Project 3: A novel telomere-targeted agent for neoadjuvant therapy of early-stage HCC

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

Although surgical resection offers a curative option for patients with early-stage hepatocellular carcinoma (HCC), more than 50% experience recurrence within two years. Perioperative therapy to reduce recurrence has been a high priority, but prior attempts have failed. PD-1/PD-L1 inhibitors show efficacy for advanced-stage HCC but have unclear benefit for RFS in the adjuvant setting. Neoadjuvant immunotherapy appears more successful than adjuvant therapy in inducing pathological responses and preventing recurrence across multiple tumor types, potentially due to higher intact neoantigen exposure; however, this approach has not been thoroughly evaluated in patients with HCC. Efficacious therapies in this setting remain an unmet need. We propose to evaluate a first-in-class anti-cancer agent repurposed at UT Southwestern targeting a novel pathway in telomerase reverse transcriptase (TERT)-activated HCC cells. Our study leverages our basic science discovery of a nucleoside prodrug analog, 6-thio-2’-deoxyguanosine (6-thio-dG), which efficiently and selectively targets telomerase-positive cancer cells but not non-malignant hepatocytes. Our preliminary data indicate that 6-thio-dG not only induces cell cycle arrest and apoptosis in telomerase-reactivated HCC cells, but also activates the innate/adaptive immunity (i.e., cGAS-STING pathway and CD8+ T cells) and enhances response to checkpoint inhibitors in mouse models. Based on promising preliminary data, we hypothesize 6-thio-dG will enhance efficacy of immune checkpoint inhibitor–based therapies. Partnering with MAIA Biotechnology, we propose the following aims: Aim 1. Determine the safety and efficacy of neoadjuvant 6-thio-dG plus cadonilimab in 60 patients with early-stage HCC undergoing surgical resection. We will conduct a randomized phase 1b clinical trial with three arms: 1) cadonilimab alone, 2) 6-thio-dG alone, or 3) cadonilimab plus 6-thio-dG. The primary endpoint is safety as measured by treatment-related delay of surgical resection >28 days following last treatment dose. Secondary endpoints are major pathologic response rate, overall response rate, 1-year RFS, overall survival, and adverse events. Aim 2. Assess the mechanism of action and identify predictive biomarkers of 6-thio-dG activity in patient specimens. Incorporation of 6-thio-dG into telomeres will damage telomeric DNA allowing the use of telomere induced dysfunctional foci, SLC43A3 expression, and TERT promoter alterations as potential predictive markers of 6-thio-dG activity and possibly tumor response. Aim 3. Evaluate synergistic anti-tumor immunity of 6-thio-dG plus cadonilimab in patient specimens. Based on the proposed mechanism of 6-thio-dG-mediated anti-tumor immune activation, we hypothesize biomarkers from specific steps will be associated with 6-thio-dG plus PD-1 blockade efficacy: (i) cGAS-STING pathway activity induced by telomere associated DNA damage, (ii) cross-priming of adaptive immunity, and (iii) activation of cytotoxic CD8+ T cells (i.e. transition from immunologically “cold” to “hot” tumor microenvironment).Collectively, our study will test a novel agent in the neoadjuvant setting and identify molecular factors associated with response to guide patient selection with translation to future trials.