No abstract

Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

Background Uveal melanoma is a rare tumor with no established treatments once metastases develop. Although a variety of immune based therapies have demonstrated efficacy in metastatic cutaneous melanoma, their use in ocular variants has been disappointing. Recently, adoptive T cell therapy has shown salvage responses in multiple refractory solid tumors. Thus, we sought to determine if adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) could mediate regression of metastatic uveal melanoma. Methods In this ongoing single-center, two-stage phase 2, single-arm trial, patients with histologically confirmed metastatic ocular melanoma (aged ≥ 16 years) were enrolled. Key eligibility criteria were an ECOG performance status of 0 or 1, progressive metastatic disease, and adequate hematological, renal, and hepatic function. Metastasectomy operations were performed to procure tumor tissue to generate autologous TIL cultures, which then underwent large scale ex vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy followed by intravenous infusion of autologous TIL and high-dose interleukin-2. The primary end-point was objective tumor response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors (RECIST), version 1.0. An interim analysis of this ongoing trial is currently being reported. The trial is registered with ClinicalTrials.gov as NCT01814046. Findings From the completed first stage and ongoing expansion stage of this trial, a total of twenty-one consecutive metastatic uveal melanoma patients were enrolled and received TIL therapy. Seven of 20 evaluable patients demonstrated objective tumor regression (35%; 95% CI: 16%-59%). Among the responders, six patients achieved partial response (PR), two of which are ongoing and have not reached maximum response. One patient achieved complete response (CR) of numerous hepatic metastases currently ongoing at 21 months post therapy. Three of the responders were refractory to prior immune checkpoint blockade. Common grade 3 or more toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] of patients for each toxicity); anemia (14 [67%] of patients); infection (6 [29%] of patients). There was one treatment-related mortality secondary to sepsis induced multi-organ failure. Interpretation To our knowledge, this is the first report describing the ability of adoptive transfer of autologous TIL to mediate objective tumor regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune based therapies for this cancer. Refinement of this T cell therapy is critical to improve the frequency of clinical responses and the general applicability of this treatment modality. This research was fully supported by the Intramural Research Program of the NIH, NCI, Center for Cancer Research.