Peripheral memory T cells with self-renewing properties increase with tumor-targeting IL-12 immunocytokine therapy 2308731

Abstract Introduction Stem-like memory T cells (TSCM) are a rare subset of multipotent, self-renewing cells important for antitumor control. Accumulation in the tumor or tumor-draining lymph node of TSCM or T cells expressing TCF1, critical in self-renewal, are associated with improved response of patients to immune checkpoint blockade. These tissues, however, are often not available for study. Here, we evaluated the effects of a tumor-targeting IL-12 immunocytokine PDS01ADC (previously termed NHS-IL12), with promising activity in preclinical and clinical studies, on peripheral T cell stemness in murine hosts and cancer patients. Methods Prevalence of TSCM and expression of the murine T cell stemness marker SCA1 were evaluated by flow cytometry in spleens of mice treated with PDS01ADC. Similarly, TSCM and TCF1+ T cells were assessed in peripheral blood of 28 patients with advanced solid tumors treated with PDS01ADC (NCT01417546). Results PDS01ADC treatment in mice increased peripheral CD8+ and CD4+ TSCM and effector memory T cells (TEM) expressing SCA1. In patients, treatment with PDS01ADC increased CD8+ and CD4+ TSCM and TEM in the periphery expressing TCF1, with increased TCF1+ T cells associated with disease control. Most peripheral TSCM were negative for PD-1 and TIGIT throughout treatment, indicating their continued quiescence and self-renewal. Additionally, expanded TCF1- CD8+ TEM expressing PD-1 and/or TIGIT showed increased intensity of granzyme B, indicating that treatment did not induce CD8+ T effector cell dysfunction. Conclusion This is the first report of a cytokine-based therapy increasing peripheral T cell stemness in mice and humans. Increases in peripheral T cell stemness induced by PDS01ADC correlated with disease stabilization and may serve as an indicator of which patients are more likely to benefit from therapy. These data support future studies combining PDS01ADC with other agents to synergize with this increase in T cell stemness. Funding Source NIH/NCI Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)