Abstract A109: Cabozantinib sensitizes microsatellite stable colorectal cancer to immune checkpoint inhibition by immune modulation in humanized mouse models
Authors: Lang Julie , Leal Alexis D. , Hartmann Sarah J. , Marin-Jimenez Juan , Shulman Jeremy , Capasso Anna , Bagby Stacey M. , Yacob Bethlehem W. , Blanchford Patrick J. , Lieu Christopher H. , Messersmith Wells A. , Pitts Todd M. 
Published: March 2020

The success of single-agent checkpoint inhibitors has been unfortunately limited to a subset of cancers. For colorectal (CRC) cancers, anti-PD1 therapies have proven to be successful in the clinic for microsatellite instable (MSI-high) tumors but have no efficacy in the majority of CRC patients who have microsatellite stable (MSS) cancers. The tumor antigen burden as well as the tumor microenvironment are two key important features that distinguish “hot,” or immunogenic, from “cold” tumors. Cabozantinib is a small-molecule tyrosine kinase inhibitor that has received FDA approval as a cancer treatment in renal cell, medullary thyroid, and hepatocellular carcinoma. Using humanized mice, we tested the ability of cabozantinib to “prime” the tumors and the human immune system to enhance the potency of nivolumab (anti-PD1). In four independent experiments, we implanted distinct MSS CRC patient-derived xenografts (PDXs) into the flanks of humanized BRGS (BALB/c, Rag2-/-, IL2RγC-/-, NODSIRPα) mice that had been engrafted with human hematopoietic stem cells at birth. For each PDX, humanized mice cohorts were treated with vehicle, nivolumab, cabozantinib, or a combination of nivolumab plus cabozantinib. In three out of the four models, the combination had a better survival experience versus the nivolumab-treated group. The fourth model demonstrated an equal survival experience in the combination versus nivolumab treated. Furthermore, the human immune system in the immune organs and tumors was interrogated by flow cytometry to assess changes in the cellular composition and the activation state of the immune system as a result of treatments. In addition, the expression of immune-related molecules was assessed on the tumor cells themselves. Over the four experiments, we found consistent changes in some immune parameters within treatment arms, including increases in CD4+ T cells as a result of cabozantinib treatment alone or CD8+ T cells with nivolumab alone. Similar to reports from mouse and human immunotherapy trials, we also observed increases in IFNγ-producing T cells in the tumors of combination-treated mice. Notably, inhibitory receptors, such as TIM-3 and PD-L1, were shown to be increased on both the human T cells and the tumors themselves as a result of cabozantinib alone or in combination with nivolumab. Furthermore, we also observed upregulation of other IFNγ-responsive genes including antigen-presenting molecules, MHC Class I and II, on the tumor cells from mice treated with both drugs. Thus, our data from humanized mice bearing CRC MSS xenografts show reduced tumor growth that correlates with activation of human T cells and increased “immunogenicity” of the tumors themselves following treatment with cabozantinib and nivolumab. These preclinical in vivo data warrant translation to testing in human trials for patients with MSS CRC.

Citation Format: Julie Lang, Alexis D. Leal, Sarah J. Hartmann, Juan Marin-Jimenez, Jeremy Shulman, Anna Capasso, Stacey M. Bagby, Bethlehem W. Yacob, Patrick J. Blanchford, Christopher H. Lieu, Wells A. Messersmith, Todd M. Pitts. Cabozantinib sensitizes microsatellite stable colorectal cancer to immune checkpoint inhibition by immune modulation in humanized mouse models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A109.