In the context of metastatic castration-resistant prostate cancer (mCRPC), the presence of NK cells within the tumor microenvironment is associated with improved patient prognosis,1 highlighting their potential as therapeutic agents. To enhance the anti-tumor activity of NK cells against prostate cancer, our team has developed a novel tri-specific killer engager (TriKE) targeting prostate-specific membrane antigen (PSMA) on prostate cancer cells. PSMA TriKE binds to PSMA, a marker commonly overexpressed on prostate cancer cells, ensuring tumor specificity. Simultaneously, it activates NK cells via the CD16 receptor, driving potent antibody-dependent cellular cytotoxicity (ADCC). Finally, the inclusion of an IL-15 cytokine moiety directly fuels NK cell survival, proliferation, and priming.
By leveraging NK cells, the PSMA TriKE molecule introduces a highly targeted immune-based strategy that addresses several unmet needs in advanced prostate cancer management. Besides achieving specific and highly effective NK cell anti-tumor responses against PSMA-expressing prostate cancer cells in vitro and in vivo, we demonstrated that PSMA TriKE can reduce unwanted adverse immune response, address tumor antigen escape, maintain NK cell functionality in the suppressive tumor microenvironment (TME) and enhance combination therapy potential for treatment of mCRPC.
Our PSMA TriKE molecule can selectively deliver IL-15 to CD16-expressing NK cells rather than T cells. This therapy minimizes the risk of CRS and other adverse immune responses while allowing lower treatment doses to achieve optimal NK cell expansion capacity. This feature could make it suitable for a broader patient population, including those who are older or have comorbidities that preclude more aggressive treatments like chemotherapy.
A common challenge of targeted therapy is tumor antigen escape. In the context of prostate cancer, resistance to targeted therapies often arises when tumors downregulate or lose the expression of specific antigens, like PSMA. One key aspect of NK cell immunotherapy, that differentiates it from T cell immunotherapy, is that NK cells are able to kill tumor cells through recognition of stress ligands in a process termed natural cytotoxicity. Aside from inducing NK cell ADCC, we showed that PSMA TriKE treatment upregulates natural cytotoxicity receptors on the surface of NK cells and enhances the natural cytotoxicity of NK cells. This enables NK cells to attack stressed cells, like tumor cells, even in the absence of PSMA expression.
Prostate tumors often create a "cold" TME that suppresses immune cell activity. Hypoxia and the presence of myeloid-derived suppressor cells (MDSCs) are hallmarks of the prostate cancer TME that are significant barriers to the success of immunotherapies in prostate cancer. By modeling these hostile settings in vitro, we show that PSMA TriKE can help NK cells overcome these hurdles, maintaining robust anti-tumor activities under adverse conditions.
Finally, PSMA TriKE treatment may potentially enhance the efficacy of combination therapy. NK cells have the ability to orchestrate interactions between the innate and adaptive arms of the immune response. The release of pro-inflammatory cytokines by PSMA TriKE-activated NK cells may “warm up” the “cold” TME of prostate cancer and increase T cell recruitment and activation. The ability to mobilize the immune system could also synergize with immune checkpoint inhibitors, potentially expanding their utility in prostate cancer.
In a microcosm of exciting new therapies for prostate cancer, including antibody drug conjugates, targeted radioligands, vaccine approaches, CAR T cells, and bi-specific T cell engagers, we believe that the TriKE therapeutic approach has a unique place amongst these novel therapies. For patients whose tumors have become resistant to hormone therapies or other PSMA-targeted treatments, PSMA TriKE provides an alternative that leverages the immune system’s natural surveillance mechanisms. Our research represents a potential leap forward in prostate cancer treatment, combining precision, efficacy, and safety. By addressing key challenges like tumor antigen escape and the hostile TME, PSMA TriKE could redefine how we approach advanced prostate cancer.
Written by:
- Shee Kwan Phung, Masonic Cancer Center, Minneapolis, Minnesota
- Nicholas A. Zorko, Masonic Cancer Center, Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
- Martin Felices, Masonic Cancer Center, Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
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