Abstract 2313: Improved killing of tumor cells by a novel flexible antibody-based modular T cell retargeting system

Abstract In recent years, bispecific antibodies (bsabs) and chimeric antigen receptors (CARs) emerged as promising candidates for an antigen-specific cancer immunotherapy. Bsabs and CARs redirect T cells in an antigen-specific manner towards tumor cells and unleash their enormous cytotoxic potential to attack the tumor. Nevertheless, several challenges have to be solved to pave the way for a more widespread application of both strategies. Both approaches are monotherapies bearing the inherent risk for development of antigen-loss tumor variants under treatment. In addition, due to their single antigen specificity each given bsab or CAR is only curative for a restricted number of tumor indications and long-lasting and demanding research is necessary to bring a new bsab- or CAR-based drug to patients in need. Moreover, current CAR T cell approaches do not allow for any control of the magnitude and duration of T cell reactivity, thus bearing the risk for overshooting anti-tumor reactions leading to severe side effects and ongoing destruction of healthy tissue carrying the target antigen after tumor clearance. To overcome these limitations, we recently introduced a novel flexible antibody-based modular platform (UniTARG) that can be rapidly and easily adapted for redirection of T cells to any TAA in both a bsAb- or CAR-setting. The UniTARG technology consists of a universal effector arm and individual targeting modules (TMs). The effector arm is either a universal CAR (UniCAR), which has specificity for a short peptide motif of 10 amino acids derived from a human nuclear protein, or a bsAb (UniMAB) with specificity for human CD3 on T cells and the respective peptide epitope. The antigen-specificity of the system is provided by TMs comprising a binding domain e.g., a tumor-antigen specific scFv, fused to the nuclear antigen motif recognized by the UniCAR/UniMAB binding domain. Here we provide first in vitro and in vivo prove of concept for these new approaches. Redirection of T cells armed with the universal effector modules was effective at picomolar concentrations of targeting modules directed against various antigens. The modular composition of both platforms prompted us to explore, if T cell retargeting against several antigens simultaneously might be feasible. Using either two single-specific TMs or single bi-specific TMs significantly enhanced specific lysis of tumor cells in vitro and durable responses in vivo were observed. Furthermore, our results proof that TMs against new targets can be developed in a couple of weeks and all TMs tested so far engaged effector module armed T cells with similar potencies. Taken together, the UniTARG platform technology represents a promising tool in the field of both bsAbs and CARs with the advantage of simultaneous or consecutive dual or even multispecific T cell retargeting. Furthermore the platform approach allows a rapid development of new therapeutic options against additional targets. Citation Format: Armin Ehninger, Marc Cartellieri, Anja Feldmann, Claudia Arndt, Stefanie Koristka, Simon Loff, Malte von Bonin, Gerhard Ehninger, Michael Bachmann. Improved killing of tumor cells by a novel flexible antibody-based modular T cell retargeting system. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2313.