Posted July 26, 2017

Xin Lu, Ph.D., University of Notre Dame
Y. Alan Wang, Ph.D., M.D. Anderson Cancer Center
Ronald DePinho, M.D., M.D. Anderson Cancer Center

A significant proportion of patients with advanced prostate cancer who are treated with androgen deprivation therapy eventually relapse with their cancer presenting as lethal metastatic castration resistant prostate cancer (mCRPC). Targeting the immune system would provide an alternative to hormone therapy, and immune checkpoint blockade antibodies have been successful for the treatment of many cancer types. However, mCRPC has shown resistance to these immune checkpoint inhibitors, so development of alternative targeted immune therapies is greatly needed. Towards this goal, Drs. Xin Lu, Y. Alan Wang and Ronald DePinho, with support from a FY13 Idea Development Award, developed a new combination therapy approach to test immune checkpoint blockade antibodies together with small-compound drugs that target a specific type of white blood cells, called myeloid-derived suppressor cells (MDSCs), which strongly suppress anti-tumor immune cells.

To accomplish this, Dr. Lu and colleagues at M.D. Anderson Cancer Center first engineered a novel mouse model based on mouse embryonic stem cell technology to model and run combination therapy trials for mCRPC. This approach allowed them to gain 4-fold increase in the efficiency of producing the mouse cohorts, thus dramatically shortening the time for the in vivo drug trials. They selected the MDSC-targeting drugs cabozantinib and BEZ235, and combined them with a cocktail of immune checkpoint blocking antibodies (anti-CTLA4 and anti-PD1). Through this combination approach, they observed significant synergism between the agents against mCRPC in their model. They further uncovered in-depth molecular mechanisms for the combinatorial efficacy, provided clinical relevance to their study, and expanded their approach to demonstrate synergistic efficacy by adding more specific drugs to combine with immunotherapy.

Following the recent publication of these results in the journal Nature, clinical trials will be needed to substantiate these findings and further explore this combination therapy in men with mCRPC. Dr. Xin Lu recently started his independent faculty position at the University of Notre Dame, and is affiliated with the Indiana University Simon Cancer Center. His research team continues to pursue this line of research and aims to discover new and better strategies for combination immunotherapy against lethal prostate cancer in the next few years.

Model depicting the combination therapy strategy in treating metastatic castration-resistant prostate cancer (CRPC). As demonstrated in the new CRPC animal models, molecularly targeted therapy with agents that inhibit myeloid-derived suppressor cell (MDSC) infiltration frequency and immunosuppressive activity can synergize with immune checkpoint blockade (anti-CTLA4 and anti-PD1 antibodies) to invigorate T cell immunity in the prostate tumor microenvironment and thus impair CRPC progression.

Publication:

Lu X, Horner J, Paul E et al. 2017. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 543, 728�732.

Link:

Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

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