T-cell based immunotherapy is a promising therapeutic modality for cancer. However, a major limitation in the effectiveness of this approach is the inefficiency of T-cell migration to the tumor site. T-cell localization into tissues depends on molecular interactions with endothelium mediated by chemokines and adhesion molecules. We have found that T-cells do not express the receptors capable of recognizing some of the chemokines expressed by tumors as well as integrins found on tumor vasculature. Specifically, we found that tumors can secrete the chemokine CXCL1 but tumor-reactive T cells fail to express the corresponding receptor, CXCR2. Similarly, T-cells fail to recognize avb3 integrin, which is over expressed on tumor vasculature. Therefore, we are investigating methods to enhance the ability of T cells to migrate to tumor, by introducing chemokine receptor genes such as CXCR2. In addition, we have designed a novel fusion protein receptor (RGD-PSGL1) containing an RGD peptide motif which binds to avb3 on tumor vasculature. In our preliminary studies, we have found that transduction of T-cells with these receptor genes mediates specific chemotaxis and adhesion in vitro. In this proposal, we will evaluate the ability of these receptor genes to enable improved migration to and destruction of tumor using an in vivo murine tumor model. Our hypothesis is that lymphocyte migration to tumor can be improved by expressing specific chemokine receptor and novel adhesion receptor genes into T-cells. Specifically, we will: 1) Construct retro viral vectors encoding CXCR2 or RGD-PSGL1 which also contain reporter genes that can be used for molecular imaging studies. We will then evaluate the in vitro ability of gene modified murine T-cells to function in vitro using chemotaxis and binding assays. 2) Evaluate the ability of receptor gene-modified T-cells to migrate to tumor and other organs in vivo, using flow cytometry and molecular imaging techniques. 3) Evaluate the ability of gene-modified tumor specific transgenic T-cells to mediate an antitumor response in a murine tumor model.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116206-02
Application #
7104371
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Hecht, Toby T
Project Start
2005-08-01
Project End
2010-05-31
Budget Start
2006-08-04
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$291,217
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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