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- ItemRetargeting of UniCAR T cells with an in vivo synthesized target module directed against CD19 positive tumor cells([Erscheinungsort nicht ermittelbar] : Impact Journals LLC, 2017) Bachmann, Dominik; Aliperta, Roberta; Bergmann, Ralf; Feldmann, Anja; Koristka, Stefanie; Arndt, Claudia; Loff, Simon; Welzel, Petra; Albert, Susann; Kegler, Alexandra; Ehninger, Armin; Cartellieri, Marc; Ehninger, Gerhard; Bornhäuser, Martin; von Bonin, Malte; Werner, Carsten; Pietzsch, Jens; Steinbach, Jörg; Bachmann, MichaelRecent 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.
- ItemCryogel-supported stem cell factory for customized sustained release of bispecific antibodies for cancer immunotherapy(London : Nature Publishing Group, 2017) Aliperta, Roberta; Welzel, Petra B.; Bergmann, Ralf; Freudenberg, Uwe; Berndt, Nicole; Feldmann, Anja; Arndt, Claudia; Koristka, Stefanie; Stanzione, Marcello; Cartellieri, Marc; Ehninger, Armin; Ehninger, Gerhard; Werner, Carsten; Pietzsch, Jens; Steinbach, Jörg; Bornhäuser, Martin; Bachmann, Michael P.Combining stem cells with biomaterial scaffolds provides a promising strategy for the development of drug delivery systems. Here we propose an innovative immunotherapeutic organoid by housing human mesenchymal stromal cells (MSCs), gene-modified for the secretion of an anti-CD33-anti-CD3 bispecific antibody (bsAb), in a small biocompatible star-shaped poly(ethylene glycol)-heparin cryogel scaffold as a transplantable and low invasive therapeutic machinery for the treatment of acute myeloid leukemia (AML). The macroporous biohybrid cryogel platform displays effectiveness in supporting proliferation and survival of bsAb-releasing-MSCs overtime in vitro and in vivo, avoiding cell loss and ensuring a constant release of sustained and detectable levels of bsAb capable of triggering T-cell-mediated anti-tumor responses and a rapid regression of CD33 + AML blasts. This therapeutic device results as a promising and safe alternative to the continuous administration of short-lived immunoagents and paves the way for effective bsAb-based therapeutic strategies for future tumor treatments.