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-

Adoptive Transfer of Cytotoxic T Lymphocytes Targeting Two Different Antigens Limits Antigen Loss and Tumor Escape

“…Continued expression of a highly immunogenic antigen, in a high proportion of tumors, is significant because it opens new avenues for the design of rational second-line therapies to target escape tumors still expressing the antigens that were initially present in the primary tumor. This may be especially relevant to trials of adoptive T-cell therapy using T cells redirected with novel, designer, high-potency receptors that, typically, have so far targeted single antigens (Morgan et al, 2006;Chinnasamy et al, 2010;Kochenderfer et al, 2010;Lo et al, 2010;Zhao et al, 2010;Kochenderfer and Rosenberg, 2011;Porter et al, 2011;Robbins et al, 2011). Our data here suggest that combining several of these T-cell populations into the same protocol may increase the durability of responses achieved.…”

Identification and angiogenic role of the novel tumor endothelial marker CLEC14A

“…Targeting can then be achieved with antibodies, antibody conjugates or more recently vaccines (reviewed in Heath and Bicknell, 2009;Chinnasamy et al, 2010;Huijbers et al, 2010). Nevertheless, despite success in targeting the tumor vasculature in animal models (Burrows and Thorpe, 1993;Huang et al, 1997;He et al, 2009), the translation of vascular targeting agents to the clinic has been slow, owing to some extent to the absence of a rigorously characterized tumor endothelial marker (TEM) in man.…”

Robo4 is an effective tumor endothelial marker for antibody-drug conjugates based on the rapid isolation of the anti-Robo4 cell-internalizing antibody

“…[31][32][33] Although VEGFR expression is upregulated on tumor vessels, it is also observed on the endothelium in healthy tissues. Previous reports also mentioned the toxicity associated with the anti-VEGFR therapies in mouse models 50 and the clinical trial. 51 Therefore, alternative therapies that target tumor angiogenesis are desired.…”