The expression of phosphatidylserine (PS) on cell surfaces drives immunosuppressive mechanisms associated with tolerogenic cell death. In the tumor microenvironment, PS is exposed on tumor cells and tumor vascular endothelial cells and is further exposed with conventional anti-neoplastic therapies. PS signals through multiple immune cell signaling receptors where it drives the expansion of myeloid-derived suppressor cells (MDSCs), regulatory T cells, M2 macrophages, and stimulates the production of immunosuppressive cytokines. PS targeting antibodies have significant anti-tumor effects in multiple preclinical tumor models to re-activate the immune response in the tumor microenvironment.
The combination of PS-targeting antibody ch1N11 with anti-PD-1 or anti-PD-L1 antibodies was compared to single agent therapy in E0771 and EMT-6 mouse syngeneic breast tumor models. Mice were treated IP up to twice per week with ch1N11, anti-PD-1, or anti-PD-L1 as single agents or combinations of antibodies. Tumor and spleen tissue were analyzed by FACS, ELISPOT, immunohistochemistry and RNA expression profiling.
In both tumor models examined, the anti-tumor effect of ch1N11 with combination therapy was significantly superior to single agent therapy. Combination therapy of ch1N11 with anti-PD-1 or anti-PD-L1 significantly inhibited tumor growth by over 90% with greater complete tumor regression compared to single agent therapy in E0771 tumors. Furthermore, combination treatment induced greater rejection of tumors upon tumor re-challenge. Analysis of the tumor microenvironment indicated that the combination of antibody-mediated blockade of PS and PD-1 significantly enhanced tumor infiltration by CD8+ T cells, up regulation of immune activation genes and a decrease in tumor promoting genes.
These results support the combination of PS-targeting antibodies with anti-PD-1 or anti-PD-L1 antibodies for immunotherapy of cancer, including breast cancer.
Clinical trial identification
Legal entity responsible for the study
J. Hutchins: I am an employee of Peregrine Pharmaceuticals, the sponsor of this work.