Dr. Chatzkel on the Rationale for the IMMCO-1 trial in mCRPC and Other Immunologically Cold Tumors

Jonathan Chatzkel, MD, assistant professor of Medicine, the Division of Hematology and Oncology, the University of Florida College of Medicine, University of Florida Health, discusses the rationale for the phase Ib/II IMMCO-1 trial (NCT05000294) investigating the combination of atezolizumab (Tecentriq) plus tivozanib (Fotivda) in metastatic castration-resistant prostate cancer (mCRPC) and other immunologically cold tumors.

The phase Ib/II study is actively enrolling patients toward an upcoming preplanned interim analysis, and investigators noted in a trial-in-progress presentation at the 2023 Genitourinary Cancers Symposium that no unexpected toxicities have been observed thus far.

The increasing use of immune checkpoint inhibitors has revolutionized cancer care, Chatzkel begins. However, some cancers are defined as immunologically hot and allow T-cell infiltration, and immunologically cold tumors do not have high T-cell infiltration, Chatzkel explains. Traditionally, immunotherapy has been heavily utilized in hot tumors, and immune checkpoint inhibitors have demonstrated limited efficacy in tumors classified as cold, including those in pancreatic cancer, prostate cancer, non–triple-negative breast cancer, non–microsatellite instability–high colorectal cancer, well-differentiated neuroendocrine cancer, and ovarian cancer. Cold tumors are believed to scarcely express PD-L1 and have a low tumor mutational burden, Chatzkel notes.

PD-1 is a coinhibitory receptor expressed on activated T cells, B cells, and natural killer cells, Chatzkel continues. Moreover, VEGF is secreted by tumors and leads to endothelial cell proliferation, vascular permeability, and vasodilation. This, in turn, leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, which limits immune surveillance, Chatzkel explains.

VEGF also inhibits dendritic cell differentiation by limiting the presentation of tumor antigens to CD4 and CD8 T-cells, Chatzkel emphasizes. Therefore, investigators hypothesize that VEGF inhibition can increase the effect of immune checkpoint inhibitors in cold tumors through vascular normalization and decreasing inhibitory immune signals, Chatzkel concludes.