Increased Peripheral T Stem Cell-like Memory Features in Patients with Advanced Solid Tumors Treated with Tumor-Targeting IL-12 Immunocytokine Therapy.

Purpose: T-cell stemness is important for antitumor immunity. The presence in tumor-draining lymph nodes and tumor of stem-like memory T (TSCM) cells and T cells expressing the transcription factor T-cell factor 1 (TCF1), critical in T-cell self-renewal, is associated with improved response to immune checkpoint inhibitors.

Experimental design: 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 stem cell antigen 1 (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 stem cell antigen 1-positive 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 cells 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.