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2024 Larry Leeds, Penny & Larry Goichman, and Ben Shenkman – PCF Young Investigator Award

Targeting Gene Fusion Derived pMHC Neoantigens in Prostate Cancer

Daniel Rosen, MD, PhD
Harvard: Massachusetts General Hospital

Mentors: Nir Hacohen, PhD; Anthony D’Amico, MD, PhD

Description:

  • Checkpoint immunotherapy can cure some forms of advanced metastatic cancer, but trials in prostate cancer have not shown clinical efficacy in unselected patients. Targeted immunotherapy, such as bispecific T cell engagers (BiTE) or antibody-drug conjugates against tumor mutations, are being investigated in prostate cancer.
  • Fusion genes are common genomic drivers of prostate cancer and because they produce altered proteins  foreign to the immune system (termed “neoantigens”), they may induce tumor-specific immune responses. 
  • Dr. Daniel Rosen’s project aims to develop novel, targeted immunotherapies against fusion neoantigens in prostate cancer.
  • This project will identify fusion neoantigen candidates from prostate cancer models and patients and validate whether the neoantigens are presented on the surface of prostate cancer cells via the MHC, a molecule that allows immune cell recognition.  
  • Antibody fragments will be developed to target the prostate cancer fusion neoantigens on MHC. These antibody fragments will then be incorporated into new BiTEs and tested for anti-tumor activity in pre-clinical models.
  • If successful, this project will demonstrate the feasibility of targeting fusion neoantigens for immune-mediated control of prostate cancer despite the immunosuppressive tumor microenvironment and produce validated neo-antigen targeting BiTEs ready for preclinical trials. 

What this means to patients: Immunotherapy has the potential to be curative, but has yet to be optimized for prostate cancer. Dr. Rosen’s project will develop and pre-clinically validate a new type of immunotherapy for prostate cancer that would engage immune cells to target the fusion genes that commonly drive prostate cancer. This will set the stage for clinical trials to validate this approach and could lead to a more effective new treatment for patients with currently incurable disease.