Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has proven efficacious in metastatic melanoma (Mel). Nevertheless, long-term clinical efficacy remains unsatisfactory for the majority of patients. Therefore, understanding TILs and the orchestrated tumor-microenvironment (TME) states associated with clinical response is of paramount importance.
We report the translational analysis of a single-center phase I study to assess feasibility and efficacy of TIL-ACT in Mel patients (NCT03475134). We performed comprehensive translational studies on patients` tumor longitudinal samples including multispectral immuno-fluorescence (mIF) imaging, bulk RNA-sequencing and single-cell RNA-sequencing before and after TILs infusion (30 days).
Thirteen patients successfully completed TIL-ACT therapy and were included in the analysis. Best overall response was 46.1% (6/13) at 3 months, including two patients with ongoing complete response 3 years after infusion. Responders (Rs) exhibited immunogenic tumor cell states with higher inferred CNVs and overexpressed DNA sensing/IFN and class I antigen presentation-related genes. Multiplex IF imaging revealed that Rs had increased densities of polyfunctional intra-epithelial (ie)CD8+ T cells marked by higher PD-1 expression at baseline, and these cells persisted 30 days after TILs infusion. Single-cell transcriptomic analyses confirmed higher cytotoxic and exhaustion CD8 T cell states at baseline. PDCD1 (PD-1), CXCL13, TNFRSF9 (CD137), GZMB, HAVCR2 (TIM3) and PRF1 genes were overexpressed in CD8+ TILs and associated to clinical responses. Cell-cell interaction predictions corroborated by spatial neighborhood analyses revealed that tumors of Rs were highly enriched for ie-and stromal T-cell networks involving activated myeloid and costimulatory B cells. Successful TIL-ACT therapy reprogrammed the myeloid compartment and further increased CD8 TIL-myeloid cell networks.
Our systematic target discovery study reveals CD8 T-cell network-based biomarkers that could improve patient selection and guide the design of ACT clinical trials.
NCT03475134.
Centre Hospitalier Universitaire Vaudois (CHUV), Ludwig Institute for Cancer Research.
Centre Hospitalier Universitaire Vaudois, Lausanne Branch of the Ludwig Insitute for Cancer Research.
O.A. Michielin: Financial Interests, Institutional, Invited Speaker: BMS, Amgen, Pierre Fabre, Roche, BMS; Financial Interests, Institutional, Advisory Board: BMS, Amgen, Roche, Novartis, Pierre Fabre, MSD; Financial Interests, Personal, Other, Advisory Role: BMS, MSD, Roche, Novartis, Pierre Fabre, Amgen, GSL; Financial Interests, Institutional, Research Grant: BMS, MSD, Pierre Fabre, Amgen, Merck; Financial Interests, Institutional, Funding: BMS, MSD, Pierre Fabre, Amgen, MSD; Non-Financial Interests, Personal, Principal Investigator: BMS, MSD, Amgen, Roche, Pierre Fabre, Novartis. G. Coukos: Financial Interests, Personal, Invited Speaker: CHUV. All other authors have declared no conflicts of interest.