Tumor-Infiltrating Lymphocyte Therapy Receives FDA Approval
Strong, Jennifer 
Miller, David M.
Brownell, Isaac
PlumX
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The treatment landscape for melanoma has changed dramatically with the advent of immune checkpoint inhibitor (ICI) therapy. However, resistance to ICI immunotherapy is common and treatment options are limited for these patients. Adoptive cell therapy is a promising option in this population. In one approach, tumor infiltrating lymphocytes (TILs) are extracted from a patient’s tumor and expanded. The patient is then given lymphodepleting chemotherapy and the cells are infused back into the patient with interleukin-2 to further enhance in vivo expansion. TIL was first pioneered for advanced melanoma in the 1990s and since then, multiple phase I and II trials have demonstrated objective response rates (ORR) around 50%.1
In the January 2023 Perspectives on the Science, we discussed a phase III trial by Rohaan et al of patients with unresectable stage IIIC or IV melanoma randomized in a 1:1 ratio to TIL or the anti-CTLA-4 monocolonal antibody (mAb) ipilimumab.1 A response to TIL was seen in 49% of patients compared to 21% in the ipilimumab alone group.2 Eighty-six percent of patients had disease refractory to anti-PD-1 treatment.2 Attendees of the Society of Cutaneous Oncology Journal Club found these results encouraging for TIL as an additional option for patients who are refractory to previous immunotherapy, especially when considered with the Iovance-sponsored C-144-01 trial.
In C-144-01, a multi-cohort, multicenter, multiregional study, patients who had previously received PD-1 inhibitors or BRAF +/- MEK inhibitors for advanced melanoma were treated with the TIL lifileucel. In an initial cohort of 66 patients, the ORR was 36%, with two complete responses (CR) and 22 partial responses (PR).3 Both the Rohaan et al and C-144-01 studies demonstrated adverse events in all patients. These included prolonged cytopenias, infection, hemorrhage and cardiopulmonary and renal impairment; events consistent with the known effects of lymphodepleting chemotherapy1 and interleukin-2.2,3 At that point in time, Iovance had been preparing the submission of their Biologics Licenses Application (BLA) for lifileucel to the US Food and Drug Administration (FDA).
1 In C-144-01 the lymphodepletion regimen consisted of cyclophosphamide 60 mg/kg intravenously (IV) with mesna daily for 2 days followed by fludarabine 25 mg/m2 IV daily for 5 days preceding lifileucel infusion.(FDA Summary Basis for Regulatory Action)
In a second cohort of C-144-01 - the primary efficacy set of BLA 125773 (n = 82) - the ORR of lifileucel was 28.0% with a CR rate of 3.7% (n = 3) and a PR rate of 24.4% (n=20)2.4 The median time to response was 1.5 months with 43.5% of responders demonstrating durable responses at 12 months. In a pooled analysis of the two cohorts (n = 153), 4-year overall survival was 22.2% with 20.8% of responses ongoing.5,6 No new serious adverse events were reported 6 months after initial lifileucel infusion, demonstrating reassuring long-term safety.
2 The primary efficacy analysis set included 82 patients who received AMTAGVI. Among these, nine patients received AMTAGVI at a dose less than 7.5 x 109 viable cells and did not achieve an objective response. Therefore, the efficacy set in the product label is 72 patients. Of those 72, the ORR was 31.5%, CR rate was 4.1% and PR rate was 27.4%.(AMTAGI Product Label)
Based on these data, the FDA granted accelerated approval3 for lifileucel on February 16, 2024. Lifileucel, which has the proprietary name of AMTAGVI, is indicated for adults with metastatic or unresectable melanoma previously treated with anti-PD-1 therapy or with BRAF inhibition with or without MEK inhibition. The recommendation for accelerated approval was based on objective response rate and duration of response conferring substantial evidence of effectiveness in a population with a high unmet medical need.4
3 The Accelerated Approval pathway, established in 1992 under 21 CFR 314 Subpart H for drugs and 21 CFR 601 Subpart E for biologics, targets therapies for serious conditions lacking adequate treatments. The Federal Food, Drug, and Cosmetic Act (FD & C), modified by the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, authorizes the FDA to confer Accelerated Approval based on certain criteria. Specifically, upon “determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.”(FDA Guidance for Industry)
The approval of lifileucel follows a path paved by chimeric antigen receptor (CAR) T-cell therapy. In CAR T, T-cells purified from peripheral blood are genetically edited to target a specific protein over-expressed on cancer cells before being expanded and infused into patients.7 In contrast, in TIL, a diverse population of tumor-reactive T cells that have been negatively selected against autoimmunity are amplified. This results in less targeting of healthy tissue, which contributes to the side effects seen in CAR T. However, it is much more difficult to produce TIL on a large scale, as each patient receives an individualized infusion. Furthermore, it is difficult to create a standardized quality control method for TIL, since it targets unspecified antigens. In CAR-T therapy, potency can be assessed through challenge with a known antigen wherein CAR transgene expression levels and interferon-ƴ production can be measured.7 Iovance had to address these significant logistical barriers to make this landmark approval happen. Dr. Graf Finckenstein, an author of C-144-01, noted that a matrix approach looking at several different aspects of the TILs could be used as a measure of quality control.7
Manufacturing of TILs is time-consuming, with initial TILs requiring approximately 8 weeks to manufacture.8 Iovance has created a centralized manufacturing model, in which 30 academic hospitals are approved to collect tumor samples before sending them to a manufacturing center in Philadelphia.8 Iovance has shortened the production time to 22 days and are able to generate therapies for 2,000 patients per year.7 They have plans to further scale up their production volume and number of referring academic centers. A single treatment costs $515,000; however, Iovance states that insurance coverage should be comparable to what is seen with CAR-T.
Given some of these challenges, exactly where and how lifileucel will be integrated into the current standard of care remains unclear. Results from the DREAMSeq trial has established ICI therapy as the new first line therapy for most patients, regardless of BRAF mutation status.9 Given the FDA label, patients with actionable BRAF mutations will likely be treated with BRAF/MEK inhibitors prior to TIL therapy. For patients with BRAF wild-type melanoma, the choice of second-line therapy may depend on which anti-PD1-based treatment strategy is used in the front-line setting. Data from CheckMate-06710 and RELATIVITY-04711 suggest improved outcomes for patients treated with dual-immune checkpoint inhibitor therapy compared with monotherapy anti-PD1. Consequently, there has been a shift towards treating patients possessing poor prognostic features (e.g. high LDH, liver or intracranial metastases) with combination immunotherapy at the outset and utilizing monotherapy anti-PD1 only for those with low-burden disease or significant comorbidities.12 Therefore, patients who progress on combination ICI will likely be offered TIL therapy, when a clinical trial is not available or appropriate. For patients without an actionable mutation that receive single agent anti-PD1 as the initial therapy, providers can now choose between standard of care approaches such as combination anti-PD1/anti-CTLA-4 mAbs, anti-PD-1/anti-LAG-3 mAbs and TIL therapy. In our previous commentary examining Rohaan et al’s study, the minority of respondents said TIL, if FDA approved, would become their preferred second-line treatment strategy for single-agent anti-PD-1 refractory disease, citing toxicity and logistics as reasons.1 Indeed, response rates for dual anti-PD1/anti-CTLA-4 mAbs in the PD-1 refractory setting (21-31%13–15) closely mirror those seen in the BLA-enabling C-144-01. In contrast, anti-PD-1/anti-LAG-3 mAbs appears to have less efficacy in the post-PD-1 progression setting than either approach (ORR 16%).16 Thus, given that access to TIL therapy remains somewhat limited and time-to-treatment is longer than combination ipilimumab/nivolumab, it is likely that a substantial portion of patients with BRAF-wild type melanoma treated with single agent anti-PD-1 ICI will receive non-TIL therapy as second-line treatment.
In addition to challenges with access and time-to-treatment, additional limitations to TILs still need to be addressed. Patients must have accessible tumor tissue to be appropriate candidates. To address this, a phase I trial of TILs generated from the peripheral blood is currently under investigation (NCT04625205). Genetic editing to further improve expansion and selection for neoantigen-reactive T cells may allow for reduced dosing of interleukin-2 in the future, and subsequently fewer adverse events.7 Reduced dosing of lymphodepleting chemotherapy and interleukin-2 is also under investigation (NCT06151847).
Although immune checkpoint inhibitor therapy has profoundly improved outcomes in patients with advanced melanoma, nearly one out of every two patients do not respond to first-line anti-PD1-based treatments, and a similar proportion see their disease progress within the first year of therapy. Therefore evaluating TIL as front-line therapy is an important next step. IOV-MEL-301, a phase III trial of lifileucel plus pembrolizumab versus pembrolizumab alone for untreated advanced melanoma (NCT05727904) is currently recruiting patients.4 Patient selection for this trial, however, may be challenged by the evolving treatment landscape mentioned previously. It is likely that some investigators will be hesitant to enroll patients with poor prognostic features in a trial that randomizes to monotherapy anti-PD1. Similarly, given that over 90% of patients in C-144-01 experienced at least one Grade 3 Treatment Emergent Adverse Event, there will be concern enrolling patients with either significant comorbidities or low disease burden to a trial of TIL therapy. This situation emphasizes the critical need for careful patient selection to optimize the effectiveness of emerging treatments.
4 IOV-MEL-301 is part of the post-marketing requirement (PMR) for the accelerated approval of BLA 125773. ORR and progression-free survival are the co-primary endpoints for the trial, with overall survival as the key secondary endpoint. If the required PMR clinical trial does not demonstrate clinical benefit, the accelerated approval of lifileucel may be withdrawn.(FDA Summary Basis for Regulatory Action)
The FDA approval for lifileucel is promising for the future of cellular therapies. Iovance has demonstrated that it is possible to produce personalized therapies on a larger scale. As a result of Rohaan’s et al study, hospital-derived TIL is available in the Netherlands and Denmark as an investigational agent and the authors plan to apply for approval in Europe.8 The approval of lifileucel for melanoma will likely serve as a model for the FDA approval of cellular therapy for other solid tumors. Multiple studies are underway for the use of TIL in other solid cancers, including cervical cancer, colorectal cancer and head and neck tumors (NCT03108495, NCT05417750, NCT03610490). We look forward to further advances and approvals for TIL to increase treatment options for patients with refractory cancers.
Bibliography
Appendix
Abbreviations
BLA, biologic license application. CAR, chimeric antigen response. CR, complete response. FDA, food and drug administration. ICI, immune checkpoint inhibitor. JC, Journal Club. ORR, objective response rate. TIL, tumor infiltrating lymphocyte. mAb, monoclonal antibody. PR, partial response. SoCO, Society of Cutaneous Oncology.
Disclosures
DMM has received honoraria for participation on advisory boards for Merck, EMD Serono, Regeneron, Sanofi Genzyme, Pfizer, Castle Biosciences, Checkpoint Therapeutics, Incyte, Bristol-Myers Squib. DMM has stock options from Checkpoint Therapeutics and Avstera Therapeutics. DMM has received research funding from Regeneron, Kartos Therapeutics, Xilio Therapeutics, NeoImmune Tech, Inc, Project Data Sphere, ECOG-ACRIN and the American Skin Association. The other authors have no relevant disclosures.
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This editorial piece was published using Quarto®. The image on the “Editorials” page was created by the authors (DMM) using R (version 4.0.0) and the tidyverse suite of packages,17 including ggplot218 with code derived from Art from code by Danielle Navarro.
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Citation
@article{strong2024,
author = {Strong, Jennifer and Miller, David M. and Brownell, Isaac},
publisher = {Society of Cutaneous Oncology},
title = {Tumor-Infiltrating {Lymphocyte} {Therapy} {Receives} {FDA}
{Approval}},
journal = {Journal of Cutaneous Oncology},
volume = {2},
number = {1},
date = {2024-05-01},
url = {https://journalofcutaneousoncology.io/editorials/Vol_2_Issue_1/lifileucel_receives_accelerated_approval},
doi = {10.59449/joco.2024.05.01},
issn = {2837-1933},
langid = {en}
}