Abstract A032: Chimeric antigen receptor (CAR) targeted epitope determines optimal CAR spacer length for therapy against medulloblastoma

Abstract

Improved therapeutic outcomes for children with embryonal brain tumors (EBTs) hinge on the development and optimization of novel, targeted therapies able to eradicate tumors without serious treatment-related damage to the central nervous system (CNS). To this end, we describe the design and validation of optimized chimeric antigen receptors (CARs) T-cells that target the EBT-associated antigen Her2. Our studies demonstrate that Her2CAR extracellular spacer domains actively influence T-cell in vitro functional outputs and in vivo responses, with the medium (M-) spacer able to confer the greatest antitumor activity against the most common EBT, medulloblastoma. Furthermore, we show that the juxtamembrane epitope targeted on Her2 precluded short spacer Her2CAR activity; yet, this activity could be rescued when the targeted epitope was expressed in a membrane distal position. Similarly, while modifications that abrogate Fc region interactions in the long spacer Her2CAR rescued in vivo activity, the resultant functional outputs failed to reach the antitumor potency elicited by the M-spacer CAR. Here we also demonstrate the in vitro and in vivo activity of M-spacer CAR T-cells produced by our clinical manufacturing process. Results from this preclinical dataset have directed the implementation of a clinical trial that delivers Her2CAR T-cells locoregionally to patients with EBT tumors, coined BrainChild-01. Collectively, these results reiterate the necessity to tailor CARs to their respective targeted antigen epitope and describe the optimization of Her2-targeted CARs for the treatment of EBT tumors. Citation Format: Adam J. Johnson, Cindy A. Chang, Michael L. Baldwin, Jason K. Yokoyama, Michael C.M. Jensen. Chimeric antigen receptor (CAR) targeted epitope determines optimal CAR spacer length for therapy against medulloblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A032.