Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence

Autor: Afroditi Katsarou, Maria Sjöstrand, Jyoti Naik, Jorge Mansilla-Soto, Dionysia Kefala, Georgios Kladis, Alexandros Nianias, Ruud Ruiter, Renée Poels, Irene Sarkar, Yash R. Patankar, Elena Merino, Rogier M. Reijmers, Kristine A. Frerichs, Huipin Yuan, Joost de Bruijn, Dina Stroopinsky, David Avigan, Niels W. C. J. van de Donk, Sonja Zweegman, Tuna Mutis, Michel Sadelain, Richard W. J. Groen, Maria Themeli
Přispěvatelé: Hematology laboratory, Hematology, AII - Cancer immunology, CCA - Cancer biology and immunology, VU University medical center
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Sci Transl Med
Katsarou, A, Sjöstrand, M, Naik, J, Mansilla-Soto, J, Kefala, D, Kladis, G, Nianias, A, Ruiter, R, Poels, R, Sarkar, I, Patankar, Y R, Merino, E, Reijmers, R M, Frerichs, K A, Yuan, H, de Bruijn, J, Stroopinsky, D, Avigan, D, van de Donk, N W C J, Zweegman, S, Mutis, T, Sadelain, M, Groen, R W J & Themeli, M 2021, ' Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence ', Science Translational Medicine, vol. 13, no. 623, pp. eabh1962 . https://doi.org/10.1126/scitranslmed.abh1962
Science Translational Medicine, 13(623). American Association for the Advancement of Science
ISSN: 1946-6234
DOI: 10.1126/scitranslmed.abh1962
Popis: Despite the high remission rates achieved using T cells bearing a chimeric antigen receptor (CAR) against hematogical malignancies, there is still a considerable proportion of patients who eventually experience tumor relapse. Clinical studies have established that mechanisms of treatment failure include the down-regulation of target antigen expression and the limited persistence of effective CAR T cells. We hypothesized that dual targeting mediated by a CAR and a chimeric costimulatory receptor (CCR) could simultaneously enhance T cell cytotoxity and improve durability. Indeed, concomitant high affinity engagement of a CD38-binding CCR enhanced the cytotoxicity of BCMA and CD19-CAR T cells by increasing their functional binding avidity. In comparison to second generation BCMA- or CD19-CAR T cells, double targeted CAR+CD38-CCR T cells exhibited increased sensitivity to recognize and lyse tumor variants of multiple myeloma (MM) and acute lymphoblastic leukemia (ALL) with low antigen density in vitro. Additionally, complimentary co-stimulation by 4-1BB and CD28 endodomains provided by the CAR and CCR combination conferred increased cytokine secretion and expansion, and improved persistence in vivo. Notably, the cumulatively improved properties of CAR+CCR T cells enabled the in vivo eradication of antigen-low tumor clones, which were otherwise resistant to treatment with conventional CAR T cells. Therefore, multiplexing targeting and co-stimulation through the combination of a CAR and a CCR is a powerful strategy to improve the clinical outcomes of CAR T cells by enhancing cytotoxic efficacy and persistence, thus preventing relapses of tumor clones with low target-antigen density.
Databáze: OpenAIRE
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