This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACTOver recent years the Scott Department of Urology at Baylor College of Medicine has developed a comprehensive program of gene therapy for prostate cancer. This translational research program has resulted in the first in situ gene therapy clinical trials involving adenovirus vector delivery of suicide gene tehrapy with Herpes Simplex Virus-thymidine kinase (HSV-tk) plus the pro-drug gancioclovir in patients with local prostate cancer recurrence following radiation therapy. These studies have now been completed and have extended into additional clinical trials. These efforts as well as pre-clinical experimental studies with mice have led us to conclude that a necessary component of any successful gene therapy appraoch directed against prostate cancer that may spread to other parts of the body (metastases) must include a component that activates the host immune system. In our preclinical studies using ADV/RSV-tk (ganciclovir), treated mice were found to have immune cells (ymphocytic infiltration) in the treated tumors. Further studies revealed suppression of pre-established lung metastases by ADV/RSV-tk+gangciclovir treatment of the primary prostate tumor, which suggested an immune response. Activation of other specific immune cells called cytotoxic T lymphocytes (CTL's) and natural killer (NK)cells are considered to play an important role in antitumoral activity and may provide a new approach for systemic treatment of human prostate cancers. One possible way to achieve the further immune stimulation against tumors is to administer specific cytokines, which are known to play a role in immune activation. Since the discovery of interleukin-12 (IL-12)less than 10 years ago, much knowledge has been gained on the importance of this cytokine in immunoregulation and its antitumoral properties. IL-12 has been demonstrated to activate and enhance NK and CTL activity, stimulate proliferation of T and NK cells and induce production of IFN-y by NK and T cells. The antitumoral properties of IL-12 have been demonstrated in multiple preclinical studies. These studies revealed a dose dependent effect of IL-12 causing regression of a variety of tumor cell lines, inhibition of metastasis and in some studies a long lasting protective immune response. In our preclinical (mouse)trials, adenovirus-mediated expression of mouse IL-12 was used to treat a prostate cancer model we developed. We demonstrated a significant reduction in prostate tumor weight and suppression of pre-established lung metastasis as well as a survival advantage in IL-12 virus treated mice.The purpose of this study is to conduct a Phase I clinical trial to extend preclinical studies involving in situ IL-12 gene therapy for prostate cancer. We will conduct necessary safety evaluations on a new adenovirus that contains the human genes for IL-12. This virus will ghen be evaluated for safety in men with prostate cancer that has recurred after radiation therapy. These men have no other treatment option. We will inject the IL-12 virus into the prostate starting with a low dose and carefully watch the men for any toxic side effects and hopefully a beneficial effect.HYPOTHESISOur proposal is a Phase I study of direct intraprostatic injection of a replication deficient adenovirus mediating expression of the human IL-2 gene in patients who have failed definitive radiotherapy for prostate cancer. Patients wih locally recurrent prostate cancer after definitive radiatherapy do not have any standard treatment available that has proven to be highly efficacious in eradicating the tumor with a reasonable degree of safety. Salvage surgery and cryosurgery have low rates of progression free survival and the complication rate is unacceptably high. Hormonal ablation is only a pallative measure and hormone resistant disease develops over time in most patients. Therefore the potential risks of this protocol seem justifiable and reasonable. The objective of this study is to assess the long-term toxicity resulting from this treatment will be evaluated. A maximum tolerated dose of the treatment will be determined.
SPECIFIC AIMS1. To evlauate the safety of ADV/IL-12 gene therapy for patients with local recurrence of prostate cancer after definitive radiation therapy.2. To collect data on tumor responses produced by the study treatment.3. To collect data on immune responses induced by the study treatment.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
5M01RR000188-44
Application #
7717742
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2007-12-01
Project End
2008-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
44
Fiscal Year
2008
Total Cost
$1,561
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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