Cabozantinib sensitizes microsatellite stable colorectal cancer to immune checkpoint blockade by immune modulation in human immune system mouse models

Abstract

Immune checkpoint inhibitors have been found to be effective in metastatic MSI-high colorectal cancers (CRC), however, have no efficacy in microsatellite stable (MSS) cancers, which comprise the majority of mCRC cases. Cabozantinib is a small molecule multi-tyrosine kinase inhibitor that is FDA approved in advanced renal cell, medullary thyroid, and hepatocellular carcinoma. Using Human Immune System (HIS) mice, we tested the ability of cabozantinib to prime MSS-CRC tumors to enhance the potency of immune checkpoint inhibitor nivolumab. In four independent experiments, we implanted distinct MSS-CRC patient-derived xenografts (PDXs) into the flanks of humanized BALB/c-Rag2nullIl2rγnullSirpαNOD (BRGS) mice that had been engrafted with human hematopoietic stem cells at birth. For each PDX, HIS-mice cohorts were treated with vehicle, nivolumab, cabozantinib, or the combination. In three out of the four models, the combination had a lower tumor growth rate compared to vehicle or nivolumab-treated groups. Furthermore, interrogation of the HIS in immune organs and tumors by flow cytometry revealed increased Granzyme B+, TNFα+ and IFNγ+ CD4+ T cells among the human tumor infiltrating leukocytes (TIL) that correlated with reduced tumor growth in the combination-treated HIS-mice. Notably, slower growth correlated with increased expression of the CD4+ T cell ligand, HLA-DR, on the tumor cells themselves. Finally, the cabozantinib/nivolumab combination was tested in comparison to cobimetinib/atezolizumab. Although both combinations showed tumor growth inhibition, cabozantinib/nivolumab had enhanced cytotoxic IFNγ and TNFα+ T cells. This pre-clinical in vivo data warrants testing the combination in clinical trials for patients with MSS-CRC.

Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors

“…Immune exclusion mechanisms provide potential therapeutic targets that may open the door for MSS CRCs to respond to ICI 67,68 . Biomarkers of immune exclusion may likewise act as predictors of the roughly 30 - 60 % of ICI non-responders in the MSI-H group that are currently immunotherapy candidates 69 .…”

“…Immune exclusion correlates with poor patient outcomes in multiple cancer types and negatively predicts immune checkpoint inhibitor (ICI) response 24,64,65,19,66,28,62 . Immune exclusion mechanisms provide potential therapeutic targets that may open the door for MSS CRCs to respond to ICI 67,68 . Biomarkers of immune exclusion may likewise act as predictors of the roughly 30 -60 % of ICI non-responders in the MSI-H group that are currently immunotherapy candidates 69 .…”

The role of immunotherapy in microsatellites stable metastatic colorectal cancer: state of the art and future perspectives

“…Slightly better results were obtained from the CAMILLA trial, were pMMR mCRC patients who progressed after 2 or more lines of therapy were treated with durvalumab plus cabozantinib. The trial followed preclinical results in which cabozantinib with anti-PD1 showed to slow tumor’s growth and increase expression of the CD4+ T cell ligand HLA-DR on the tumor cells themselves ( 36 ). Despite the different immunotherapeutic agent used, CAMILLA’s efficacy analyses revealed an ORR of almost 30% and a disease control rate of 86.2% (25/29), with a median PFS of 4.4 months and a median OS of 9.1 months ( 37 ).…”

“…Moreover, in a humanized mice model, the association of cobimetinib, bevacizumab and pembrolizumab was not able to act on tumor growth. However, an immune modulation in TILs was observed, suggesting that the combination could potentially enhance immune susceptibility in MSS CRC ( 36 ). The use of dual therapy with VEGF inhibitors and immunotherapy has been widely evaluated in many different malignancies, although no thrilling results were obtained in CRCs ( 24 , 45 , 49 , 50 ).…”

Modeling the Tumor Microenvironment and Cancer Immunotherapy in Next-Generation Humanized Mice

“…Combination of anti-PD-1 antibody with histone deacetylase inhibitors has also shown successful treatment outcomes in breast cancers [182]. Cabozantinib, a multi-tyrosine kinase inhibitor, sensitized MSS CRC PDXs to anti-PD-1 therapy by increasing the frequency of cytotoxic and IFN-γ + T cells in BRGS humanized mice [181]. This treatment also decreased the expression of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), which is an inhibitor immune checkpoint and a marker of exhaustion on CD8 + T cells [213,214].…”