, including cancers of the bladder, central nervous system, head and neck, hepatobiliary system, kidney, pancreas, stomach, thyroid, and non–small-cell lung cancer. The absence of guideline recommendations supports the policy's investigational stance and indicates that conventional, guideline-supported therapies are generally preferred prior to considering adoptive immunotherapy in these tumor types.

This medical policy does not apply to Medicare Advantage membership. Hematologic malignancy chimeric antigen receptor (CAR) T–cell therapies and related indications are addressed separately in related policy 8.01.63. Providers should consult that policy for CAR T–related coverage decisions and note that coverage determinations remain subject to the member's benefit limitations and Company prior authorization procedures.

A randomized trial evaluating tumor-infiltrating lymphocytes (TILs) as adjuvant therapy after standard chemoradiation for individuals with EBV-associated nasopharyngeal carcinoma found no difference in progression-free survival (PFS) or other clinical outcomes compared with standard chemoradiation alone. This negative randomized result is cited in the policy as evidence that TILs have not been shown to improve net health outcomes in this adjuvant setting.

For cytotoxic T lymphocytes (CTLs) directed at EBV-associated cancers, the evidence includes one randomized controlled trial and two small prospective noncomparative cohorts; the RCT showed no significant difference in overall survival or progression-free survival when CTLs were added to chemotherapy for EBV‑positive nasopharyngeal carcinoma. For CMV‑associated cancers, available evidence is limited to a single case series. Overall, current CTL data are inadequate to establish efficacy or improved net health outcomes.

Across adoptive immunotherapy approaches reviewed in this policy, the evidence base is dominated by small, noncomparative studies, limited randomized trials, and trials conducted outside the U.S. Many studies have heterogeneous treatment protocols and methodological limitations. Additionally, there are currently no adoptive immunotherapy products within the scope of this review that are FDA‑approved. Taken together, these factors result in insufficient evidence to determine that these adoptive immunotherapy techniques improve net health outcomes for the tumor types discussed.

Historically, multiple adoptive immunotherapy applications have been documented in this policy as investigational, including cytotoxic T‑lymphocytes, genetically engineered T cells, antigen‑loaded dendritic cells, and cytokine‑induced killer cells. Policy history entries reflect repeated annual reviews and coding updates while maintaining an investigational policy stance for these applications.

Provider Requirements, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for adoptive immunotherapy services. Coverage determinations are subject to the member's benefit plan and medical necessity review per this policy; providers should obtain prior authorization before scheduling or delivering services to avoid potential denials.

Prior authorization implied by policy; contact Premera for PA requirements and submission procedures.
Coverage is subject to member benefit limits and medical necessity review.

Denial Risk

Regulatory Status Impacts Coverage

No adoptive immunotherapy products within the scope of this review are currently FDA‑approved. The regulatory status may result in investigational determinations and denials when services are not supported by FDA approval and applicable coverage criteria.

Lack of FDA approval for products in scope may trigger investigational / not‑covered determinations.
Policy statements and denials will follow the investigational coverage position in this document.

Billing Rule

Coding and Billing Documentation

Document coding and billing when submitting prior authorization requests and claims. Use the listed CPT and HCPCS codes where applicable and include procedure- and service-level documentation to support medical necessity.

CPT 36511 — Therapeutic apheresis; for white blood cells.
HCPCS S2107 — Adoptive immunotherapy (e.g., tumor-infiltrating lymphocyte therapy) per course of treatment.
Include operative reports, apheresis records, product manufacture/handling documentation, and the FDA product prescribing information (if applicable).

Documentation Required

Trial and Research Documentation

For investigational or trial-related services, include trial identifiers and enrollment details when submitting requests or claims. Ongoing and unpublished clinical trials should be documented to allow prospective or retrospective review.

Provide NCT number, trial title, sponsor, enrollment status, and expected completion date when applicable.
Indicate whether the service is provided as part of a clinical trial and provide protocol documentation and consent forms.

Denial Risk

Investigational Indications and Denial Triggers

Adoptive immunotherapy techniques described in this policy are considered investigational for the listed indications; when services meet investigational criteria or are not addressed by relevant FDA labeling and national guidelines, they are subject to denial. Providers should confirm prior authorization and submit complete documentation to support any request.

Preferred standard therapies (per NCCN and other specialty guidelines) should be exhausted where applicable prior to consideration of investigational adoptive immunotherapy.
Documentation requirements were added (11/17/18); submit required clinical records to support medical necessity determinations.

Definitions and Terminology

Adoptive cellular therapy — definition entry

DefinitionAdoptive cellular therapy: the administration of an individual's own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lymphodepleting preparative regimen, typically involving lymphocyte harvesting, in vitro propagation/selection of tumor-reactive lymphocytes, host lymphodepletion, and adoptive transfer.

Common stepsLymphocyte harvesting (peripheral blood or tumor biopsy); propagation of tumor-specific lymphocytes in vitro; selection of lymphocytes reactive to tumor antigens; lymphodepletion of the host; adoptive transfer of lymphocytes back into the host.

PurposeTo provide quantities of immune cells with antitumor reactivity sufficient for transfer to tumor-bearing individuals to mediate an anti-tumor immune response.

Autolymphocyte therapy — definition entry

DefinitionAutolymphocyte therapy: nonspecific, polyclonal proliferation of lymphocytes induced by cytokines (immune system growth factors) to increase the number of activated lymphocytes.

MechanismNonspecific activation and expansion of lymphocytes rather than selection for tumor-specific reactivity.

Therapeutic intentUsed as a treatment modality to increase circulating activated lymphocytes for potential anti-tumor effects.

Dendritic cell therapy — definition entry

DefinitionDendritic cell therapy (antigen-loaded dendritic cells): autologous dendritic cells harvested from the individual that are pulsed with tumor antigen or transfected with a vector encoding a tumor antigen, then re-infused to present antigen to effector lymphocytes and stimulate a cytotoxic anti-tumor response.

Clinical roleIntended to activate CD4+ and CD8+ T cells (and sometimes B cells) in vivo to mount cytotoxic responses against tumor cells expressing the target antigen.

Evidence contextStudied in multiple tumor types (e.g., non-small-cell lung cancer, medullary thyroid cancer, pancreatic cancer) with limited, heterogenous trials; current evidence insufficient to establish net health benefit.

Peripheral T lymphocyte therapy (TCR-engineered) — definition entry

DefinitionPeripheral T lymphocyte therapy (TCR-engineered): autologous peripheral T lymphocytes that have tumor antigen–specific T-cell receptors (TCRs) used to target tumor cells.

Investigated indicationsStudied in melanoma, Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma among others.

Evidence limitationsAvailable data are multiple small, noncomparative observational studies with small sample sizes; evidence insufficient to determine improvement in net health outcome.

Adoptive immunotherapy — overarching definition

DefinitionAdoptive immunotherapy (adoptive cellular therapy): techniques that enhance immune-mediated anti-tumor effects by transferring activated lymphocytes or other immune cells (e.g., tumor-infiltrating lymphocytes, TCR-transduced T cells, cytokine-induced killer cells, virus-specific T cells, dendritic cell vaccines) after ex vivo modification or expansion.

Approaches includedNonspecific lymphocyte activation (autolymphocyte therapy), tumor-specific lymphocyte propagation (adoptive cellular therapy), antigen-loaded dendritic cell infusions, and genetically engineered T-cell therapies (excluding CAR T for hematologic malignancies addressed in a related policy).

Clinical contextProtocols often include harvest, ex vivo manipulation/selection, host lymphodepletion, and reinfusion; evidence for many indications is limited and investigational status applies to multiple tumor types.

0537T	TC/PC codes previously added or removed (historical coding changes)
0538T	TC/PC codes previously added or removed (historical coding changes)
0539T	TC/PC codes previously added or removed (historical coding changes)
0540T	TC/PC codes previously added or removed (historical coding changes)
Q2040	HCPCS code (removed 1/1/2019; historical)
Q2041	HCPCS code (removed)
Q2042	HCPCS code (removed)
J3590	Noted in historical coding updates
S2107	Noted in historical coding updates
Q2042	Listed historically (coding section changes)

OpenPayer

Adoptive Immunotherapy

Coverage Criteria and Evidence Conclusions

Billing Codes and Coding History

Provider Requirements, Prior Authorization, and Documentation

Background on Adoptive Immunotherapy

Definitions and Terminology