01 May 2024: Editorial
Editorial: First Regulatory Approval for Adoptive Cell Therapy with Autologous Tumor-Infiltrating Lymphocytes (TILs) – Lifileucel (Amtagvi)
Dinah V. Parums1A*DOI: 10.12659/MSM.944927
Med Sci Monit 2024; 30:e944927
Abstract
ABSTRACT: On February 16, 2024, the US Food and Drug Agency (FDA) granted accelerated approval to lifileucel (Amtagvi), an adoptive immune cell therapy with autologous ex vivo-expanded tumor-infiltrating lymphocytes (TILs) 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, with the potential for adverse events at each stage of treatment. In early 2024, expert consensus guidelines were published on best practices and patient management for adoptive cell therapy with autologous, ex vivo-expanded TILs, and an international TIL Working Group was formed in anticipation of further regulatory approvals bringing these treatments to the clinic. This editorial aims to provide an update on the importance of a first approval for adoptive cell therapy with autologous, ex vivo-expanded TILs and the challenges of implementing a complex, time-consuming, and potentially costly immunotherapy.
Keywords: Editorial, Adoptive Cell Therapy, Melanoma, Tumor-Infiltrating Lymphocytes
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,
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,
Conclusions
Treatment of advanced sold malignant tumors using adoptive cell therapy with autologous,
References
1. Rosenberg SA, Yannelli JR, Yang JC, Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2: J Natl Cancer Inst, 1994; 86(15); 1159-66
2. Gooden MJ, de Bock GH, Leffers N, The prognostic influence of tumour-infiltrating lymphocytes in cancer: A systematic review with meta-analysis: Br J Cancer, 2011; 105(1); 93-103
3. Hori S, Nomura T, Sakaguchi S, Control of regulatory T cell development by the transcription factor FOXP3: Science, 2003; 299(5609); 1057-61
4. Zhao Y, Deng J, Rao S, Tumor infiltrating lymphocyte (TIL) therapy for solid tumor treatment: progressions and challenges: Cancers (Basel), 2022; 14(17); 4160
5. Food and Drug Administration (FDA): FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma February 16, 2024 Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
6. Sarnaik AA, Hamid O, Khushalani NI, Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma: J Clin Oncol, 2021; 39(24); 2656-66
7. Chesney J, Lewis KD, Kluger H, Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: Pooled analysis of consecutive cohorts of the C-144-01 study: J Immunother Cancer, 2022; 10(12); e005755
8. , Highlights of prescribing information for AMTAGVI (lifileucel) suspension for intravenous infusion: Initial U.S. Approval February, 2024 Available from: https://www.fda.gov/media/176417/download
9. Warner AB, Hamid O, Komanduri K, Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy: J Immunother Cancer, 2024; 12(2); e008735
In Press
16 Mar 2024 : Clinical Research
Diagnostic Efficiency of ACR-TIRADS Score for Differentiating Benign and Malignant Thyroid Nodules of Vario...Med Sci Monit In Press; DOI: 10.12659/MSM.943228
08 May 2024 : Clinical Research
Effect of Individualized PEEP Guided by Driving Pressure on Diaphragm Function in Patients Undergoing Lapar...Med Sci Monit In Press; DOI: 10.12659/MSM.944022
21 Mar 2024 : Clinical Research
Impact of Serum Vitamin D, B6, and B12 and Cognitive Functions on Quality of Life in Peri- and Postmenopaus...Med Sci Monit In Press; DOI: 10.12659/MSM.943249
17 Mar 2024 : Clinical Research
Protective Role of TRPC3 Gene Polymorphism (rs10518289) in Obstructive Sleep Apnea Hypopnea Syndrome Among ...Med Sci Monit In Press; DOI: 10.12659/MSM.942667
Most Viewed Current Articles
17 Jan 2024 : Review article
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
14 Dec 2022 : Clinical Research
Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase LevelsDOI :10.12659/MSM.937990
Med Sci Monit 2022; 28:e937990
16 May 2023 : Clinical Research
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387
01 Jan 2022 : Editorial
Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...DOI :10.12659/MSM.935952
Med Sci Monit 2022; 28:e935952