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

Abstract

Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) 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 multi-step 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 interleukin-2 administration. Objective response rates between 30% and 50% have consistently been observed in heavily pretreated metastatic melanoma patients, 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.

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma

“…To enable an increased activity, one approach is to decrease the immunosuppressive effect in the TME through, for example, combining TIL therapy with checkpoint inhibitors. 67 Combining checkpoint inhibition with TIL therapy has been investigated in small studies, which showed feasibility and safety in 13 patients with metastatic melanoma, 68 and several trials are still ongoing (NCT02621021, NCT03374839, NCT03645928, NCT01701674). Furthermore, internal checkpoint alterations have yielded promising initial results as well, as presented by Palmer et al, 69 who used CRISPR/Cas9 to disrupt CISH, an internal regulator of T-cell effector function.…”

“…Strategy 4: The last improvement strategy focuses on increasing T-cell function within the TME. To enable an increased activity, one approach is to decrease the immunosuppressive effect in the TME through, for example, combining TIL therapy with checkpoint inhibitors 67 . Combining checkpoint inhibition with TIL therapy has been investigated in small studies, which showed feasibility and safety in 13 patients with metastatic melanoma, 68 and several trials are still ongoing (NCT02621021, NCT03374839, NCT03645928, NCT01701674).…”

Molecular Frontiers in Melanoma: Pathogenesis, Diagnosis, and Therapeutic Advances

“…However, challenges remain, including the variability in response rates among patients and the logistical complexities involved in cell extraction and expansion. Moreover, the therapy’s side effects, such as cytokine release syndrome, necessitate careful patient monitoring [ 112 ]. Future research is directed towards enhancing the efficacy of TIL therapy through combination treatments, improving patient selection criteria, and understanding the genomic correlates of response to therapy [ 113 , 114 ].…”

One signal activated TIL enables potent anti-tumor activity across solid tumor types

“…TIL can naturally target the tumor-specific antigen of the patient and infiltrate into the tumor tissue to kill tumor cells through direct contact or release of cytokines. This capability positions TIL as a promising solution to overcome the challenge of recognizing tumor antigens in the context of solid tumor therapy 7,8 . However, TIL therapy still faces challenges in the treatment of solid tumors due to various microenvironments and immune cell states of solid tumors.…”