Tumor-Infiltrating Lymphocyte Therapy in Melanoma: Facts to the Future

Abstract

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) is gaining momentum and demonstrating durable responses in patients with advanced melanoma. Although increasingly considered as a treatment option for select patients with melanoma, TIL therapy is not yet approved by any regulatory agency. Pioneering studies with first-generation TIL therapy, undertaken before the advent of modern melanoma therapeutics, demonstrated clinical efficacy and remarkable long-term overall survival, reaching beyond 20 months for responding patients. TIL therapy is a multistep process of harvesting patient-specific tumor-resident T cells from tumors, ex vivo T-cell expansion, and re-infusion into the same patient after a lymphodepleting preparative regimen, with subsequent supportive IL2 administration. Objective response rates between 30% and 50% have consistently been observed in heavily pretreated patients with metastatic melanoma, including those who have progressed after modern immune checkpoint inhibitors and BRAF targeted agents, a population with high unmet medical need. Although significant strides have been made in modern TIL therapeutics, refinement strategies to optimize patient selection, enhance TIL production, and improve efficacy are being explored. Here, we review past and present experience, current challenges, practical considerations, and future aspirations in the evolution of TIL therapy for the treatment of melanoma as well as other solid tumors.

Figure 1.

Overview of TIL therapy. Current TIL therapy begins with physician consultation, patient identification, and tumor procurement through surgical resection (step 1). Tumors are then transported centrally to a manufacturing facility or processing hub. TILs are manufactured beginning with digestion and culture or fragmentation of tumors, which yields a suspension of T cells, followed by stimulation and rapid expansion. Manufacturing of unmodified TIL is relatively quick (3 weeks) compared with modified or neoantigen-enriched TIL, which could take several months. The final TIL product is cryopreserved (step 2). TILs are held for later use or immediately transferred to the treatment site. The patient receives NMA-LD for 5 to 7 days, followed by a one-time intravenous infusion of TILs, and supportive IL2 therapy for 3 to 5 days (step 3 A, B, C). The patient is discharged following resolution of chemotherapy and IL2-related toxicity before being evaluated for response (step 4).

Figure 2.

Strategies to optimize T-cell activation in next-generation TIL. Immune-modulation strategies involve improvements in intracellular and extracellular signaling. Strategy 1. Extracellular T-cell activation occurs via TCR/neoTCR-mediated recognition of TAA or neoAg peptides. Novel therapeutic products select and enrich for pre-existing tumor antigen-specific T cells. Strategy 2. Intracellular and extracellular enhancements of T-cell activation and effector function occur through dual CD28 and CD40 intracellular signaling domain-mediated costimulation upon TCR-mediated antigen recognition. Strategy 3. Extracellular T-cell activation through the local delivery of immunomodulatory molecules such as IL7 and CCL19, as well as cell-anchored IL12, or drug-inducible membrane-bound IL15 expression. Strategy 4. Increasing T-cell fitness and reducing T-cell exhaustion with intracellular strategies such as PDCD-1 knockout with TALEN, and CT-1 knockout with CRISPR/Cas9. CCL, chemokine (C–C motif) ligand; FRα, folate receptor alpha; neoAg, neoantigens; TAA, tumor-associated antigens.