PD-1 blockade drug holiday improves exhausted progenitor CD8 T cell (Tpex) reinvigoration by avoiding Tpex adaptive resistance

Abstract Blocking the programmed cell death 1 (PD-1) pathway using monoclonal antibodies reinvigorates exhausted T cells (Tex), enhancing control of chronic viral infections and cancer. Considerable effort has focused on evaluating different PD-1 blockade agents in preclinical and clinical cancer settings, but relatively little information exists on how to optimize the pharmacodynamic effects of PD-1 pathway blockade on reinvigorating Tex. To address this question, we performed longitudinal tracking of Tex reinvigoration during chronic infection with lymphocytic choriomeningitis virus (LCMV) following different regimens of PD-1 blockade. We compared single-cycle (2 weeks of treatment), long-term continuous PD-1 pathway blockade (i.e. 3 months), or blockade followed by a drug holiday and then re-blockade (intermittent treatment). These studies revealed little benefit of continuous versus single-cycle PD-1 blockade, with both resulting in a single peak of Tex reinvigoration and similar effects on viral replication. In contrast, intermittent blockade resulted in a new cycle of secondary Tex reinvigoration upon redosing after a washout and this secondary Tex reinvigoration improved disease control. Mechanistically, long-term blockade eroded the ability of Tex progenitor cells (Tpex) to give rise to downstream, more functional Tex intermediate (Tex-Int) progeny, whereas the drug holiday restored this Tpex proliferative and differentiation capacity. Tpex from long-term treated mice showed evidence of adaptive resistance and additional layers of negative regulation, including sustained expression of the inhibitory receptor CD22. Indeed, co-blockade of PD-1 and CD22 using combination antibodies or bispecific antibody approaches improved disease control and reinvigoration of Tex. These data have implications for clinical immune pharmacodynamics of PD-1 blockade and provide insights into the biology of Tex reinvigoration. One Sentence Summary Modifying the immunopharmacology of PD-1 blockade reveals a benefit of a drug holiday and identifies mechanisms of Tex progenitor deficiency provoked by prolonged loss of PD-1 signals including the inhibitory receptor CD22. Competing Interest Statement EJW is a member of the Parker Institute for Cancer Immunotherapy which supported this study. E.J.W. is an advisor for Arpelos Bio, Arsenal Biosciences, Coherus, Danger Bio, IpiNovyx, New Limit, Marengo, Pluto Immunotherapeutics, Related Sciences, Santa AnaBio, and Synthekine. E.J.W. is a founder of Arpelos Bio, Arsenal Biosciences, Danger Bio, and holds stock in Coherus. YJH and RPS are currently Merck employees. JRG is a consultant for Arsenal Biosciences, Cellanome, Seismic Therapeutics and GVM1. The authors declare no additional conflicts of interest.