Abstract 3261: SQ3370, a doxorubicin-based click chemistry therapeutic, promotes a shift from an immunosuppressive towards a T-cell permissive tumor microenvironment in patients

Abstract

Abstract Click chemistry encompasses chemical reactions that are highly efficient, rapid, and proceed in complex environments. The 2022 Nobel Prize in Chemistry was awarded to Sharpless, Meldal, and Bertozzi in recognition of the transformative effect click chemistry has had in research and drug development. Shasqi is pioneering the use of click chemistry in humans with the Click Activated Protodrugs Against Cancer (CAPAC™) platform, which enables localization of an activator to tumors and conversion of attenuated protodrugs to active drugs though click chemistry reactions. Shasqi’s lead candidate, SQ3370, is a therapeutic based on click chemistry in humans to activate doxorubicin (Dox) specifically at tumors. SQ3370 consists of an intratumorally-injected tetrazine-modified biopolymer and a systemically administered trans-cyclooctene-modified Dox protodrug. SQ3370 provides enhanced safety and efficacy in preclinical models compared to conventional Dox and is being evaluated in a Phase 2a study in solid tumors (NCT04106492). Here, we report the findings from immune cell profiling of samples collected from patients enrolled in the SQ3370-001 Phase 1 study. Tumor biopsies and PBMCs isolated at baseline and after each of the initial two treatment cycles were analyzed using multiplex immunohistochemistry and mass cytometry, respectively. SQ3370 treatment induced immune activation in tumors despite a heavily pre-treated patient population. Specifically, we saw elevated cytolytic lymphocyte activity in tumors after SQ3370 treatment, marked by an increase in Granzyme B+ CD8+ T-cells relative to baseline. Moreover, SQ3370 promoted a shift from an immune suppressive towards a T-cell permissive tumor immune microenvironment, in part by modulating the myeloid-to-CD8+ T-cell ratio in tumors. No changes in major lymphocyte populations with treatment were observed by mass cytometry, suggesting no systemic treatment-related toxicity or immunosuppression. Minor changes were indicative of a favorable systemic response to SQ3370. Trends in the expansion of circulating plasmacytoid dendritic cells, central memory CD8+ T-cells, and transitional monocytes coupled with a reduction in systemic neutrophils and T regulatory cells indicate subtle shifts within adaptive and innate immune cell compartments that correspond with anti-tumor responses. Our assessment of immune changes after SQ3370 treatment confirms that observations in preclinical models are translatable to humans, as similar T-cell supportive immune changes were observed in syngeneic tumor models with SQ3370. Consistency between immune responses in clinical and preclinical samples underlines the translatability of the click chemistry-based drug and suggests that its broad therapeutic potential may be further enhanced with combined immunotherapies. Citation Format: Masa Aleckovic, Sangeetha Srinivasan, John Lee, Jesse M. McFarland, Leslie Priddy, Matthew Tso, Tri-Hung Nguyen, George Coricor, Jose M. Mejía Oneto. SQ3370, a doxorubicin-based click chemistry therapeutic, promotes a shift from an immunosuppressive towards a T-cell permissive tumor microenvironment in patients [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 3261.