Increased peripheral T stem cell-like memory features in patients with advanced solid tumors treated with tumor-targeting IL-12 immunocytokine therapy

Abstract Purpose: T cell stemness is important for anti-tumor immunity. The presence in tumor draining lymph node and tumor of stem-like memory T cells (TSCM) and T cells expressing the transcription factor TCF1, critical in T cell self-renewal, are associated with improved response to immune checkpoint inhibitors. Methods: We studied the effects of the tumor-targeting immunocytokine PDS01ADC (NHS-IL12) on peripheral T cell stemness in murine hosts and in patients with advanced solid tumors. TSCM and expression of the murine T cell stemness markers SCA1 (Ly6a) and Tcf7 were evaluated in naïve and tumor-bearing mice receiving murine PDS01ADC (NHS-muIL12). Peripheral blood from patients treated in a clinical trial with PDS01ADC was analyzed for TSCM and expression of TCF1 on T cell subsets. Results: NHS-muIL12 treatment in naïve mice increased SCA1+ peripheral T cells with stem-like phenotypes and promoted tumor infiltration of CD8+ T cells displaying increased stemness. In patients with advanced solid tumors, PDS01ADC treatment increased peripheral CD8+ and CD4+ TSCM frequencies and effector memory T cells expressing TCF1, with greater increases associated with disease control. Most peripheral TSCM were negative for PD-1 and TIGIT throughout treatment, suggesting their quiescence and self-renewal capacity. Expanded TCF1-negative effector memory CD8+ T cells expressed PD-1 with increased intensity of granzyme B, indicating an activated, cytotoxic state. Conclusions: PDS01ADC treatment in patients with advanced solid tumors boosts peripheral T cells with stem-like characteristics, correlating with disease stabilization. Further studies combining PDS01ADC with other immunotherapies to synergize with this peripheral burst of T cell stemness are warranted.