Driving Natural Killer Cell Immunotherapy in the Castration-Resistant Prostate Cancer Setting with Novel Trispecific Killer Engager Molecules
Abstract
Prostate cancer is one of the most common cancers found in men, second only to skin cancer. In the majority of cases it can be treated successfully. However, in some cases the cancer will metastasize and the best form to prevent its progression is to deprive it of androgen. The best way to do this is castration, which allows for much longer-term disease free survival. If the cancer comes back again, termed metastatic castration-resistant prostate cancer (mCRPC), the outcomes are much more dire. In the past decade, new treatments have come to market, including abiraterone, enzalutamide, or docetaxel, which can be life-prolonging, but not curative and all mCRPC patients eventually progress. The current proposal focuses on this patient population and addresses the FY19 PCRP Overarching Challenge to “Develop treatments that improve outcomes for men with lethal prostate cancer.” To improve outcomes in men with mCRPC, we propose using an entirely new format of immunotherapy. Immunotherapies, or therapies that enhance the ability of the body’s own cells to kill tumor, are surging in all forms of cancer therapy, including prostate cancer. However, the current immunotherapeutic approaches in the metastatic setting have shown lackluster results. Instead of using checkpoint or T cell mediated approaches, which have demonstrated little efficacy and some toxicities in prostate cancer, we propose targeting a different type of immune cell, natural killer (NK) cells, to prostate cancers. We will achieve this targeting by creating new molecules, called TriKEs, which will form killing “bridges” between the NK cells and the metastatic prostate cancer tumors. The TriKEs have three arms: an arm that grabs onto and activates NK cells, an arm that makes NK cells replicate (so you have more cells to kill the tumor), and an arm that grabs onto a protein expressed by the prostate cancer cells. We will create two TriKE proteins, one that targets a very well established protein expressed on prostate cancer, PSMA, and one that targets a relatively new/promising target in metastatic prostate cancer, Trop-2. We will produce these new TriKEs in cellular factories that export out our drug into the solution they are in and isolate the TriKEs from the solution. TriKEs will then be tested first on normal donor NK cells against cell lines of prostate cancer and later on patient-derived NK cells and against patient-derived prostate tumors. This an entirely new approach to treatment of mCRPC. We hope in the 3 years of this award to generate enough pre-clinical data to file for Food and Drug Administration (FDA) permission for treatment of mCRPC patients with no other recourse. Using a similar model, and earlier Department of Defense funding, we have previously generated TriKE molecules that target blood malignancies and we are about to treat the first patients fall 2019 in a clinical trial for Acute Myeloid Leukemia and Myelodysplastic Syndromes (NCT03214666). The TriKE molecule for that trial is entirely homegrown at the University of Minnesota and was produced for testing into patients by our molecular and cellular therapeutics resource. We hope to do the same with the prostate cancer-specific TriKEs and believe we could produce the clinical batch and obtain FDA permission to test it on patients within a year of the conclusion of these studies. In other words, if the studies proposed here are successful, we believe we could be treating patients with this very novel immunotherapy within 4 years. Though we do not predict much risk to this approach, given the safety profile of NK cells and the tumor-specific pattern of expression of the proteins targeted, we will know more after our first clinical trial on blood cancers. While treatment would occur first at the end of the mCRPC setting, after failure with abiraterone, enzalutamide, or docetaxel, success would push treatment upstream (before those lines of treatment). To attain this goal,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010659
Entities
People
- Martin Felices
Organizations
- United States Army
- University of Minnesota