Abstract 3265: Temozolomide combined with ipilimumab + nivolumab enhances T cell killing of MGMT-expressing, MSS colorectal cancer cells

Abstract

Abstract Colorectal cancer (CRC) is the third most frequently diagnosed cancer and third-deadliest cancer globally. Approximately 95% of patients with metastatic CRC have tumors that are microsatellite stable (MSS) and do not respond to immune checkpoint inhibitors (ICI). Results from the 2022 MAYA clinical trial suggest that the DNA-damaging agent temozolomide (TMZ), which is usually used to treat glioblastoma (GBM), sensitizes patients with MSS, MGMT-silenced CRC to ipilimumab + nivolumab ICI. The benefit of adding ipilimumab + nivolumab to TMZ and the impact of MGMT silencing remain unclear. Here, we aimed to determine in a controlled in vitro system if adding ICI to TMZ enhances T cell killing of MSS CRC cells. We also aimed to determine the role of MGMT in this response. MGMT protein expression was measured by western blot in CRC (n=4) and GBM (n=4) cell lines. Cell viability assays were conducted to measure sensitivity to TMZ. CRC and GBM cells were co-cultured with TALL-104 cells -/+ TMZ and -/+ ICI to measure TALL-104-mediated cell death. Western blot analysis indicated that CRC cells had significantly elevated MGMT expression as compared to GBM cells likely due to MGMT promoter methylation in GBM cells. In line with this, CRC cells were slightly more resistant to TMZ (IC50=100-150 µM) compared to GBM cells (IC50=10-90 µM) after five days of treatment. TMZ + ICI sensitized MGMT-expressing, MSS CRC cells to T cell killing. TMZ alone did not enhance T cell killing of MSS or MSI CRC cells but did enhance T cell killing of T98G GBM cells. Our results indicate that TMZ sensitizes MSS, MGMT-expressing CRC cells to ipilimumab + nivolumab ICI. Importantly, this suggests that TMZ-mediated sensitization to ipilimumab + nivolumab is independent of MGMT status and the patient cohort that may benefit TMZ + ipilimumab + nivolumab may be expanded to CRC patients with MGMT-expressing, MSS tumors. Citation Format: Zenovia Gonzalez, Lindsey J. Carlsen, Wafik S. El-Deiry. Temozolomide combined with ipilimumab + nivolumab enhances T cell killing of MGMT-expressing, MSS colorectal cancer cells [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 3265.