CAR Technology Meets Theranostics – A New Era of Immunotheranostics for Hematological and Solid Tumors

Modification of autologous T cells with tumor-specific chimeric antigen receptors (CARs) has been shown to be an effective tool for treatment of hematologic malignancies. However, clinical translation towards solid tumors is still limited as demonstrated by the suboptimal performance of CAR T cells in first in-human studies. Combining advances in CAR-T cell therapy and cancer theranostics may provide a promising multimodal approach to increase therapeutic efficacy and achieve durable responses in cancer patients.
Here we present the development and functional characterization of different peptide- or antibody constructs targeting tumor-associated antigens or different structures of the tumor microenvironment. Equipment of these molecules with the E5B9 peptide epitope, enabled their use in the well-established UniCAR system. Accordingly, the constructs were able to specifically activate UniCAR T cells for efficient killing of both hematological and solid tumors in vitro and in vivo. Upon conjugation of chelators like DOTAGA and NODAGA, the peptide- or antibody derivates were further successfully applied for cancer theranostics, using e.g. 68Ga, 64Cu as diagnostic radionuclides and e.g. 67Cu, 225Ac as therapeutic radionuclides. PET imaging in xenotransplanted mice has demonstrated high contrast tumor accumulation. Consistent with the stable tumor accumulation, 225Ac-labeled molecules demonstrated therapeutic efficacy in a xenograft mouse model.
In summary, E5B9-tagged peptide- or antibody constructs open a new era of cancer immunotheranostics as they can be used multimodally for (i) UniCAR-T cell therapy, (ii) non-invasive diagnostic imaging and (iii) targeted radioimmunotherapy. Prospectively, they could thus bridge the gap between the fields of CAR-T cells and cancer theranostics.