In 2015, prostate cancer will be diagnosed in an estimated 220,800 men and will account for 27,540 deaths, second only to lung cancer for men (1). Initial treatments for this disease include surgical prostatectomy and radiation therapy, each of which is associated with major morbidities. As a result, many men elect to receive active surveillance and avoid these definitive treatments in the hope that their cancer does not progress. However, those that do progress now face a poorer prognosis, and are commonly treated with androgen deprivation therapy (2-5). Despite initial tumor regression, all patients eventually recur, resulting in the formation of castration-resistant prostate cancer (CRPC) and a median survival time of 9-30 months (6-8). No individual treatment for CRPC has provided greater than 5.2 months of survival benefit, including the first FDA approved cancer immunotherapy (10-16). The long-term goal of this project is to create a more efficacious and safer treatment for both men with early stage prostate cancer and those who have progressed to CRPC. This application proposes to develop a novel immunotherapy utilizing CP1, a unique uropathogenic E. coli strain that was isolated from the prostatic secretion of a patient with chronic prostatitis. CP1 is unique in that it is able to coloize the prostate of mice for over 28 days, during which time it induces a local inflammatory response involving prostate infiltration by Th1/Th17 lymphocytes and the upregulation of multiple cytokines and chemokines (17-19). These infiltrating T cells are imprinted with long-lasting specificity for prostatic antigens, as evident by ex vivo and adoptive transfer studies (17. Therefore, it is hypothesized that a strong and tumor-specific host T cell immune response will be generated by administering genetically engineered CP1, which will express prostate cancer-associated antigen within the pro-inflammatory environment it induces. This hypothesis and the efficacy of CP1 as an immunotherapeutic tool will be tested utilizing a clinically relevant model of active surveillance, using prostate-specific PTEN knockout mice (20) in Aim 1, and of CRPC, by implanting tumor cells intra-prostatically, castrating mice, and following tumor regression and subsequent CRPC recurrence in Aim 2. These experiments will be carried out by Jonathan Anker, who will be under the mentorship of Dr. Sarki Abdulkadir, with his prostate cancer expertise, and Dr. Praveen Thumbikat, with his immunology and prostate inflammation expertise. They will provide Jonathan with all of the equipment and facilities within both of their laboratories and the core facilities offered at Northwestern University.

Public Health Relevance

Prostate cancer is the second-most prevalent non-skin cancer and accounts for the second-most number of cancer deaths in men. Our goal is to create a novel and translational bacterial immunotherapy that we will evaluate in clinically relevant mouse models of both early and late stages of the disease. We hypothesize that this genetically engineered bacteria will act to both enhance and redirect the host's own immune system to better attack the tumor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30CA203472-03
Application #
9438510
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2016-03-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611