DeepTM IL-15 Primed T cells Avoid Toxicity and Synergize with PD-L1 Blockade to Overcome Checkpoint Resistance in Cancer

Abstract

Abstract Interleukin-15 (IL-15) is an attractive asset for cancer immunotherapy which activates and expands CD8+ T cells and NK cells but not immunosuppressive Treg cells. IL-15 can also promote protective T cell memory. However, IL-15 systemic administration is limited by toxicities, and IL-15 efficacy can be dampened by PD-1 checkpoint upregulation on T cells. To overcome IL-15 toxicities by focusing its activity on the tumor microenvironment, we have developed DeepTM IL-15, a multimer of crosslinked IL-15/IL-15 Rα/Fc heterodimers. In DeepTM IL-15 Primed T cells, DeepTM IL-15 is surface anchored to tumor reactive T cells prior to adoptive cell transfer (ACT) into tumor-bearing hosts. Here, we show that DeepTM IL-15 coating enables autocrine activation and expansion of the engrafted but not host T cells, protects mice from tumor re-challenge, and limits IL-15 systemic exposure and toxicities. We further show that PD-L1 blockade synergizes with DeepTM IL-15 coated T cell ACT to eradicate checkpoint-resistant tumors in mice. Based on these data, Torque is currently initiating a Phase I clinical study of TRQ15-01 (DeepTM IL-15 Primed multi-targeted human T cells) and planning a combination arm with checkpoint blockade in solid tumors.