Abstract 2731: STX-001, a locally administered LNP-formulated self-replicating mRNA that encodes the therapeutic payload IL-12, induces deep systemic immune responses to solid tumors
Authors: Sowell Ryan T. , Khurana Jaspreet S. , Su Zhijun , Zhao Weiyu , Shenoy Gautam N. , Dey Madhuri , Lemaire Alexander C. , Simon Anna J. , Njiru Ashley G. , Patenaude Ryan A. , DiMarzio Britt A. , Dzurko Daniel T. , Gately Daniel W. , Coia Aidan B. , Abraham Wuhbet D. , Quiñones Julian , Shah Aalok , Barberio Joseph L. , Nambiar Prashant R. , Becraft Jacob R. , Kitada Tasuku 
Published: June 2023

Abstract
Critical advances in immunotherapies have expanded treatment options and improved patient outcomes across many solid tumor indications. However, durable clinical responses conferred by immunotherapies such as immune checkpoint inhibitors are experienced in only a minority of patients, in part because these therapies fail to sufficiently activate and recruit T cells into the tumor. Therapeutic use of cytokines to potently stimulate tumor-reactive T cells have shown great promise in treating solid tumors but a narrow therapeutic index has precluded their development in the clinic. To overcome these limitations, we developed STX-001, a multi-modal synthetic self-replicating mRNA technology that delivers a prolonged and locally-acting IL-12 cytokine to the tumor microenvironment. STX-001, when delivered directly to the tumor, induces a highly immunogenic tumor cell death while the mRNA-encoded IL-12 payload promotes recruitment of effector T cells and NK cells into the tumor microenvironment. The self-replicating nature of STX-001 enables delivery of therapeutic quantities of IL-12 at dose levels that are orders of magnitude lower than conventional mRNA. STX-001 produces IL-12 upon intratumoral delivery to patient-derived xenografts and the IL-12 payload encoded in STX-001 exhibits similar activity to native IL-12. Using a murine surrogate, a single dose of STX-001 induces deep anti-tumor responses, eradicating tumors in multiple murine models, and promoting responses that are durable against subsequent rechallenge. Furthermore, intratumoral delivery of a single dose of STX-001 controls the growth of distal untreated tumors suggesting capability of promoting systemic immune responses or abscopal effects. Lastly, combination of STX-001 with PD-1/PD-L1 axis inhibitors further enhances efficacy in PD-1 refractory preclinical models. Taken together, our preclinical data demonstrates that STX-001 has potential to overcome limitations of current immunotherapy approaches to improve clinical responses to solid tumors.
Citation Format: Ryan T. Sowell, Jaspreet S. Khurana, Zhijun Su, Weiyu Zhao, Gautam N. Shenoy, Madhuri Dey, Alexander C. Lemaire, Anna J. Simon, Ashley G. Njiru, Ryan A. Patenaude, Britt A. DiMarzio, Daniel T. Dzurko, Daniel W. Gately, Aidan B. Coia, Wuhbet D. Abraham, Julian Quiñones, Aalok Shah, Joseph L. Barberio, Prashant R. Nambiar, Jacob R. Becraft, Tasuku Kitada. STX-001, a locally administered LNP-formulated self-replicating mRNA that encodes the therapeutic payload IL-12, induces deep systemic immune responses to solid tumors [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 2731.