Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma: Intent-to-Treat Analysis and Efficacy after Failure to Prior Immunotherapies

Abstract

Purpose: Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies.Experimental Design: Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning.Results: TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8 þ cells as independent predictive markers for clinical outcome.Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment. Conclusion: Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed.

BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models

“…Recent clinical trials have shown that adoptively transferred T cells generated with different approaches can induce clinically relevant responses for a variety of malignancies (4)(5)(6)(7)(8)(9)(10)(11). However, although some of the patients can achieve complete eradication of the tumors, many of the patients with partial responses eventually relapse (4,5,7,12,13). The data from these clinical trials have suggested that persistence of the transferred T cells is highly correlated with treatment outcome (5,14,15).…”

Cytomegalovirus-Based Vaccine Expressing a Modified Tumor Antigen Induces Potent Tumor-Specific CD8+ T-cell Response and Protects Mice from Melanoma

“…Another approach that has been used recently is to perform adoptive T-cell therapy (ACT), in which tumor-infiltrating lymphocytes (TIL) are isolated from metastases in patients, massively expanded in vitro, and transferred back into patients. Clinical trials have revealed great efficacy of ACT with an objective response rate of about 40% to 50% and a complete response rate of about 10% to 20% (18)(19)(20)(21)(22). However, the process for generating a large number of TILs can be complex and time consuming; as a result, a high percentage of patients have to drop out during TIL preparation.…”

Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

“…A GMP-compliant TIL production process has been established in Manchester in partnership with colleagues at the NKI, Amsterdam; Herlev Hospital, Copenhagen; and the Sheba Medical Centre, Israel, based upon studies carried out at the National Cancer Institute, Bethesda, MD. 3,4 Currently, seven patients have received melanoma TIL outside of the clinical trial situation under a ''specials'' protocol where patients are treated on a compassionate-use basis. A phase II study funded by the NIHR Efficacy and Mechanism Evaluation (EME) program comparing high-and low-dose IL-2 cytokine support in malignant melanoma patients receiving TIL (METILDA) is currently on-hold because of NHS budget issues.…”

“…Ex vivo expansion in a cocktail of various cytokines may reverse the functional deficit before reinfusion. Reports of objective clinical responses in 50-70% of patients with advanced chemoresistant melanoma after TIL therapy 3,4 suggest that this hypothesis has been proven. The long-term goal in this area now becomes to make TIL therapy practical and the antitumor effect durable.…”