Targeting Ovarian Carcinoma with TSP-1:CD47 Antagonist TAX2 Activates Anti-Tumor Immunity.

Abstract

Simple SummaryDue to the nonspecific nature of disease symptoms and late diagnosis, prognosis for ovarian cancer remains poor, while its incidence is increasing dramatically. Current treatment options lead to recurrence for over 80% of patients, and there is a real and urgent need to identify new therapeutic targets, especially in the field of immuno-oncology. Among possibilities, thrombospondin-1 (TSP-1) is a matricellular protein being overexpressed within ovarian tumors, for which interaction with CD47 receptor was reported as directly inhibiting adaptive immunity. We engineered the first-ever orthosteric antagonist that is selective for TSP-1:CD47 interaction, namely TAX2. TAX2 is a cyclic peptide targeting tumor-overexpressed thrombospondin-1 (TSP-1) to prevent CD47 receptor activation. TAX2 acts as a modulator of the tumor-tolerant microenvironment, reprogramming highly vascularized tumors into poorly angiogenic ones, while concomitantly activating the tumor-inhibiting immune system. A large body of in vivo efficacy data support the proof-of-concept for TAX2 use as an anti-cancer therapy.TAX2 peptide is a cyclic peptide that acts as an orthosteric antagonist for thrombospondin-1 (TSP-1) interaction with CD47. TAX2 was first described for its anti-angiogenic activities and showed anti-cancer efficacy in numerous preclinical models. Here, we aimed at providing an extensive molecular characterization of TAX2 mode of action, while evaluating its potential in ovarian cancer therapy. Multidisciplinary approaches were used to qualify a TAX2 drug candidate in terms of stability, solubility and potency. Then, efficacy studies, together with benchmark experiments, were performed in relevant mouse models of ovarian carcinoma. TAX2 peptide appears to be stable and soluble in clinically relevant solvents, while displaying a favorable safety profile. Moreover, clinical data mining allowed for the identification of TSP-1 as a relevant pharmacological target in ovarian cancer. In mice, TAX2 therapy inhibits ovarian tumor growth and metastatic dissemination, while activating anti-cancer adaptive immunity. Interestingly, TAX2 also synergizes when administered in combination with anti-PD-1 immune checkpoint inhibitiors. Altogether, our data expose TAX2 as an optimized candidate with advanced preclinical characterization. Using relevant syngeneic ovarian carcinoma models, we highlighted TAX2’s ability to convert poorly immunogenic tumors into ones displaying effective anti-tumor T-cell immunity.