Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma

Abstract

PURPOSE Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product. METHODS We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1. RESULTS Sixty-six patients received a mean of 3.3 prior therapies (anti–programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti–PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2. CONCLUSION Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti–PD-1 or PD-L1 therapy subset.

ACT Up TIL Now: The Evolution of Tumor-Infiltrating Lymphocytes in Adoptive Cell Therapy for the Treatment of Solid Tumors

“…In a recent data analysis of clinical trials at our own institution, we have further concluded that disease progression after CPI therapy does not negate the ability for response to adoptive TIL therapy [88]. Even more recently the TIL-based ACT product, Lifileucel produced by Iovance Biotherapeutics, was shown to produce a durable response against metastatic melanoma in large cohorts of anti-PD-1 and PL-L1 refractory patients [89]. While CPI-resistance does not definitively nullify the success of TIL-based ACT, methods for optimizing treatment of this patient population should continue to be explored.…”

Molecular Markers and Targets in Melanoma

“…A recent meta-analysis by Dafni and colleagues found an ORR of 41% and a complete response rate of 12% in a total of 410 patient treated with TILs [130]. Recently, phase II results evaluating the efficacy of lifileucel (an autologous TIL product) in patients with advanced melanoma who had been previously treated with ICIs and BRAF/MEK-targeted agents observed an ORR of 36% and in patients refractory to anti-PD1/PD-L1 an ORR of 41% [132]. Additionally, a randomized phase III trial (NCT02278887) that is currently recruiting aims to show a better survival rate after TIL infusion compared to standard-of-care ipilimumab in patients with advanced-stage progressive melanoma in the first line of anti-PD1 treatment.…”

Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy

“…Since immune checkpoint inhibitors (ICIs), such as ipilimumab (anti-CTLA-4 antibody), nivolumab, and pembrolizumab (both anti-PD-1 antibodies) achieved FDA approval, the landscape of immunotherapy for treating various solid tumors in recent years has changed [157]. Most clinical trials with ICIs in combination with cell therapy are combining tumor-infiltrating lymphocytes (TILs, e.g., lifileucel) [158], with one of the ICIs for treating melanoma, NSCLC, or head and neck cancer (NCT02027935, NCT03296137, NCT03638375, NCT03645928, NCT01993719). The clinical trials for treating solid tumors using CAR-T cells in combination with PD-1 blockade have been scheduled [159,160] and reviewed in [161].…”