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 4

Adoptively transferred DC101-CAR–engineered mouse T cells inhibit multiple types of established syngeneic tumors in vivo.

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Adoptively transferred DC101-CAR–engineered mouse T cells inhibit multip...
(A) Mice bearing established subcutaneous tumors were sublethally irradiated at 5 Gy TBI and treated with 2 × 107 DC101-CD828BBZ–transduced (red triangles) or empty vector–transduced (green squares) syngeneic mouse T cells in conjunction with rhIL-2. Control groups received rhIL-2 alone (blue diamonds) or no treatment (black circles). Mice bearing CT26 or Renca tumors were treated with 5 × 106 T cells. (B) The antitumor effect of DC101-CAR–transduced T cells was cell mediated and not due to an antibody effect. C57BL/6 mice bearing subcutaneous B16-F10 tumors were treated as described in A. One group in this experiment received a single dose of 800 μg/mouse DC101 (orange triangles) or rat IgG1 (purple triangles) antibodies plus rhIL-2. (C) C57BL/6 mice bearing subcutaneous B16-F10 tumors were treated with T cells transduced with DC101-CAR (red triangles) or SP6-CAR vector (blue diamonds), containing intact mouse intracellular signaling sequences, 28BBZ, DC101-CD8 vector that lacked all the signaling domains (purple triangles), or an empty vector (green squares) plus rhIL-2, or were untreated (black circles). (D) C57BL/6 mice bearing B16-F10 tumors were treated with 2 × 107 (red triangles), 1 × 107 (black triangles), 5 × 106 (purple triangles), or 2 × 106 (orange triangles) syngeneic T cells transduced with DC101-CD828BBZ plus rhIL-2. Control groups received 2 × 107 T cells transduced with an empty vector plus rhIL-2 (green squares), rhIL-2 alone (blue diamonds), or received no treatment (black circles). Each treatment group included a minimum of 5 mice. Serial, blinded tumor measurements were obtained, and the products of perpendicular diameters were plotted ± SEM.