Abstract 572: Tumor-activated PD1-directed IL-2 increased antigen specific T cells in tumors and demonstrated anti-tumor activity in mice

Abstract

Although PD-1/PD-L1 therapies have shown significant activity across a range of tumor types, only a subset of patients (10-30%) achieve durable responses. With the goal of improving response and application to PD-1/PD-L1 therapies, we have leveraged our proprietary Xilio Advanced Cytokine Therapies (X-ACT) platform to develop PD1/IL2-ACT, a PD-1 blocker enhanced with a tumor-activated, engineered IL-2 agonist. The activity of IL-2 is blocked by a protein domain that prevents IL-2Rβγ binding until activated in the tumor microenvironment by matrix metalloproteinases . Tumor selective activation of IL-2 enables dosing of PD1/IL2-ACT at sufficient exposure levels to block immunosuppressive PD1/PD-L1 signaling as well as mitigating systemic IL-2 driven toxicity. PD1/IL2-ACT is designed to enable in cis engagement of IL-2 receptors on antigen experienced PD-1+ CD8+ T cells in the tumor microenvironment (TME), inducing effector T cell functions while preventing regulatory T cell (Treg) mediated immune suppression. In a preclinical model, PD1/IL2-ACT, compared to anti-PD1 alone, induced significant tumor growth inhibition. Further, PD1/IL2-ACT was better tolerated than a PD-1 directed unmasked IL-2Rβγ biased agonist in the same preclinical model. Pharmacodynamic studies showed that PD1/IL2-ACT did not significantly change immune cell profiles in the periphery but increased antigen specific CD8+ T cells in the TME, consistent with preferential engagement of PD1+ effector T cells at the tumor site. Ex vivo protease cleavage assays performed in human tumors demonstrated significant activation of PD1/IL2-ACT by tumors of multiple indications but minimal activation in human plasma. A pharmacokinetic study in nonhuman primates revealed PD1/IL2-ACT can achieve comparable exposure levels to existing PD-1 blocking immunotherapies. Taken together, these data illustrate that PD1/IL2-ACT has the potential to broaden the activity of existing immunotherapies by inhibiting the PD1/PDL1 axis as well as directing an immunostimulatory cytokine to antigen specific T cells in the TME. Citation Format: Ertan Eryilmaz, Wilson Guzman, Dheeraj S. Tomar, Parker Johnson, Stephanie Hsiao, Lisa Quinn, Nancy Chan, Jimit Lakhani, Brendan Whalen, Rosa Quiroz, Kurt Jenkins, Oleg Yerov, Will Scott, Justin Greene, Zhen Liu, Megan McLaughlin, Sallyann Vu, Chelsea Turcotte, Hanumantha R. Madala, Jacob Taylor, Caitlin O'Toole, Magali Pederzoli-Ribeil, Haley Duprey, Natalia Malkova, Damiano Fantini, David Crowe, Sean Yang, Kyle Smith, Joseph Card, Janice Lee, Kerri Smith, Benjamin Nicholson, Jijun Dong, Jennifer O'Neil, Carl U. Bialucha. Tumor-activated PD1-directed IL-2 increased antigen specific T cells in tumors and demonstrated anti-tumor activity in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 572.