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Developing Engineered Cell Therapies for Metastatic Castrate-Resistant Prostate Cancer to Increase Efficacy and Decrease Toxicity

Carl June, MD

Project Title: Developing Engineered Cell Therapies for Metastatic Castrate-Resistant Prostate Cancer to Increase Efficacy and Decrease Toxicity

Principal Investigators: Carl June, MD (University of Pennsylvania), Saul Priceman, PhD (City of Hope), Joseph Fraietta, PhD (University of Pennsylvania), Naomi Haas, MD (Abramson Cancer Center at the University of Pennsylvania Perelman School of Medicine), Avery Posey, PhD (University of Pennsylvania), Tanya Dorff, MD (City of Hope), John Maris, MD (Children’s Hospital of Philadelphia), James Gulley, MD, PhD (National Cancer Institute)

Co-Investigators: Vivek Narayan, MD (Abramson Cancer Center at the University of Pennsylvania Perelman School of Medicine), Priti Lal, MD (University of Pennsylvania), Regina Young, PhD (University of Pennsylvania), Evan Weber, PhD (Children’s Hospital of Philadelphia), Yi Xing, PhD (Children’s Hospital of Philadelphia), Nikolaous Sgourakis, PhD (Children’s Hospital of Philadelphia), Peter Choyke, MD (National Cancer Institute), Scott Norberg, DO (National Cancer Institute), Wiem Lassoued, PhD (National Cancer Institute), Jennifer Marte, MD, MPH (National Cancer Institute), Nan-Ping Weng, MD, PhD (National Institute on Aging), Peter Kuhn, PhD (University of Southern California), Kara Maxwell, MD, PhD (The Corporal Michael J. Crescenz VA Medical Center), Daniel Lee, MD (The Corporal Michael J. Crescenz VA Medical Center), Darshana Jhala, MD (The Corporal Michael J. Crescenz VA Medical Center)

Young Investigators: Andrew Rech, MD, PhD (University of Pennsylvania), Mark Yarmarkovich, PhD (Children’s Hospital of Philadelphia)

Description:

  • Chimeric Antigen Receptor (CAR) T cells are a powerful type of immunotherapy in which a patients’ own T cells are engineered to target and kill their cancer. CAR T cells have demonstrated dramatic efficacy and even cures in patients with various blood cancers, including lymphomas, certain types of leukemia, and multiple myeloma. CAR T cells are now under development for solid tumors including prostate cancer.
  • In prostate cancer, the efficacy and longevity of CAR T cells is limited by an immuno-suppressive tumor microenvironment. The team has previously identified multiple genes in T cells that when deleted may improve tumor-killing potential and overcome the suppressive tumor microenvironment.  In this project, they will comprehensively test the effects of deleting these genes in CAR T cell preclinical models. The team will also apply advanced analytic technologies to define the tumor and immune factors that impact CAR T cell therapy in patients with mCRPC, to identify new therapeutic targets for improving CAR T efficacy.
  • The efficacy of CAR T cells in combination with various other immunotherapies will be tested.
  • CAR T cells are engineered to target tumor-associated antigens, such as PSMA and PSCA in prostate cancer. The team will identify new target antigens in African American and racially diverse prostate cancer populations as well as in neuroendocrine-variant tumors, and test the efficacy of CAR T cells targeting these new antigens in preclinical models.
  • The efficacy of CAR T cells in solid tumors is also limited by genomic heterogeneity and loss of the target antigen. To overcome this barrier, the team will develop and test a “polytherapy” that combines CARs against multiple targets.
  • Together these preclinical studies, which employ prostate cancer models and samples and data from patients with mCRPC enrolled in CAR T cell trials, will create a roadmap for the development of more efficacious and safer next-generation CAR T cell therapies for mCRPC.
  • If successful, the team will launch a clinical trial testing the most promising CAR T clinical candidate(s) and strategies by year 3 of the project.

What this means for patients: This team will develop new clinic-ready CAR T cell therapies for mCRPC that can overcome the limitations of prior CAR T cell products for prostate cancer. This may ultimately lead to a powerful new arsenal of immunotherapy treatments for advanced prostate cancer patients, that are effective in racially diverse populations and against heterogenous advanced disease types. This knowledge may also advance immunotherapy in patients with other types of solid tumors.

View all the PCF TACTICAL Award-Class of 2022 recipients.

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