Alleviating Immunosuppression to Enhance CAR T-Cell Efficacy in Metastatic Prostate Cancer
Posted January 29, 2021
Saul Priceman, Ph.D., City of Hope Medical Center
In recent years, the idea of using one’s own immune system to fight off cancer has blossomed into a promising therapeutic strategy. T-cells, which are white blood cells that can recognize and kill other cells, can be harvested from patients and engineered to target their specific cancer. These modified Chimeric Antigen Receptor (CAR) T-cells are then introduced back into the patient to hunt and destroy cancer cells. This process known as Adoptive T-Cell therapy, has been used to effectively treat different blood cancers. However, it has not been successful with prostate cancer as the tumor can hijack the local immune environment to block and evade treatment.
Dr. Saul Priceman and his team at the City of Hope Medical Center have been working on developing a therapy that can overcome immunosuppression so CAR T-cells can recognize and target prostate cancer cells in the body. With the support of a FY16 Idea Development Award he identified that a cyclophosphamide treatment can deplete the immunosuppressive environment that surrounds prostate tumors. This is combined with T-cells that are engineered to recognize Prostate Stem Cell Antigen (PSCA), a protein that is highly expressed on the cell surface of prostate cancers.
They found that treatment with PSCA-CAR T-cells alone was ineffective at reducing tumor burden in mouse models of prostate cancer. However, pre-treatment with cyclophosphamide reduced the blockage of the local tumor microenvironment, allowing the PSCA-CAR T-cells to go into the tumor and kill the prostate cancer cells. This combination was highly effective at both reducing the size of prostate tumors and improving the overall survival of the mice when compared to single therapy. Moreover, the combinational therapy was effective at limiting metastases to the bone and promotes the formation of immune memory against the tumor cells, preventing disease recurrence.
Figure 1. Treatment with cyclophosphamide (Cy) significantly increases survival of mice treated with PSCA targeting mouse CAR T-Cells (PSCA-mCAR).
Dr. Priceman hopes to take the innovations learned from the laboratory bench to the bedside, in order to advance the most innovative and effective therapies for prostate cancer patients. Currently, the team has a Phase I clinical trial (NCT03873805) evaluating the efficacy and side effects of PSCA-CAR T-cells after pre-treatment with cyclophosphamide in patients with PSCA+ metastatic castration-resistant prostate cancer.
John P. Murad, Dileshni Tilakawardane, Anthony K. Park, Kelly T. Kennewick, Lupita S. Lopez, Hee Jun Lee, Brenna J. Gittins, Wen-Chung Chang, Chau P. Tran, Catalina Martinez, Anna M. Wu, Robert E. Reiter, Tanya B. Dorff, Stephen J. Forman, Saul J. Priceman. Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity. bioRxiv 2020.11.18.388892; doi: https://doi.org/10.1101/2020.11.18.388892
Last updated Friday, January 29, 2021