Tumor infiltrating lymphocytes (TIL) therapy in metastatic melanoma: boosting of neoantigen-specific T cell reactivity and long-term follow-up

Abstract

Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses.PurposeExecute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial.ExperimentalTen patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products.ResultsFive out of 10 patients, who were all anti-PD-1 naïve at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion.ConclusionThe clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial.

T cells expanded from renal cell carcinoma display tumor-specific CD137 expression but lack significant IFN-γ, TNF-α or IL-2 production

“…Intriguingly, with the identical protocol we used here, we generated clinical-grade melanoma TILs at our facilities that readily produce effector cytokines against autologous tumor digest for seven out of seven patients. 42 , 54 Similarly, 76% of our NSCLC-derived TIL products showed tumor-specific cytokine responses to autologous tumors, of which 25% was even polyfunctional. 21 Thus, the restricted tumor-specific cytokine production we observed for RCC-derived TIL products is tumor-type specific.…”

Promises and challenges of adoptive T-cell therapies for solid tumours

“…18 However, despite~90% of cancer incidences globally being caused by solid tumours, only around half of these trials are targeting solid tumours, and they have rarely been extended to non-melanoma cancers, due to a lower immunogenicity of these tumours. [19][20][21][22][23] Moreover, although clinical trials using cell therapy products directed against cancer neoantigens derived from somatic mutations hold promise, evidence of success is still limited to case reports of patients with particular tumour types such as cervical cancer, 24 cholangiocarcinoma, 25 metastatic melanoma, [26][27][28][29] colorectal cancer, 30 breast cancer 31 and thymoma. 32 Further studies are thus needed to advance the potentially curative approach of ACT.…”

Adoptive T Cell Therapy for Solid Tumors: Pathway to Personalized Standard of Care

“…After the initial clinical trials in metastatic melanoma conducted by the NCI, TIL-ACT has been adopted by numerous other institutions around the world for the treatment of a variety of solid tumors [ 11 , 12 , 13 , 14 ]. While objective responses have been replicated in subsequent clinical trials, a significant percentage of patients experience therapy failure by displaying innate or acquired therapy resistance.…”