Combination of Targeted Radionuclide Therapy and Immunotherapy for the Treatment of Castration-Resistant Prostate Cancer
Abstract
Immunotherapies are a type of cancer therapy that uses a person’s own immune system to target and kill tumor cells. Checkpoint inhibition therapy is an important type of immunotherapy that enhances the ability of immune cells (T-cells) to attack and kill cancers. These therapies have achieved impressive responses and even cures in certain advanced cancers. Unfortunately, most cancers find ways to counteract the immune attack of T-cells by activating multiple suppressive mechanisms. In proof-of-concept studies, we have demonstrated that low-dose internal radiation therapy using a radioactive agent that selectively targets cancer cells can revert the suppressive character of non-responsive tumors and re-sensitize them to checkpoint inhibition therapies (immunomodulation). Compared to other radiation therapies, our approach is uniquely qualified to deliver immunomodulatory radiation to all sites of disease, regardless of anatomical location, which is an indispensable requirement in the metastatic setting. Thus, this research proposal seeks to investigate the mechanisms by which internal radiation therapy modulates the immune susceptibility of tumors and to leverage this information to design treatment combinations that maximize the efficacy of immunotherapies. Given that, after initial treatment, most prostate cancer patients progress into a lethal form of castration-resistant prostate cancer that is typically refractory to standard therapies and immunotherapies, virtually all men with prostate cancer would benefit at some point in the course of their disease from the new therapeutic approach we plan to investigate. If successful, our treatment combining internal radiation therapy with checkpoint inhibition immunotherapies will offer a potentially lifesaving option to these patients. More importantly, given the prospective benefits and low associated risk of low-dose internal radiation therapy, we project that this approach will be implemented seamlessly into immunotherapy clinical trials. In addition to performing the specific proposed research, I have laid out a training plan that will ensure I receive the necessary instruction in cancer immunology to complement my expertise in radiation therapy. This unique set of skills will allow me to become a leader in the field and achieve my goal of establishing an independent prostate cancer research program in the near future. I have subdivided my training plan into four main objectives/portions: (1) didactic training in immunology, (2) seminars and meetings, (3) clinical exposure, and (4) mentored research. The first two portions are designed to expand my knowledge of general basic immunology and, more specifically, my learning about the latest advances in cancer immunology. To gain clinical exposure, I plan to regularly shadow clinicians who specialize in prostate cancer diagnosis and treatment, including urologists, radiation and medical oncologists, and nuclear medicine physicians, to observe current clinical practices and see how clinical decisions influence the way in which basic research is translated. The last portion of my training will be via mentored research, in which I will be teaming up with Drs. Douglas McNeel and Jamey Weichert, who have extensive expertise in prostate cancer immunology and translational research, to conduct the research described above. This will both enhance my training in translational research study design and consolidate the skills I will use throughout my career, such as scientific writing, data presentation, and state-of-the-art laboratory procedures. These various training elements are designed to complement each other to form an integrated training program that will prepare me for a career in prostate cancer research and help me understand and navigate all the components of interdisciplinary clinical translational efforts. Our research proposal seeks to investigate a whole new area of cancer research: one that combines pro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910285
Entities
People
- Reinier Hernandez
Organizations
- United States Army
- University of Wisconsin–Madison