Abstract 2193: Patient-derived colorectal microtumors predict response to anti-PD1 therapy

Abstract Immune checkpoint inhibitors have made remarkable impacts in treating various cancers, including colorectal cancer (CRC). However, CRC still remains a leading cause of cancer-related deaths. While microsatellite instability (MSI) colorectal cancer (CRC) has shown positive responses to anti-PD1-therapy, this subgroup represents a minority of all CRC patients. Extensive research has focused on identifying predictive biomarkers to understand treatment response in CRC. Interestingly, a growing number of clinical cases have reported favorable outcomes from a subtype of supposedly non-responder microsatellite stable (MSS) CRC, characterized by DNA polymerase ε (POLE) proofreading domain mutations with high tumor mutational burden (TMB). This subtype has shown a notable response, either partial or complete, to pembrolizumab as salvage treatment, often following significant disease progression. To improve efficiency, cost-effectiveness, and clinical outcomes, there is an essential need for a testing platform capable of promptly identifying evidence of anti-PD-1 response to inform treatment strategies. Here, we established a novel ex vivo immunotherapy model using patient-derived tumor microexplants (or microtumors <1 mm) co-cultured with autologous peripheral blood mononuclear cells (PBMCs) from treatment-naïve CRC patients. We demonstrate here that long-term ex vivo treatment with pembrolizumab induced a heterogeneous but appreciable interferon-gamma (IFN-gamma) secretion, accompanied by infiltrating PBMCs. Intriguingly, a case study involving an MSS CRC phenotype harboring POLE mutation and associated ultrahigh TMB demonstrated a response to PD-1 blockade, potentially from the intratumoral immune cell population. Ultimately, this novel model could serve as a valuable tool in complementing clinical diagnostics and guiding personalized treatment plans for CRC patients, particularly those with specific phenotypes and mutational profiles. Citation Format: Duy T. Nguyen, Matthew A. Schaller, Krista P. Terracina, Xia Xu, Diego I. Pedro, Alfonso Pepe, Juan M. Urueña, Zadia Dupee, Nickolas Diodati, Ryan Smolchek, Jack E. Famiglietti, Tran Yen Nhi Nguyen, Gerik Tushoski, Kuoyuan Cheng, Lan Chen, Doug Linn, Vania Vidimar, Aquila Fatima, Soon Woo Kwon, Dongyu Sun, Hongmin Chen, Haiyan Xu, Brian Long, Lily Y. Moy, Bonnie J. Howell, George H. Addona, W. Gregory Sawyer. Patient-derived colorectal microtumors predict response to anti-PD1 therapy [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 2193.