Clinical feasibility and treatment outcomes with unselected autologous tumor infiltrating lymphocyte therapy in patients with advanced cutaneous melanoma

Abstract

Introduction: A minority of patients (pts) with advanced melanoma achieve long-term survival with immunotherapy and those who relapse following immune checkpoint inhibition (ICI) or BRAFi have limited treatment options. The intrinsic anti-tumor activity and broad neoantigen-specific TCR repertoire of unselected autologous TIL may provide advantages over other treatments in solid tumors, including ICI-refractory melanoma. Methods: This is a retrospective analysis of a single-center experience of TIL for treatment of advanced cutaneous melanoma. Unselected autologous young TIL derived from digested tumor tissue were manufactured under a MHRA Manufacturing Specials license. Pts with advanced cutaneous melanoma and no other treatment options received non-myeloablative lymphodepleting chemotherapy (cyclophosphamide 60 mg/kg/d x 2d, fludarabine 25 mg/m2/d x 5 d [Cy/Flu]), followed by TIL infusion and post-TIL high-dose (HD) IL-2 (600,000-720,000 IU/Kg) on a compassionate use basis. Efficacy for 15 imaging-evaluable pts was reported by investigator assessment of CT/MRI per RECIST 1.1; 6 additional pts were followed using non-RECIST 1.1 imaging (PET) and clinical monitoring. Clinically significant adverse events (AEs) with onset post-TIL infusion were reported for all treated pts. Data cutoff date: 31-DEC-2019. Results: Between OCT-2011 and AUG-2019, 21 pts with advanced cutaneous melanoma were treated with Cy/Flu, TIL (median 31.9 x109 cells infused), and HD IL-2 (median 8 doses). All had high-risk metastatic disease (median 4 sites, stage IV M1d [38%]), an average of 3 prior therapies (any ICI [91%], PD-1 [57%], BRAFi [52%], and MEKi [24%]). With a median follow up of 52.2 mos, the response rate in imaging-evaluable pts (n=15) was 53% with a CR rate of 13%; DCR was 73% including 3 (20%) pts with stable disease. Additional durable responses were observed in the 6 pts followed by PET and clinical monitoring. Responses were generally consistent across subgroups including age, number of disease sites, tumor burden, brain metastases, number of prior lines of therapies, prior PD-1 blockade, prior BRAFi, and prior MEKi. For all treated pts, the median survival was 21.3 mos. Toxicity was generally self-limited and consistent with Cy/Flu and HD IL-2. Common AEs (≥20%, any grade) were thrombocytopenia (62%), pyrexia (57%), rigors (43%), neutropenia (29%), tachycardia (29%), pulmonary edema (24%), and vascular leak (24%); no treatment-related deaths were observed. Conclusion: The high response rate observed in this series exceeds the 41% ORR estimated for TIL in advanced cutaneous melanoma (meta-analysis by Dafni et al. Ann Oncol., 2019) and highlights the successful bench-to-bedside application of unselected autologous TIL to address unmet medical need in advanced melanoma. Use of tumor digests as starting material for manufacturing of TIL demonstrates feasibility of this approach. A multicenter Phase 2 trial of this therapy in advanced melanoma is planned for 2021.