Utilization of Genetically Engineered Natural Killer Cells to Secrete Bispecific Immune Engager Molecules in the Prostate Tumor Microenvironment
Abstract
Nearly one in six men in the United States will be diagnosed with prostate cancer (PCa) in their lifetime. While survival rates for men with localized PCa, which remains in the prostate, are very good, the 15-20% percent of men diagnosed with metastatic PCa (mPCa) (cancer spread to other organs and bones) are considered to have incurable disease. Only 28% of men with mPCa will survive 5 years from diagnosis of mPCa. While treatments activating the immune system to fight cancer have led to previously unthinkable cures or long-term disease control with many other cancers, only a rare subset of men (5-10%) with mPCa have realized similar outcomes. This disparity in outcomes is thought to be due to the unique ways that PCa protects itself from attack by the immune system, namely calming down and slowing the immune response in ways that are different from those used by other tumors. One way to address this calming down of the immune system by PCa cells is to make a treatment that not only tags PCa cells for the immune system to destroy, but also stimulates the immune system to continue to kill the PCa cells. We have shown that forming a physical link with a molecule termed a bi-specific killer engager (BiKE) promotes the formation of such a link and stimulates natural killer (NK) cells to kill tumor cells. NK cells are capable of killing multiple tumor cells in a row without the need to recharge like other immune cells. NK cells essentially function guards of the body by reading badges each cell possesses showing whether it is healthy or not. NK badge readers can be redirected with a BiKE molecule to target PCa cells for destruction. The molecule B7-H3 is very commonly expressed on mPCa, but is rarely expressed on normal cells, making it an ideal target to mark mPCa cells for destruction while minimizing attack on normally functioning organs in the body. We can also engineer NK cells (iNK) to make them more effective PCa killers that do their jobs longer and more efficiently. We propose to use a combination of iNK cells which will infiltrate the tumor and then will secrete B7-H3 targeting BiKE within the tumor. BiKE stimulates increased NK cell activity, ramping up anti-tumor response within the calmed area. Our proposal addresses the FY21 PCRP Overarching Challenge to Develop treatments that improve outcomes for men with lethal prostate cancer, by prolonging survival and reducing disease burden of men with mPCa, as these patients are most likely to succumb to their disease. The treatments in this proposal would be for men with mPCa unable to be controlled by currently approved medications. While we may not be able to fully get rid of mPCa once it has spread, our goal is to better control how far and fast it continues to spread by optimizing immune activity with iNK and BiKEs. If we can slow down or stop mPCa from causing damage to other organs, we can ultimately delay the reasons patients pass away from mPCa. Importantly, limiting the spread of mPCa can not only increase duration of survival, but increase quality of life for men suffering from this disease, as mPCa can cause significant pain by compressing organs/nerves and can weaken bones it invades, causing them to break unexpectedly. While no therapy is without risks, NK cells and methods to increase their activity have been shown to be safer than T cells, which are the most common engineered immune therapy under current investigation to treat cancers. Unlike T cells, NK cells (graft) tend not to attack the body of the host (patient) indiscriminately (graft vs. host effect) and focus on the signal they receive from the BiKE to decide which cells to attack and kill. NK cells only very rarely cause an overwhelming inflammatory response, called cytokine release syndrome (CRS), which can cause severe toxicity and death, a common occurrence with T cell treatments. The studies in this proposal would form the rationale for our team to apply for approval t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210242
Entities
People
- Nicholas Zorko
Organizations
- United States Army
- University of Minnesota