An investigator-initiated phase I study to assess the safety and tolerability of ex vivo next-generation neoantigen-selected tumor-infiltrating lymphocyte (TIL) therapy in advanced immune checkpoint blockade (ICB) resistant solid tumors (NEXTGENTIL-ACT)

Lymphocytes play a crucial role in cancer immunity and patient survival, representing an attractive treatment option for melanoma and diverse epithelial tumors. Neoantigen-reactive TILs can recognize and kill cancer cells, inducing tumor regression and potentially increasing the efficacy of adoptive cell therapies (ACT). NEXTGENTIL-ACT consists of TIL selected based on identifying somatic non-synonymous mutations or viral neoantigens encoded in tandem minigenes and presented by autologous peripheral B cells. This is an investigator-initiated phase 1, single-center, open-label study assessing the safety, tolerability, and anti-tumor activity of single-dose NEXTGENTIL with high-dose IL-2 (720.000 IU/kg) following non-myeloablative lymphodepleting chemotherapy in adults with confirmed metastatic or unresectable advanced ICB-resistant solid tumors. The NEXTGENTIL product contains a polyclonal autologous lymphocyte population of TILs ranging from 5x108 to 1.11x1011 cells expanded from core tumor biopsies and selected based on neoantigen recognition using a high-throughput personalized screening approach. A bridge treatment during TIL expansion and screening for neoantigen recognition is allowed. The primary objectives are to evaluate the safety, tolerability, feasibility, and initial clinical activity. Four more patients will be included if a maximum of one treatment-limiting toxicity is observed in the first six patients. The preliminary anti-tumor activity will be assessed by RECIST v1.1. Patients must be at least 18 years old, have ECOG 0-1, and have received standard therapy (including ICB when indicated). One target lesion must be accessible for a biopsy/resection that allows TIL generation, and another must meet RECIST criteria. Patients must be medically fit enough to undergo all study procedures and interventions and have adequate cardiovascular and pulmonary functions. Patients with an autoimmune disease requiring immunosuppressive treatments will be excluded. EudraCT 2020-005778-90 (27.01.2021), NCT05141474. Vall d’Hebron Institute of Oncology. Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) supported by the BBVA Foundation (grant 89/2017) and Instituto de Salud Carlos III under the “Independent Clinical Investigation” call 2020 (ICI20/00076).