Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice
Dhanalakshmi Chinnasamy, … , Nicholas P. Restifo, Steven A. Rosenberg
Dhanalakshmi Chinnasamy, … , Nicholas P. Restifo, Steven A. Rosenberg
Published October 11, 2010
Citation Information: J Clin Invest. 2010;120(11):3953-3968. https://doi.org/10.1172/JCI43490.
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Research Article Genetics

Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice

Abstract

Immunotherapies based on adoptive cell transfer are highly effective in the treatment of metastatic melanoma, but the use of this approach in other cancer histologies has been hampered by the identification of appropriate target molecules. Immunologic approaches targeting tumor vasculature provide a means for the therapy of multiple solid tumor types. We developed a method to target tumor vasculature, using genetically redirected syngeneic or autologous T cells. Mouse and human T cells were engineered to express a chimeric antigen receptor (CAR) targeted against VEGFR-2, which is overexpressed in tumor vasculature and is responsible for VEGF-mediated tumor progression and metastasis. Mouse and human T cells expressing the relevant VEGFR-2 CARs mediated specific immune responses against VEGFR-2 protein as well as VEGFR-2–expressing cells in vitro. A single dose of VEGFR-2 CAR-engineered mouse T cells plus exogenous IL-2 significantly inhibited the growth of 5 different types of established, vascularized syngeneic tumors in 2 different strains of mice and prolonged the survival of mice. T cells transduced with VEGFR-2 CAR showed durable and increased tumor infiltration, correlating with their antitumor effect. This approach provides a potential method for the gene therapy of a variety of human cancers.

Authors

Dhanalakshmi Chinnasamy, Zhiya Yu, Marc R. Theoret, Yangbing Zhao, Rajeev K. Shrimali, Richard A. Morgan, Steven A. Feldman, Nicholas P. Restifo, Steven A. Rosenberg

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Figure 5

Adoptive transfer of multiple doses of DC101-CAR–transduced mouse T cells effectively controlled the tumor growth and increased the survival of tumor-bearing mice.

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Adoptive transfer of multiple doses of DC101-CAR–transduced mouse T cell...
Mice bearing established subcutaneous B16 or MCA205 tumors were sublethally irradiated at 5 Gy TBI and injected with a single dose of 2 × 107 DC101-CD28BBZ–transduced (red triangles) or empty vector–transduced (green squares) syngeneic mouse T cells, in conjunction with rhIL-2. Some groups received 3 sequential doses of 5 × 106 DC101-CAR–transduced (black triangles) or empty vector–transduced (blue squares) T cells at 7- to 10-day intervals and 2 daily doses of rhIL-2 for 3 days following cell transfer. The control group did not receive T cells or rhIL-2 (black circles). Each treatment group included a minimum 5 of mice. Serial, blinded tumor measurements were obtained, and the products of perpendicular diameters were plotted ± SEM.