Abstract
Recent treatments of leukemias with T cells expressing chimeric antigen receptors (CARs) underline their impressive therapeutic potential but also their risk of severe side effects including cytokine release storms and tumor lysis syndrome. In case of cross-reactivities, CAR T cells may also attack healthy tissues. To overcome these limitations, we previously established a switchable CAR platform technology termed UniCAR. UniCARs are not directed against typical tumor-associated antigens (TAAs) but instead against a unique peptide epitope: Fusion of this peptide epitope to a recombinant antibody domain results in a target module (TM). TMs can cross-link UniCAR T cells with tumor cells and thereby lead to their destruction. So far, we constructed TMs with a short half-life. The fast turnover of such a TM allows to rapidly interrupt the treatment in case severe side effects occur. After elimination of most of the tumor cells, however, longer lasting TMs which have not to be applied via continous infusion would be more convenient for the patient. Here we describe and characterize a TM for retargeting UniCAR T cells to CD19 positive tumor cells. Moreover, we show that the TM can efficiently be produced in vivo from producer cells housed in a sponge-like biomimetic cryogel and, thereby, serving as an in vivo TM factory for an extended retargeting of UniCAR T cells to CD19 positive leukemic cells.
Highlights
T cell-engaging bispecific antibodies and T cells genetically modified to express chimeric antigen receptors (CARs) represent promising tools for immunotherapy of tumors [1,2,3,4,5]
The aims of the presented manuscript are schematically summarized in Figure 1: We wanted to (i) develop and functionally characterize a target module (TM) for redirection of UniCAR T cells to CD19 positive tumor cells (Figure 1A) and (ii) challenge the idea to manufacture the TM in vivo from the producer cell line housed in a starPEG-heparin cryogel (Figure 1B) for retargeting of UniCAR T cells in experimental mice (Figure 1C)
Clinical studies using CAR T cells directed against CD19 have demonstrated the impressive therapeutic potential of CAR-modified T cells in patients [23,24,25,26,27]
Summary
T cell-engaging bispecific antibodies (bsAbs, BiTEs) and T cells genetically modified to express chimeric antigen receptors (CARs) represent promising tools for immunotherapy of tumors [1,2,3,4,5]. Both BiTEs and CARs establish immune synapse-like interactions between T cells and cancer cells [6, 7]. CARs currently used in the clinic consist of three domains: (i) an extracellular binding moiety, (ii) a transmembrane domain and (iii) an intracellular domain containing signaling motif(s). According to the number and origin of the signalling domains, CARs are devided into first, second and third generation CARs
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