Abstract 5819: Anti-cancer immune effects of PT-112 monotherapy across two disease indications

Abstract Background: PT-112 is a small molecule inhibitor of ribosome biogenesis under development for several cancer indications. Preclinical studies have demonstrated PT-112’s ability to induce immunogenic cell death (ICD) and synergize with various anti-cancer agents, including immune checkpoint inhibitors (ICIs). PT-112 has shown durable benefit in patients with advanced cancers, with pre-clinical data supporting an immune-mediated mechanism of action. This report aims to further elucidate the immunological effects of PT-112 through comprehensive immune profiling of blood and tissue samples from ongoing Phase II trials in thymic epithelial tumors (TETs, NCT05104736) and metastatic castration-resistant prostate cancer (mCRPC, NCT02266745). Methods: Patient samples from the TET trial were analyzed by flow cytometry for 158 subsets of peripheral blood mononuclear cells and serum cytokines and soluble factors. Paired tumor biopsies from a subset of patients were analyzed for changes in immune cell composition before and on treatment. Patient blood samples from the mCRPC trial were analyzed via TCR sequencing to identify novel and expanding T cell clones and to monitor changes in the T cell fraction. Results: In the TET trial (14 patients), peripheral immunome changes reflective of immune activation included an increase in proliferative CD4+ T cells, activated and proliferative CD8+ T cells and NK cells, including NKp46+ NK cells, and PD-L1-expressing refined monocytes, and a decrease in naïve CD4+ T cells. Furthermore, increases in proinflammatory cytokines IFN-γ and TNF-α, along with decreases in immunosuppressive factors VEGF and TGF-β1 were observed (n = 7). Pooled results from tumor biopsies (n=3) showed an increase in immune cell density with increased expression of markers of immune activation (granzyme B and IFN-γ). In the mCRPC trial, 26/74 (35%) patients showed evidence of marked T cell clonal expansions, many of which were novel clones not detected at baseline. Across the population there was a statistically significant (Wilcoxon signed-rank test, p < 0.0005) median increase in the T cell fraction of 20%. Conclusions: In line with prior non-clinical and clinical findings, data from these ongoing Phase II trials show that PT-112 induces robust signals of immune activation and ICD across the adaptive and innate immune systems and are indicative that PT-112’s immune effects play a significant role in its anti-cancer mechanism. Citation Format: Arun Rajan, Tyler D. Ames, Carolina Celades-Errando, Christina Y. Yim, Shannon Swift, Meredith J. McAdams, Laercio DaSilva, Wiem Lassoued, Hana Bagheri, Maria T. Congenie, Howard I. Scher, Alan H. Bryce, James L. Gulley, Jeffrey Schlom, Renee N. Donahue. Anti-cancer immune effects of PT-112 monotherapy across two disease indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5819.