High specificity of engineered T cells with third generation CAR (CD28-4-1BB-CD3-ζ) based on biotin-bound monomeric streptavidin for potential tumor immunotherapy.

Article

作者: Gonzalez-Navarro, Europa Azucena ; Correa-Rocha, Rafael ; Gil-Manso, Sergio ; Castellá, María ; Pérez-Fernández, Verónica Astrid ; Gallego-Valle, Jorge ; Juan, Manel ; Pion, Marjorie ; Rosales-Magallares, Jesús

IntroductionImmunotherapy has revolutionized cancer treatment, and Chimeric Antigen Receptor T cell therapy (CAR-T) is a groundbreaking approach. Traditional second-generation CAR-T therapies have achieved remarkable success in hematological malignancies, but there is still room for improvement, particularly in developing new targeting strategies. To address this limitation, engineering T cells with multi-target universal CARs (UniCARs) based on monomeric streptavidin has emerged as a versatile approach in the field of anti-tumor immunotherapy. However, no studies have been conducted on the importance of the intracellular signaling domains of such CARs and their impact on efficiency and specificity.MethodHere, we developed second-generation and third-generation UniCARs based on an extracellular domain comprising an affinity-enhanced monomeric streptavidin, in addition to CD28 and 4-1BB co-stimulatory intracellular domains. These UniCAR structures rely on a biotinylated intermediary, such as an antibody, for recognizing target antigens. In co-culture assays, we performed a functional comparison between the third-generation UniCAR construct and two second-generation UniCAR variants, each incorporating either the CD28 or 4-1BB as co-stimulatory domain.ResultsWe observed that components in culture media could inhibit the binding of biotinylated antibodies to monomeric streptavidin-CARs, potentially compromising their efficacy. Furthermore, third-generation UniCAR-T cells showed robust cytolytic activity against cancer cell lines upon exposure to specific biotinylated antibodies like anti-CD19 and anti-CD20, underscoring their capability for multi-targeting. Importantly, when assessing engineered UniCAR-T cell activation upon encountering their target cells, third-generation UniCAR-T cells exhibited significantly enhanced specificity compared to second-generation CAR-T cells.DiscussionFirst, optimizing culture conditions would be essential before deploying UniCAR-T cells clinically. Moreover, we propose that third-generation UniCAR-T cells are excellent candidates for preclinical research due to their high specificity and multi-target anti-tumor cytotoxicity.

2023-09-01·Cancer Immunology, Immunotherapy

Multivalent adaptor proteins specifically target NK cells carrying a universal chimeric antigen receptor to ErbB2 (HER2)-expressing cancers

Article

作者: Prüfer, Maren ; Feldmann, Anja ; Arndt, Claudia ; Pfeifer Serrahima, Jordi ; Bachmann, Michael ; Zhang, Congcong ; Wels, Winfried S ; Kiefer, Anne ; Tonn, Torsten ; Kühnel, Ines ; Röder, Jasmin ; Bodden, Malena ; Oberoi, Pranav

AbstractChimeric antigen receptor (CAR)-engineered immune effector cells constitute a promising approach for adoptive cancer immunotherapy. Nevertheless, on-target/off-tumor toxicity and immune escape due to antigen loss represent considerable challenges. These may be overcome by adaptor CARs that are selectively triggered by bispecific molecules that crosslink the CAR with a tumor-associated surface antigen. Here, we generated NK cells carrying a first- or second-generation universal CAR (UniCAR) and redirected them to tumor cells with so-called target modules (TMs) which harbor an ErbB2 (HER2)-specific antibody domain for target cell binding and the E5B9 peptide recognized by the UniCAR. To investigate differential effects of the protein design on activity, we developed homodimeric TMs with one, two or three E5B9 peptides per monomer, and binding domains either directly linked or separated by an IgG4 Fc domain. The adaptor molecules were expressed as secreted proteins in Expi293F cells, purified from culture supernatants and their bispecific binding to UniCAR and ErbB2 was confirmed by flow cytometry. In cell killing experiments, all tested TMs redirected NK cell cytotoxicity selectively to ErbB2-positive tumor cells. Nevertheless, we found considerable differences in the extent of specific cell killing depending on TM design and CAR composition, with adaptor proteins carrying two or three E5B9 epitopes being more effective when combined with NK cells expressing the first-generation UniCAR, while the second-generation UniCAR was more active in the presence of TMs with one E5B9 sequence. These results may have important implications for the further development of optimized UniCAR and target module combinations for cancer immunotherapy.

2021-06-03·Blood1区 · 医学

Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed/refractory AML

1区 · 医学

Article

作者: Kreissig, Carla ; Middeke, Jan Moritz ; Bornhäuser, Martin ; Ehninger, Armin ; Einsele, Hermann ; Kraus, Sabrina ; Cartellieri, Marc ; von Bonin, Malte ; Koedam, Jan ; Ehninger, Gerhard ; Bargou, Ralf C. ; Pehl, Michael ; Goebeler, Maria-Elisabeth ; Wermke, Martin

Despite recent therapeutic advances, the outcome of patients with relapsed/refractory acute myeloid leukemia (rrAML) remains poor.The primary objective of the study is to determine safety, maximum tolerated dose, and recommended phase 2 dose of this next-generation 2-component CAR-T system.Secondary objectives include objective response rate and response duration.Here we report the results of the first 3 patients that were dosed and completed treatment in this trial. Dose finding follows a 2-dimensional matrix, using a Bayesian optimal interval (BOIN) design for drug combination trials (COMB).These initial clin. results of UniCAR-T-CD123 represent, to our understanding, evidence for a well-tolerated rapidly switchable CAR-T product.

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适应症	最高研发状态	国家/地区	公司	日期
乳腺癌	临床1期	德国	GEMoaB Monoclonals GmbH	2020-12-26
非小细胞肺癌	临床1期	德国	GEMoaB Monoclonals GmbH	2020-12-02
前列腺癌	临床1期	德国	GEMoaB Monoclonals GmbH	2020-11-21