Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers.

Abstract

<b>Purpose:</b> CD70 expression in normal tissues is restricted to activated lymphoid tissues. Targeting CD70 on CD70-expressing tumors could mediate "on-target, off-tumor" toxicity. This study was to evaluate the feasibility and safety of using anti-human CD70 CARs to treat cancer patients whose tumors express CD70.<b>Experimental Design:</b> Seven anti-human CD70 CARs with binding moieties from human CD27 combined with CD3-zeta and different costimulatory domains from CD28 and/or 41BB were constructed. <i>In vitro</i> functionality of these receptors was compared and <i>in vivo</i> treatment efficacy was evaluated in a xenograft mouse model. A homologous, all murine anti-CD70 CAR model was also used to assess treatment-related toxicities.<b>Results:</b> The CAR consisting of the extracellular binding portion of CD27 fused with 41BB and CD3-zeta (trCD27-41BB-zeta) conferred the highest IFNγ production against CD70-expressing tumors <i>in vitro</i>, and NSG mice bearing established CD70-expressing human tumors could be cured by human lymphocytes transduced with this CAR. In the murine CD27-CD3-zeta CAR model, significant reduction of established tumors and prolonged survival were achieved using CAR-transduced splenocytes in a dose-dependent manner. Host preirradiation enhanced treatment efficacy but increased treatment-related toxicities such as transient weight loss and hematopoetic suppression. The treatment did not appear to block adaptive host immune responses.<b>Conclusions:</b> Preclinical testing supports the safety and efficacy of a CD27-containing CAR targeting CD70-expressing tumors. <i>Clin Cancer Res; 23(9); 2267-76. ©2016 AACR</i>.