Conventional chemotherapeutic agents are effective for a broad array of patients, but have limited dosing capabilities, lack specificity, and often result in systemic toxicity. Conversely, newer cancer immunotherapies have been successful but benefit only a subset of patients and have varying response rates across different tumors. Here we present SQ3370, a novel approach that activates doxorubicin (Dox) at the tumor site while avoiding systemic toxicities commonly associated with the therapy, and may also activate an immune response against the tumor. SQ3370 is based on a local intratumoral injection of a prodrug-capturing biomaterial (SQL70) followed by 5 daily systemic infusions of an attenuated form of Dox (SQP33). Mutually-reactive click chemistry groups in the 2 components allow the release of active Dox at the tumor site.

While conventional Dox is known to induce immune activation [1] and enhance tumor responsiveness to checkpoint inhibitors [2], its benefit is limited by achievable tumor dose, cumulative cardiotoxicity, and systemic immunosuppression. We safely administered SQ3370 in dogs at 8.95-times the veterinary clinical dose of Dox with minimal side effects. In syngeneic mouse models, SQ3370 improved overall survival and induced a robust anti-tumor response against the injected lesion compared to conventional Dox. Surprisingly, SQ3370 also induced regression of the non-injected tumor and enhanced T-cell infiltration in both injected and non-injected tumors. We hypothesize that releasing Dox at a local site with SQ3370 activates the native immune system against the tumor. Thus, SQ3370 is a new therapeutic modality to treat tumors with a drug with known efficacy, Dox, and expanding its therapeutic window. SQ3370 may potentially also benefit patients with metastatic disease.

SQ3370-001 (NCT04106492), the first-in-human Phase 1 study, is currently open in the United States and Australia to treat patients with advanced solid tumors. Eligible patients are ≥18 years old with an injectable local or metastatic lesion for which published data indicates responsiveness to anthracyclines. Patients must be relapsed/refractory following standard of care therapy and must not have received >225 mg/m2 of Dox (or equivalent anthracycline). The cycle length is 21 days with no limit on total cycles. Primary objectives include safety, tolerability, and recommended Phase 2 dose. Additional objectives include assessment of pharmacokinetics in plasma and tumor biopsies, preliminary efficacy per RECIST 1.1, and immune response as assessed by mass cytometry.

References

1.Mattarollo, S.R., et al. Pivotal Role of Innate and Adaptive Immunity in Anthracycline Chemotherapy of Established Tumors, Cancer Res 2011; 71(14):4809-4820.

2.Zitvogel L., et al. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39:74-88.

Citation Format: Alexander Guminski, Ding Wang, Nam Bui, Vivek Bhadri, Madhawa De Silva, Robert Steffner, Nathan A. Yee, Sangeetha Srinivasan, Jose M. Mejia Oneto, M. Wayne Saville, Vivek Subbiah. Phase 1 trial of SQ3370 in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT225.