Evaluation of intravenous IPI201 in combination with anti–PD-1 therapy in a colorectal cancer mouse model.

2625 Background: Immune checkpoint inhibitors targeting PD-1 improve outcomes in colorectal cancer (CRC) but are limited by intrinsic and acquired resistance. Resorcinyl isoprenyl benzene derivatives have previously shown anti-tumor activity in multiple models, including remodeling of the tumor microenvironment (TME). IPI201 is a novel, synthetic resorcinyl isoprenyl benzene derivative administered intravenously. Here, we evaluated whether IPI201 combined with anti-PD-1 therapy alters tumor and immune outcomes in a murine model of CRC. Methods: MC38 colon tumors were implanted subcutaneously in mice and treated with vehicle, IPI201 (i.v.), anti-PD-1 (BE0156; i.p.), 5-fluorouracil (5-FU) (i.p.), or IPI201 plus anti-PD-1 at varying dose combinations once the implanted tumor reached a size of 75 mm 3 . Change in tumor volume and subject survival were assessed over 30 days. Tumor necrosis was evaluated by blinded histopathology. Tumor gene expression was analyzed using NanoString nCounter immune-focused panels with pathway and network analyses comparing combination therapy to monotherapies and vehicle controls. Results: While IPI201 or anti-PD-1 monotherapy demonstrated limited activity, combination treatment produced enhanced anti-tumor effects. The optimal dose combination resulted in a 66% reduction in tumor growth compared with anti-PD-1 alone, with a significant treatment interaction ( P =0.03). Combination therapy significantly improved survival relative to monotherapies and 5-FU (50% vs 0%, adjusted P <0.02), yielding the highest survival among treatment groups. Tumor necrosis scores were increased with combination therapy, with necrosis twofold higher than anti-PD-1 alone ( P <0.01). Transcriptomic profiling revealed differential regulation of 771 genes across 51 biological pathways, including VEGF, EGFR, MAPK/ERK, and PI3K/Akt/mTOR signaling, as well as immune-associated pathways related to antigen presentation, cytotoxic lymphocyte activation, and myeloid cell recruitment. This transcriptional signature is consistent with a pro-immune, anti-tumor TME. Conclusions: IPI201 and PD-1 blockade combination improves survival, promotes tumor necrosis, and remodels the tumor microenvironment in a preclinical CRC model. These findings support further development of IPI201 as a combination immunotherapy strategy and provide a mechanistic rationale for evaluating resorcinyl isoprenyl benzene-based enhancers of checkpoint inhibition in CRC.