Abstract A029: SQ3370: CAPAC platform enables tumor-localized therapy and minimizes systemic toxicities

Abstract

Abstract Conventional chemotherapies lack specificity for tumor tissue, have a low therapeutic index, and induce systemic toxicities including cardiomyopathy. SQ3370 utilizes the Click Activated Protodrugs Against Cancer (CAPAC) platform to localize doxorubicin (Dox) to tumor tissue while minimizing systemic exposure. SQ3370 consists of an intratumoral injection of a biopolymer followed by 5 daily intravenous doses of an attenuated protodrug of Dox. The tumor-localized activation of Dox is enabled by mutually reactive click chemistry groups on the biopolymer and protodrug, and is therefore agnostic to tumor characteristics that can vary from patient to patient. This allows the CAPAC platform to be readily applicable to diverse tumor types, including heterogeneous sarcoma subtypes. The lead candidate, SQ3370 is currently being evaluated in a Phase I study in patients with advanced solid tumors (NCT04106492). In preclinical studies, SQ3370 treatment showed reduced toxicity, enabling doses of 19.1-fold and 8.9-fold the maximum tolerated dose of conventional Dox in mice and dogs, respectively. Further, there was no evidence of cardiotoxicity in dogs at this dose. In syngeneic dual-tumor mouse models of MCA205 fibrosarcoma, MC38 colon carcinoma, and B16-F10 melanoma, only one tumor was injected with the biopolymer. Following 5 daily intravenous doses of the protodrug, dose-dependent antitumor responses were seen in the injected and non-injected lesions across all syngeneic models. Furthermore, T-cell infiltration was observed in both lesions of the MC38 dual-tumor model, suggesting activation of an antitumor immune response by SQ3370. The combination of SQ3370 with an immune adjuvant (TLR9 agonist) further prolonged overall survival, improved the antitumor response, and increased the number of complete responses compared to the monotherapy, likely by enhancing the immune activation effects of SQ3370. Conventional Dox can induce cardiomyopathy at incidences of 1-20% for cumulative doses from 300-500 mg/m2 in humans. In the Phase I trial, SQ3370 was well tolerated in patients receiving more than 1000 mg/m2 Dox in cumulative doses. Treated tumors included sarcoma (73%), breast cancer (7.7%), gyne (7.7%), and others (11.5%). Dose escalation is ongoing. Most frequent adverse events (AEs), included nausea, fatigue, and anemia. Ejection fraction (LVEF), indicative of cardiac function, remained normal during the study period. No AEs that led to discontinuation or death were related to SQ3370 by investigator assessment.In summary, SQ3370 facilitates localization of Dox at the tumor with minimal systemic toxicity and demonstrates the first proof of concept of the click chemistry-based CAPAC platform. The CAPAC Platform represents a new therapeutic modality to treat solid tumors by using a drug with known efficacy, such as Dox, and expanding its pharmacological capabilities. Citation Format: Jose M. Mejia Oneto, Sangeetha Srinivasan, Jesse M. McFarland, Matthew Tso, Masa Aleckovic. SQ3370: CAPAC platform enables tumor-localized therapy and minimizes systemic toxicities [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A029.