LAUSR

Transforming growth factor-β (TGF-β) receptors regulate SMAD signal transduction and a wide-range of biological processes including, wound healing, angiogenesis, immune modulation, epithelial-mesenchymal transition, cell differentiation, apoptosis, growth, and motility. In transformed cells, TGF-β signaling is frequently exploited to reshape the architecture of the tumor microenvironment (TME) and establish a fibrotic barrier that insulates the tumor from surrounding normal tissue. As a result, immunological threats to the tumor are restricted, as is the anti-tumorigenic potential of immunotherapeutic interventions. Clinically, TGF-β hyperactivity is associated with immunotherapy resistance and poor outcome in a variety of malignancies. We hypothesize that TP-6379, an investigational small molecule inhibitor of TGFBR1, may remodel the TME to expand the access of tumor-seeking lymphocytes to tumor tissue. Herein we describe several anti-tumorigenic effects of TP-6379 observed in multiple mouse models of cancer both as a single agent, and in combination with immunotherapy. In an EMT6 syngeneic mouse model of triple-negative breast cancer (TNBC), we observed that tumor phospho-SMAD2/3 (pSMAD2/3) levels quickly declined post-TP-6379-treatment and were suppressed by 74% after 8 hours. Preclinical data showed TP-6379 plasma levels inversely correlated with pSMAD2/3 suppression. TP-6379 alone was observed to inhibit tumor growth in EMT6 and 4T1 TNBC models, an activity that was enhanced when augmented by immunotherapy. In a Cloudman S91 syngeneic melanoma mouse model, there was a clear subset of mice that responded to combination treatment. Histological analyses of TNBCs and responsive melanomas showed that TP-6379 treatment conferred a loss of induration of tumors, increased vascularization, and increased infiltration of CD45+ leukocytes (including CD8+ T cells), particularly when combined with immunotherapy. High-throughput analyses of tumors uncovered an array of MHC class I and II factors that were observed elevated subject to TP-6379 treatment, an activity that was oftentimes enhanced when combined with immunotherapy. Collectively, these data suggest that TP-6379 may improve immune cell access to tumor tissue via TME remodeling and normalization of vascular networks. Thus, TP-6379 treatment may present a unique and multifactorial anti-tumor strategy, 1) as a single agent to improve anti-tumorigenic immunological responses, and 2) as a combination treatment to boost immunotherapeutic activity. Citation Format: David A. Kircher, Tetyana V. Forostyan, Richard E. Heinz, Curtis A. Allred, Sal Sommakia, Yuta Matsumura, Adam Siddiqui, Jason M. Foulks, Steven L. Warner. TP-6379, an investigational TGFBR1 inhibitor, shown to remodel the tumor microenvironment and enhance anti-tumorigenic immunological responses in syngeneic mouse models of cancer. [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 5171.