Adoptive Immunotherapy and Cellular Therapy

Coverage Summary

Policy 0641 — Adoptive immunotherapy and cellular therapy: Aetna considers various adoptive immunotherapy and cellular therapy approaches experimental/investigational for multiple listed indications. Status: CURRENT. Effective date: 2002-08-20. Last review: 2023-09-13. Next review: 2024-07-11. Scope: defines therapies and indications considered investigational and excludes lifileucel for advanced melanoma from this policy. Top-line evidence direction: mixed — some positive signals in specific settings but overall limited and inconclusive evidence supporting routine use; randomized trials are generally needed.

Surface key thresholds and study-stage / evidence summary

thresholds[Post/pre-culture CD8+CD28+ T lymphocyte ratio]> 2.2 associated with better PFS and OS in NSCLC CIK study

thresholds[Post/pre-culture CD4+CD25+CD127+ Treg ratio]<= 0.6 associated with better PFS and OS in NSCLC CIK study

thresholds[Median PFS example]2.2 months (EBV-CTL trial, recurrent/metastatic nasopharyngeal carcinoma)

thresholds[Median OS example]16.7 months (EBV-CTL trial, recurrent/metastatic nasopharyngeal carcinoma)

coverage_stancemixed

scope_summaryDefines Aetna's coverage position: adoptive immunotherapy and cellular therapies listed are considered experimental/investigational; excludes lifileucel for advanced melanoma from scope

policy_number0641

last_review2023-09-13

next_review2024-07-11

Medical Necessity / Experimental Determinations

Experimental and Investigational

Aetna considers the following adoptive immunotherapy and cellular therapies experimental and investigational because effectiveness has not been established.

ALL of the following

Adoptive immunotherapy (TIL/LAK with IL-2): Adoptive immunotherapy using tumor-infiltrating lymphocytes (TILs) or lymphokine-activated killer (LAK) cells activated in-vitro by interleukin-2 (IL-2) for the treatment of the listed indications is experimental/investigational due to lack of adequate evidence that it is more beneficial than IL-2 alone.
Included Indications (not all-inclusive)
- Alzheimer disease and other amyloid disorders
- Esophageal cancer

Coding — Not Covered / Related Codes

Related / Mentioned CPT codesCPT

36511	Therapeutic apheresis; for white blood cells
86357	Natural killer (NK) cells, total count
88230	Tissue culture for non-neoplastic disorders; lymphocyte
88237	Tissue culture for neoplastic disorders; bone marrow, blood cells
88239	Tissue culture for solid tumor

HCPCS codes not covered for indications listed in the CPBHCPCSNot Covered

S2107	Adoptive immunotherapy i.e., development of specific anti-tumor reactivity (e.g., tumor-infiltrating lymphocyte therapy) per course of treatment
M0075	Cellular therapy

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive)ICD-10Not Covered

A00.0 - B99.9	Certain infectious and parasitic diseases
C00.0 - D09.9	Malignant neoplasms and malignant carcinoid tumors
E85.0 - E85.9	Amyloidosis
G30.0 - G30.9	Alzheimer's disease
G72.41	Inclusion body myositis [IBM]
B20	Human immunodeficiency virus [HIV] disease
E08.0 - E13.9	Diabetes mellitus
G10	Huntington's disease
G12.20 - G12.29	Motor neuron disease
I10 - I16.2	Hypertensive disease

1–10 of 35

1/4

The HCPCS and ICD-10 codes and CPT examples listed in this policy are illustrative and not exhaustive; consult the full Clinical Policy Bulletin for the complete, authoritative code lists and billing guidance. Note specifically that the HCPCS codes S2107 and M0075 are called out in the policy as not covered for the indications listed in the CPB.

Provider Actions & Billing Impact

Denial Risk

Therapies considered experimental/investigational

Claims for adoptive immunotherapy (including tumor-infiltrating lymphocytes [TILs] and lymphokine-activated killer [LAK] cells used with interleukin-2), listed cellular therapies, and CAR T–cell therapy for solid tumors are considered experimental/investigational and are subject to denial for the listed indications. Providers should expect potential claim denials when billing the specified HCPCS codes for these services for indications covered by this policy.

Affected HCPCS codes: S2107, M0075
Referenced therapies: TILs / LAK / IL-2 combinations
Referenced therapies: CAR T-cell therapy for solid tumors

Documentation Required

Policy review and record

Clinical Background & Evidence Summary

Adoptive immunotherapy encompasses ex-vivo manipulation and reinfusion of immune cells — e.g., LAK, TIL, dendritic cell immunotherapy, NK cell therapies, and genetically modified approaches such as CAR T cells. The policy summarizes the clinical literature across tumor types and non-malignant conditions and concludes that evidence is mixed and limited; some non-randomized trials and meta-analyses report benefits in specific contexts, but randomized controlled trials with adequate follow-up are generally lacking and needed to establish effectiveness.

Evidence	Summary
{"text":"Cochrane Coppin 2004","status":""},{"text":"No clear evidence of benefit for LAK + IL-2 vs IL-2 alone (Peto OR 0.93, 95% CI 0.50-1.74)","status":""}
{"text":"HCC meta-analyses (Mo 2017; Yuan 2017)","status":""},{"text":"Adjuvant AIT associated with lower mortality and recurrence at 1, 3, 5 years; findings require cautious interpretation due to heterogeneity and study limitations","status":""}
{"text":"NSCLC meta-analyses (Mi 2016; Zeng 2016; Zhao 2017)","status":""},{"text":"Some trials/meta-analyses report OS/PFS benefits with AIT (including combinations with chemo); limitations include heterogeneity and trial quality","status":""}
{"text":"TIL trials / TIL + IL-2 (Weber 2011; Svane & Verdegaal 2014; Mullinax 2018)","status":""},{"text":"Non-randomized trials report high response rates in metastatic melanoma (up to ~50%); randomized comparative evidence lacking—phase III trials needed","status":""}
{"text":"Fan et al 2022 (NSCLC meta-analysis)","status":""},{"text":"AIT combined with chemoradiotherapy improved outcomes: curative effects OR 1.94; OS OR 2.19; adverse effects OR 1.76 (all p<0.001)","status":""}
{"text":"Lee et al (CD19 CAR T) phase I","status":""},{"text":"Feasible and active in pediatric/young adult refractory B-ALL; MTD 1x10^6 cells/kg; grade 4 CRS in 14%; toxicities reversible","status":""}
{"text":"CAR-T reviews re: solid tumors (Almasbak 2016; Holzinger 2016)","status":""},{"text":"Strong efficacy in B-cell hematologic malignancies; solid tumors face challenges (specificity, trafficking, safety) and clinical efficacy remains limited","status":""}
{"text":"Kidney transplant ONE Study (Sawitzki et al 2020)","status":""},{"text":"Regulatory cell therapies safe with similar rejection rates and fewer infections vs standard induction in pooled non-randomized phase I/II trials","status":""}

Clinical thresholds (key/value pairs)

Post/pre-culture CD8+CD28+ T lymphocyte ratio> 2.2

Post/pre-culture CD4+CD25+CD127+ Treg ratio<= 0.6

Median PFS (example)2.2 months (EBV-CTL, recurrent/metastatic NPC)

Median OS (example)16.7 months (EBV-CTL, recurrent/metastatic NPC)

Context/source

Definitions

LAK: autologous lymphocytes expanded with interleukin-2 (IL-2) ex-vivo and reinfused; initial studies did not show benefit over IL-2 alone.

TIL: lymphocytes isolated from tumor tissue, expanded with IL-2 ex-vivo, then reinfused to target tumor-specific antigens.

Adoptive immunotherapy (AIT): infusion of ex-vivo processed immune cells (e.g., T cells, NK cells, LAK, TIL) to treat disease.

CAR T: genetically modified T cells engineered to express chimeric antigen receptors that redirect T-cell specificity to tumor antigens.

Cellular therapy (historical/alternative context): injection or oral administration of processed animal embryonic/fetal/organ tissue (also termed fresh cell therapy, live cell therapy, glandular therapy, xenotransplant therapy) — considered unsupported and potentially dangerous by ACS and CMS.

CIK / DC-CIK: cytokine-induced killer cells generated ex-vivo from peripheral blood mononuclear cells; DC-CIK denotes a dendritic cell–CIK combined product.

Medicare Determinations

Determination	Number	Type	Effective Date
{"text":"National Coverage Determination for Cellular Therapy","status":""},{"text":"NCD #30.8","status":""},{"text":"NCD","status":""},{"text":"","status":""}

Revision History

2002-08-20policy_effective

Policy effective date (policy number 0641)

2023-09-13last_reviewLatest

Last review of the policy (Last Review Date: 09/13/2023)

2024-07-11next_review

Next scheduled review date (Next Review: 07/11/2024)