Our preclinical research indicates that anti-tumor immune stimulation by intratumoral delivery of immunomodulatory genes may be effective for the treatment of advanced colorectal cancer. Using an """"""""orthotopic"""""""" tumor model with pre-established metastatic colon cancer in the liver of syngeneic mice, we have shown that """"""""intratumoral"""""""" injection of an adenoviral vector expressing murine interleukin-12 (Adv.RSV-mIL12) produced high intratumoral but low systemic concentrations of the cytokine, and induced tumor regression with long term survival in 20% of treated animals. The antitumor immunity was mediated primarily by natural killer (NK) cells. We have also shown in subsequent studies that intraperitoneal administration of an agonistic monoclonal antibody against the T-cell stimulation receptor m4-1BB (Mab-anti-m4-1BB) concurrent with intratumoral delivery of Adv.RSV-mIL 12 was synergistic, and produced long-term survival in 80 - 100% of treated animals. The antitumor immunity induced by the combination treatment was systemic, long lasting, and involved both tumor-specific cytolytic T lymphocytes as well as NK cells. Both immune cell types were necessary in rejecting parental tumor cells implanted at distant sites and pre-established multi-focal lung metastases. To test if these immunotherapeutic interventions can be developed for patients with metastatic colorectal cancer, we propose to start with a Phase I trial of Adv.RSV-hIL12 administered by percutaneous injection into a metastatic tumor in the liver under ultrasound guidance and local anesthesia. The clinical protocol has been approved by the IRB, IBC, FDA, and RAC at the NIH. The primary objective of this Phase I clinical study is to determine the safety and maximal tolerable dose (MTD) of the recombinant adenoviral vector administered """"""""intratumorally"""""""". Completion of this Phase I trial will enable us to proceed in the future with a Phase IB trial of the vector at a sub-MTD dose, and to a Phase I/IB trial of the combination treatment with the sub- MTD dose of intratumoral Adv.RSV-hIL12 plus escalating doses of intravenously administered Mab-anti-h4-1BB. These two future trials will be statistically powered to test for specific systemic antitumor immunity induced by the treatment using autologous tumor targets. Successful completion of these """"""""clinical translational studies"""""""" will provide scientific evidence to support further clinical evaluation of """"""""active genetic immunization"""""""" as a new treatment modality for metastatic colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA089887-01A1
Application #
6405971
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Xie, Heng
Project Start
2001-09-07
Project End
2003-05-31
Budget Start
2001-09-07
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$228,825
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029