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2025 PCF Challenge Award

Multifactorial Antigen-Presenting Gamma-Delta T cells Targeting Cancer and Viral Antigens for the Treatment of mCRPC

Principal Investigators: Saul Priceman, PhD (University of Southern California), Branden Moriarity, PhD (University of Minnesota), John Lee, MD, PhD (University of California, Los Angeles), Beau Webber, PhD (University of Minnesota)

Young Investigator: Joseph Skeate, PhD (University of Minnesota)    

Description:

  • Metastatic castration-resistant prostate cancer (mCRPC) is a lethal stage of prostate cancer with no curative therapies and limited responsiveness to current immunotherapeutic approaches. While chimeric antigen receptor (CAR) and T cell receptor (TCR) T cell therapies have revolutionized hematologic cancer treatment, their efficacy in solid tumors, including mCRPC, is hindered by T cell exhaustion and difficulty in entering tumors, and an immunosuppressive tumor microenvironment.
  • Recent studies demonstrate that anti-viral memory T cells can be redirected to kill tumor cells by injecting viral peptides into tumors. However, this method is limited by delivery challenges and tumor accessibility.
  • Gamma-delta (γδ) T cells are a distinct, non-conventional, subset of T cells that have promise as immunotherapy candidates due to their unique mechanisms of identifying malignant cells, and ability to migrate into tumors and robustly kill tumor cells. γδ T cells also have allogeneic potential – meaning the same cells can safely be transplanted into different patients, avoiding the patient-specific cell manufacturing process that conventional T cell immunotherapies require.
  • In this project, Dr. Saul Priceman and team at USC, University of Minnesota, and UCLA are developing a novel immunotherapy platform utilizing engineered γδ T cells capable of both direct tumor killing and stimulation of anti-viral memory T cells to kill tumor cells.
  • The team will develop and optimize γδ T cells that express both T cell engagers (TCEs) targeting the prostate cancer proteins PSCA, PSMA, and/or STEAP1, along with viral peptides to stimulate anti-viral memory T cells.
  • They will also generate γδ T cells that express cleavable viral peptides which are only released by tumor enzymes, to limit T cell activity within tumors and reduce toxicities.
  • If successful, this project will establish a modular, off-the-shelf cell therapy that combines direct tumor killing with durable immune activation and could lead to an effective new therapy for prostate cancer.

What this means to patients: T cell immunotherapy has the powerful potential to treat and even cure blood cancers but has yet to be optimized in prostate cancer and other solid tumors. Dr. Priceman and team are developing a novel T cell immunotherapy platform that will target prostate tumors through both engineered tumor-killing activity and activation of anti-viral memory T cells to kill tumor cells. This could overcome limitations of current cellular therapies in mCRPC, and be extended to enable the treatment of other refractory solid tumor cancers