Data from Local Delivery of lnterleukin-12 Using T Cells Targeting VEGF Receptor-2 Eradicates Multiple Vascularized Tumors in Mice

Abstract

<div>Abstract<p><b>Purpose:</b> We investigated the feasibility of delivering the proinflammatory cytokine interleukin (IL)-12 into tumor using T cells genetically engineered to express a chimeric antigen receptor (CAR) against the VEGF receptor-2 (VEGFR-2).</p><p><b>Experimental Design:</b> Two different strains of mice bearing five different established subcutaneous tumors were treated with syngeneic T cells cotransduced with an anti–VEGFR-2 CAR and a constitutively expressed single-chain murine IL-12 or an inducible <i>IL-12</i> gene after host lymphodepletion. Tumor regression, survival of mice, and persistence of the transferred cells were evaluated.</p><p><b>Results:</b> Adoptive transfer of syngeneic T cells cotransduced with an anti–VEGFR-2 CAR and a constitutively expressing single-chain IL-12 resulted in the regression of five different established tumors of different histologies without the need for IL-2 administration. T cells transduced with either anti–VEGFR-2 CAR or single-chain IL-12 alone did not alter the tumor growth indicating that both of them had to be expressed in the same cell to mediate tumor regression. Anti–VEGFR-2 CAR and IL-12–cotransduced T cells infiltrated the tumors, expanded, and persisted for prolonged periods. The antitumor effect did not require the presence of host T and B cells but was dependent on host IL-12R–expressing cells. The anti–VEGFR-2 CAR changed the immunosuppressive tumor environment by altering/reducing both the systemic and the intratumoral CD11b<sup>+</sup>Gr1<sup>+</sup> myeloid suppressor cell subsets that expressed VEGFR-2.</p><p><b>Conclusions:</b> These results suggest that targeted delivery of IL-12 into the tumor environment with T cells redirected against VEGFR-2 is a promising approach for treating patients with a variety of solid tumor types. <i>Clin Cancer Res; 18(6); 1672–83. ©2012 AACR</i>.</p></div>