Intravesical rF-GMCSF and rF-TRICOM in the treatment of advanced bladder cancer

Project Details

Description

DESCRIPTION (provided by applicant): The overall goal of this proposed treatment strategy is the development of effective systemic immunity to bladder cancer following the rationally designed manipulation of the bladder microenvironment. For a number of years, we have focused on characterizing immune parameters at the tumor microenvironment as a means of identifying targets for manipulation with the ultimate goal of inducing tumor-specific immunity. Our novel hypothesis that manipulation of the tumor microenvironment via gene transfer using poxvirus recombinants led us to perform a series of Phase I studies of intralesional wild type vaccinia and recombinant vaccinia encoding GM-CSF in melanoma and subsequently intravesical wild type vaccinia in bladder cancer. Our current study of intravesical gene transfer in bladder cancer is a direct translation of our preclinical studies and early clinical trials. This study, required by the FDA as it represents a first-in-man intravesical administration of recombinant poxvirus, provides us a unique opportunity to assess critical questions as to the ability to modulate the bladder microenvironment with the ultimate goal of engendering a positive immune response. We have chosen agents, rF-GM-CSF and rF-TRICOM, based on our preclinical studies demonstrating depressed antigen presentation associated with the tumor-associated cytokine profile. In addition, we are using recombinants with the reporter gene B-galactosidase (B-gal) to not only quantitate efficiency of transfection but also as an antigen with which to study the ability to immunize via the bladder compartment which has not been done previously. These studies will provide critical data for subsequent use of recombinant poxvirus recombinants as local/systemic therapy for bladder cancer. More specifically, we propose to: 1. Determine local and systemic toxicity associated with the intravesical instillation of rF-GM-CSF and/or TRICOM and establish an MTD/Phase II dose. 2. Determine the efficiency of infection/transfection of the urothelium arid tumor following intravesical rF-GM-CSF and/or rF-TRICOM 3. Define the localized immune response in the bladder following intravesical rF-GM-CSF and/or rF-TRICOM and 4. Assess the ability to immunize bladder cancer patients via the bladder compartment. We believe that the results of these studies will provide critical insights as to the ability to use intravesical gene transfer as a therapeutic modality for bladder cancer and allow us an enhanced ability to design critical Phase II trials.
StatusFinished
Effective start/end date8/8/067/31/10

Funding

  • National Institutes of Health: $241,207.00
  • National Institutes of Health: $248,411.00

ASJC

  • Medicine(all)

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.