W. Nathaniel Brennen

Nathaniel Brennen
About W. Nathaniel Brennen

T cells are a type of immune cell with significant tumor cell seeking and killing capabilities, but tumor survival mechanisms cause T cell inactivation. Methods for re-arming these specialized killing cells provides powerful treatment opportunities.

Dr. Nathaniel Brennen will engineer a patient’s T cells to act as “Trojan horses”: specifically targeting tumor cells and releasing a cell wall-damaging bacterial toxin, proaerolysin (PA), to kill the tumor cells.

A patient’s T cells will be transformed with a CAR molecule, an engineered T cell-activating and targeting molecule that recognizes a tumor-associated protein, PSMA. When the CAR-T cell locates its target (PSMA), the T cell will be activated to release the toxin.

PSMA can be expressed by normal brain and kidney cells. To avoid non-specific toxicity, the toxin will be delivered in a modified inactive form, and can only be converted to its active form by a prostate-specific enzyme, prostate-specific antigen (PSA).

Dr. Brennen’s strategy will result in the development of a highly specific and highly toxic live cell therapy for the treatment of prostate cancer.

What this means for patients: What this means for patients: While significant advances have been made in the development of prostate cancer therapies, patients will eventually become resistant and progress to a lethal disease state. If successful, this project will develop an innovative and powerful new treatment strategy that uses the patient’s immune system to kill tumor cells.


2014 Clay and Lynn Hamlin-PCF Young Investigator

W. Nathaniel Brennen, PhD

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins


John Isaacs, PhD, Charles Drake, MD, PhD

Proposal Title

T cells Engineered to Selectively Deliver a PSA-activated Protoxin to Sites of Advanced Prostate Cancer