Prostate Cancer Research
Progress Report: William Redmond, PhD
Investigator: William Redmond, PhD – Assistant Professor, Providence Portland Medical Center
Reversing prostate tumor-induced CD8 T cell fatigue
T cells are specialized white blood cells that are key cellular combatants of invading microbes and tumor cells. Certain subsets of T cells recognize proteins (antigens) on tumor cells, physically engage the tumor cell, and with optimal conditioning will kill the tumor cell as though it is a foreign infectious microbe. However, since cancer is a chronic disease the T cells are repeatedly exposed to tumor antigen and as a result become fatigued in a process known as T cell anergy. In anergy, T cells become unresponsive to tumor antigens and no longer are able to kill. A protein expressed on T cells, named OX40, can enhance T cell activation and killing. During the process of anergy the OX40 stimulation pathway is blunted. An antibody that stimulates OX40, called anti-OX40 mAb, augments T cell responses and is in clinical trials for the treatment of castration-resistant prostate cancer. Dr. Redmond’s research is focused on developing combination immunotherapies using agents such as anti-OX40 to restore the immune system’s capacity to attack and destroy tumors in prostate cancer patients.
To determine which immunotherapies would cooperate with anti-OX40, Dr. Redmond first investigated how anti-OX40 treatment alone affects the quantity and function of T cells. In studies using mouse models of prostate cancer, he found that anti-OX40 increased the number of active T cells through induction of T cell proliferation and elevated their cytotoxicity by increasing their production of a tumor cell killing agent called granzyme B. Since IL-2 (a cytokine: an immune signaling molecule) enhances the level of OX40 expression on T cells, Dr. Redmond tested a combination therapy using both anti-OX40 and IL-2 in mice with prostate cancer. He found that this treatment strategy was even better than anti-OX40 treatment alone as the mice experienced a ~15% increase in overall survival time.
Ipilimumab, an immunotherapy currently in Phase III clinical trials for prostate cancer, is synergistic with anti-OX40. Ipilimumab releases the brakes on the immune system by targeting a molecular brake on T cells named CTLA-4. Dr. Redmond tested the combination of Ipilimumab and anti-OX40 in a murine prostate cancer model and discovered that the two agents were able to completely abrogate tumor formation. He showed that both agents significantly elevated the number and functional capacity of T cells in the mice. In sum, Dr. Redmond’s findings reveal the potential power of combination immunotherapy strategies. Future directions include translating these findings into the clinic for use in human prostate cancer patients.