Abstract P4-04-02: A clinical-stage toll-like receptor 5 agonist, entolimod, boosts chemo-immunotherapy in pre-clinical TNBC by generating durable antitumor immunity

Abstract

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer diagnoses, is the most aggressive form of the disease, and has the poorest clinical outcomes. Effective or durable therapies are lacking because these tumors lack targets for therapeutic intervention and rapidly develop resistance to chemotherapy (CTx). The FDA has now approved chemo-immunotherapy (CTx-I) regimens (αPD-L1/nab-Paclitaxel, αPD-1/CTx) as standard-of-care for early-stage, locally advanced, and metastatic TNBC. Despite these advancements, overall response rates remain relatively low and survival outcomes are extended for only a few months especially in the case of locally advanced or metastatic disease. Thus, the need exists to develop additional or alternative strategies to potentially build upon and improve CTx-I protocols for TNBC. To this end, our laboratory has explored the importance of engaging the innate immune response to augment the efficacy of CTx-I. Previously, we demonstrated that toll-like receptor (TLR) 5 signaling can elicit antitumor immunity against a preclinical model of metastatic TNBC. In particular, systemic administration of the TLR5 agonist, entolimod, stimulated durable CD8+ T cell immunity against 4T1, the prototypical preclinical PD-L1+ metastatic TNBC model. Here, using primary 4T1 tumors to mirror the clinical setting of locally advanced disease, we show that entolimod boosts the efficacy of CTx-I (αPD-L1/Paclitaxel) by causing tumor regression. Moreover, these mice completely reject a subsequent tumor challenge, highlighting that the entolimod/αPD-L1/Paclitaxel combination generates durable antitumor immunity in such advanced preclinical settings. Importantly, systemically administered entolimod was shown to be safe in Phase I clinical trials cumulatively involving nearly 200 subjects in both healthy volunteers and advanced cancer patients. Thus, this work will aid in formulating a more effective CTx-I treatment regimen with potentially important clinical implications for patients with locally advanced or metastatic TNBC. Citation Format: Craig M Brackett, Alyssa R Aldrich, Kellee F Greene, Bojidar Kandar, Jean Veith, Lyudmila G Burdelya, Scott I. Abrams, Andrei V Gudkov. A clinical-stage toll-like receptor 5 agonist, entolimod, boosts chemo-immunotherapy in pre-clinical TNBC by generating durable antitumor immunity [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-02.