Editorial: First Regulatory Approval for Adoptive Cell Therapy with Autologous Tumor-Infiltrating Lymphocytes (TILs) – Lifileucel (Amtagvi)

For more than three decades, studies have evaluated the roles of cells in the interstitium of solid malignant tumors, with increasing attention on tumor-infiltrating lymphocytes (TILs), identified as CD3+ T lymphocytes [1,2]. TILs are CD8+ cytotoxic T lymphocytes (CTLs) that promote a CD4+ Th1 subset cytokine-mediated antitumor response or a regulatory CD4+ Th2 subset response for FOXP3+ regulatory T cells (Tregs) [2,3]. Since the 1990s, preclinical and clinical research studies have demonstrated an association between the behavior of malignant tumors, patient prognosis, and TILs and the potential for adoptive cell therapy using TILs, focusing on melanoma [1,2]. Adoptive cell therapy with autologous, ex vivo-expanded TILs is now a promising approach to cancer treatment [1,4]. This personalized form of immunotherapy involves harvesting T lymphocytes that recognize tumor-specific antigens (TSAs) that infiltrate the microenvironment of an individual patient’s tumor [1,4]. Following lymphodepletion chemotherapy, the isolated TILs are expanded ex vivo and infused back into the patient, where they mount a targeted immune response to malignant cells throughout the body [1,4].

There is a major unmet need in patients with metastatic melanoma due to limited treatment options after failure of approved therapy, including anti-PD-1 or PD-L1 therapy [5]. On February 16, 2024, the US Food and Drug Agency (FDA) granted accelerated approval to lifileucel (Amtagvi) for adult patients with advanced or unresectable melanoma [5]. Lifileucel (Amtagvi) is a tumor-derived autologous T lymphocyte immunotherapy for patients with advanced melanoma previously treated with a PD-1 blocking antibody and, for patients with BRAF V600 positive melanoma, a BRAF inhibitor, with or without a MEK inhibitor [5]. This application to the FDA was granted a priority review and fast-track designation, as well as an orphan drug designation and Regenerative Medicine Advanced Therapy designation [5].

Regulatory approval was based on data from the C-144-01 phase 2 open-label, single-arm, multicenter study in 66 patients with advanced melanoma, previously treated with at least one checkpoint inhibitor and BRAF and/or MEK-targeted therapies (NCT02360579) [6]. Lifileucel was produced using a 22-day process from harvested tumor samples [6]. Patients underwent a lymphodepletion regimen, followed by a single infusion of lifileucel, and up to six doses of high-dose interleukin-2 (IL-2) [6]. The investigator-assessed objective response rate (ORR) was 36% (95% CI; 25–49%), with two complete responses (CRs) and 22 partial responses (PRs) [6]. The tumor control rate was 80% (95% CI; 69–89%), and the median duration of response (DOR) was not reached at a median follow-up of 33.1 months [6]. Chesney and colleagues reported a pooled analysis of safety and efficacy data from 153 lifileucel-treated patients, including the previously reported 66 patients from the C-144-01 study and 87 previously unreported patients [7]. The analysis showed a 31.4% ORR and a median DOR that was not reached at a median follow-up of 27.6 months [7].

The recommended dose of lifileucel (Amtagvi) is 7.5×109 to 72×109 viable T lymphocytes [5,8]. However, the prescribing information for lifileucel (Amtagvi) contains a Boxed Warning for treatment side effects of cardiopulmonary and renal impairment, prolonged and severe cytopenia, susceptibility to infection, and treatment-related mortality [5,8]. In more than 20% of treated patients, the most commonly reported adverse reactions were chills, pyrexia, fatigue, tachycardia, diarrhea, neutropenia, edema, rash, hypotension, alopecia, infections, hypoxia, and dyspnea [5,8].

In early 2024, expert consensus guidelines were published on best practices and patient management for adoptive cell therapy with autologous, ex vivo-expanded TILs [9]. The guidelines have been developed for multidisciplinary teams of physicians, nurses, and other healthcare professionals involved in patient care [9]. This approach to treating advanced-stage solid malignant tumors has shown efficacy and tolerable safety in clinical trials, with advances in the central manufacturing process [9]. Following the first US FDA-approved TIL cell therapy product, lifileucel (Amtagvi), the supporting clinical trials have identified potential adverse events and the complexity of the manufacturing process, which is complex, time-consuming, and potentially costly [5,8]. Awareness of these concerns has prompted the development of guidelines for delivering treatment and patient management and monitoring to ensure the successful integration of adoptive cell therapy with autologous, ex vivo-expanded TILs into clinical practice [9]. An international TIL Working Group, consisting of hematologists and oncologists with expertise in TIL cell therapy, has been formed [9]. The new guidelines and oversight by the TIL Working Group aim to provide and update recommendations for patient treatment eligibility criteria, management, screening tests and clinical and toxicity management, tumor tissue procurement surgery, lymphodepletion, IL-2 administration, and TIL infusion, to develop a standard of care for adoptive cell therapy with autologous, ex vivo-expanded TILs [9].

Conclusions

Treatment of advanced sold malignant tumors using adoptive cell therapy with autologous, ex vivo-expanded TILs is now possible following the first approval of lifileucel (Amtagvi) for adult patients with advanced or unresectable melanoma progressing after treatment with immune checkpoint inhibitors and, if BRAF V600 mutation-positive, BRAF/MEK inhibitors. The clinical studies supporting this regulatory approval have highlighted the complexity of the treatment manufacturing process and the requirements for patient selection, a pretreatment lymphodepletion regimen, followed by a single infusion of lifileucel (Amtagvi), and up to six treatments with high-dose IL-2. Also, the potential for adverse events at each stage of treatment requires close monitoring and follow-up by a specialized multidisciplinary clinical team.