Bioengineering of antibodies and human T cells with artificial chimeric antigen receptors (CARs) for therapy and diagnosis of tumors

At the HZDR we preclinically develop innovative and unique (radio)immunotheranostic strategies for the therapy and diagnosis of tumors. Our focus lies on chimeric antigen receptor (CAR)-T-cell technology based on the genetic manipulation of immune effector cells (e.g. NK- and T-cells) with artificial CARs making these cells capable of specifically recognizing and killing tumor cells. To further improve efficacy and safety of conventional CAR (cCAR)-T-cell therapy our team has established modular switchable adapter CAR platforms, termed UniCAR and RevCAR (1, 2). In contrast to cCARs, they are not directed against an antigen on the tumor cell surface and are therefore inert. UniCARs express an antibody-derived binding domain (scFv) recognizing a peptide epitope. Thus, universal UniCAR-T-cells can be redirected to tumor cells via antigen-specific target modules (UniTMs) that are equipped with this peptide epitope. Varying in their design and specificity, UniTMs allow to reversibly switch on/off and steer UniCAR-T-cells. Additionally, UniTMs can be radiolabeled and used for tumor targeting and/or imaging depending on the selected radionuclide (3). As a further development, the RevCAR platform functions in a similar manner showing high anti-tumor efficacy, safety, controllability, and flexibility. Universal RevCAR-T-cells lack the extracellular scFv and express only the short peptide epitope. Thus, they require a bispecific target module (RevTM) to be redirected to tumor cells. RevCAR-T-cells can be used for combinatorial tumor targeting of two antigens subsequently or simultaneously to increase the overall effect and precision towards the tumor site. Besides immunotherapy of different tumor malignancies, our adapter UniCAR/RevCAR platforms can be broadly applied also to treat infectious, inflammatory or autoimmune diseases.

1. Bachmann M. The UniCAR system: A modular CAR T cell approach to improve the safety of CAR T cells. Immunol Lett. 2019 Jul;211:13-22. doi: 10.1016/j.imlet.2019.05.003. Epub 2019 May 12. PMID: 31091431.

2. Feldmann A, Hoffmann A, Bergmann R, Koristka S, Berndt N, Arndt C, Rodrigues Loureiro L, Kittel-Boselli E, Mitwasi N, Kegler A, Lamprecht C, González Soto KE, Bachmann M. Versatile chimeric antigen receptor platform for controllable and combinatorial T cell therapy. Oncoimmunology. 2020 Jul 3;9(1):1785608. doi: 10.1080/2162402X.2020.1785608. PMID: 32923149; PMCID: PMC7458653.

3. Loureiro LR, Hoffmann L, Neuber C, Rupp L, Arndt C, Kegler A, Kubeil M, Hagemeyer CE, Stephan H, Schmitz M, Feldmann A, Bachmann M. Immunotheranostic target modules for imaging and navigation of UniCAR T-cells to strike FAP-expressing cells and the tumor microenvironment. J Exp Clin Cancer Res. 2023 Dec 15;42(1):341. doi: 10.1186/s13046-023-02912-w. PMID: 38102692; PMCID: PMC10722841.