The spontaneous regression of certain cancers (eg, melanoma) supports the idea that an affected individual's immune system can delay tumor progression and, on rare occasions, eliminate tumors altogether. These observations have led to research into various immunologic therapies designed to stimulate a person'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. This particular type of therapy removes cells from the affected individual, processes them for a period of time, and then infuses them back into the individual. This review focuses specifically on adoptive immunotherapy using tumor-infiltrating lymphocytes in individuals with melanoma.
For individuals with melanoma who receive tumor infiltrating lymphocytes (TILs), the evidence includes the Phase 2 approval trial. Relevant outcomes are overall survival (OS), disease-specific survival, quality of life, and treatment-related mortality and morbidity. The Phase 2, single-arm, international study demonstrated the efficacy and safety of lifileucel, an autologous TIL product, demonstrating a clinically meaningful response (complete or partial response) in 31.4% of patients with advanced melanoma who were refractory to prior immune checkpoint inhibitors and, if BRAF V600 mutation-positive, BRAF or BRAF/MEK inhibitors. This Phase 2 trial data led to accelerated U.S. Food and Drug Administration-approval of lifileucel in February 2024 for this patient population, addressing an unmet need in patients with refractory, difficult-to-treat advanced disease. Continued approval may be contingent upon verification of clinical benefit in additional confirmatory trials. Ideally, multicentric comparative trials of lifileucel, with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as a control arm showing treatment benefits, should be conducted. For use as a second line agent, in patients who have failed anti-programmed death (PD)-1 and targeted therapy, the evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
Tumor-infiltrating lymphocyte (TIL) therapy with an indication approved by the U.S. Food and Drug Administration (FDA) (e.g. lifileucel) may be considered medically necessary as a second-line treatment option in individuals with unresectable or metastatic melanoma previously treated with anti-programmed cell death-1 and, if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.
The use of lifileucel for all other indications is considered investigational.
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CPT |
no code |
|
|
ICD10-PCS |
XW033L7 |
Introduction of Lifileucel Immunotherapy into Peripheral Vein, Percutaneous Approach, New Technology Group 7 |
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XW043L7 |
Introduction of Lifileucel Immunotherapy into Central Vein, Percutaneous Approach, New Technology Group 7 |
| HCPCS | J3490 | Unclassified drugs |
| J3590 | Unclassified biologics | |
| S2107 | Adoptive immunotherapy i.e. development of specific anti-tumor reactivity (e.g., tumor-infiltrating lymphocyte therapy) per course of treatment |
| ICD10-CM | C43.0-C43.9 | Malignant melanoma code range |
| C51.0-C51.9 | Malignant neoplasm of the female genital organs (includes the skin) | |
| C60.1-C60.9 | Malignant neoplasm of the male genital organs (includes the skin) |
The lifelucel product label recommends that individuals receive treatment in an inpatient setting where specialists skilled in cardiopulmonary or intensive care medicine are available.
The product label contains several boxed warnings:
Monitor individuals for prolonged severe cytopenia and monitor for internal organ hemorrhage.
Administer filgrastim or a biosimilar product to patients beginning Day 1 after lifileucel and continue daily until the absolute neutrophil count is greater than 1000 per mm3 for 3 consecutive days, or per institutional standard.
Treat severe infections.
Monitor cardiopulmonary and renal functions throughout the treatment course.
Overall incidence rates for melanoma have been increasing for at least 30 years. In 2025 , there will be an estimated 104,960 new cases of melanoma in the United States, with 8430 estimated deaths.1, In advanced (stage IV) melanoma, the disease has spread beyond the original area of skin and nearby lymph nodes. Although only a small proportion of cases are stage IV at diagnosis, the prognosis is poor; 5-year survival for those with distant metastases is approximately 35%.
Adoptive immunotherapy uses “activated” lymphocytes or other immune cells as a treatment modality.2, 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.
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.
The first product within the scope of this review that has been approved by the U.S. Food and Drug Administration (FDA) is the TIL product lifileucel (Amtagvi, Iovance Biotherapeutics, Inc.).3, Lifileucel was granted accelerated approval in February 2024 for adult patients with unresectable or metastatic melanoma previously treated with a programmed cell death-1 blocking antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. The approval was based on objective response rate to treatment, as evaluated in a multicenter clinical trial. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.
