Activating the NLRP3 Inflammasome to Treat Advanced Prostate Cancer

Principal Investigators: Akash Patnaik, MD, PhD (University of Chicago), Amy Moran, PhD (Oregon Health & Science University), David Sykes, MD, PhD (Massachusetts General Hospital)

Co-Investigators: Peter Sorger, PhD (Harvard Medical School), Jia-Ren Lin, PhD, MS (Harvard Medical School), Michael Haffner, MD, PhD (Fred Hutchinson Cancer Research Center), Colby Thaxton, MD, PhD (Northwestern University), Massimo Loda, MD (Weill Cornell Medicine), Theodore Karrison, PhD, MS (University of Chicago), Thomas Gajewski, MD, PhD (University of Chicago),

Young Investigators: Kiranj Chaudagar, PhD (University of Chicago), Mindy Graham, PhD (Johns Hopkins School of Medicine), Taghreed Hirz, PhD (Massachusetts General Hospital), Shenglin Mei, PhD (Harvard Medical School)

Description:

• Immune checkpoint immunotherapies are cancer treatments that have been highly effective in several cancer types and can result in long term regressions and cures; however, these treatments have yet to be optimized in prostate cancer.
• A major reason for immunotherapy failure in prostate cancer is the “cold” tumor microenvironment which suppress anti-tumor immune cell activity. Strategies to improve immunotherapy in immunologically “cold” tumors such as prostate cancer are urgently needed.
• Prostate tumors are infiltrated with high levels of immunosuppressive myeloid cells, particularly tumor-associated macrophages (TAM).  Therapeutic strategies to reprogram TAMs may overcome immunosuppression within the metastatic prostate tumor microenvironment.
• Patnaik and colleagues have found that NLRP3, an immune-activating protein, is highly expressed in TAMs from patients with metastatic prostate cancer treated with ADT, and is a promising therapeutic target for reprogramming TAMs from immune-suppressive to immune-activating phenotypes.  In preclinical prostate cancer models, NLRP3 activation blocked tumor growth and was synergistic with androgen deprivation therapy (ADT).
• In this project, Dr. Patnaik and colleagues will investigate whether activation of NLRP3 will overcome TAM-mediated immunosuppression and sensitize advanced prostate cancer to immune checkpoint immunotherapy.
• The role of NLRP3 in tumor-infiltrating TAMs and other immune cells will be investigated in patient samples, before and after ADT treatment.
• The mechanisms by which ADT enhances NLRP3 expression and activity within TAMs will be investigated.
• The mechanisms and therapeutic efficacy of NLRP3 activating treatments, alone and in combination with ADT and immune checkpoint immunotherapies, will be investigated in preclinical prostate cancer mouse models.
• If successful, this project will determine the mechanisms and provide rationale for NLRP3-activation-based immuno-oncology combinations for advanced prostate cancer treatment.

What this means to patients:  Prostate cancers are typically immunologically “cold,” and thus immunotherapy rarely works.  Dr. Patnaik and team have identified NLRP3 as a promising target for reprogramming the prostate tumor microenvironment from immune-suppressive (“cold”) to immune-activating (“hot”). In this project, the team will demonstrate the mechanisms and potential for NLRP3-activation as a new treatment strategy, alone or in combination with immunotherapy and/or ADT. This will provide rationale for clinical trials testing NLRP3-activating agents in prostate cancer, which are already in clinical development.