A CD3 humanized mouse model unmasked unique features of T-cell responses to bispecific antibody treatment
© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved..
ABSTRACT: T-cell bispecific antibodies (T-BsAbs) such as blinatumomab hold great promise for cancer immunotherapy. A better understanding of the in vivo immune response induced by T-BsAbs is crucial to improving their efficacy and safety profile. However, such efforts are hindered by the limitations of current preclinical models. To address this, we developed a syngeneic murine model with humanized CD3 and target antigen (CD20). This model enables the development of disseminated leukemia with a high tumor burden, which mirrors clinical findings in human patients with relapsed/refractory acute lymphoblastic leukemia. Treatment of this model with T-BsAbs results in cytokine release syndrome, with cytokine profiles and levels reflecting observations made in human patients. This model also faithfully recapitulates the dynamics of T-cell activation seen in human patients, including the temporary disappearance of T cells from the bloodstream. During this phase, T cells are sequestered in secondary lymphoid organs and undergo activation. Clinical correlative studies that rely primarily on peripheral blood samples are likely to overlook this critical activation stage, leading to a substantial underestimation of the extent of T-cell activation. Furthermore, we demonstrate that surface expression of the T-BsAb target antigen by leukemia cells triggers a swift immune response, promoting their own rejection. Humanizing the target antigen in the recipient mice is crucial to facilitate tolerance induction and successful establishment of high tumor burden. Our findings underscore the importance of meticulously optimized syngeneic murine models for investigating T-BsAb-induced immune responses and for translational research aimed at improving efficacy and safety.
| Errataetall: |
CommentIn: Blood Adv. 2024 Jan 23;8(2):482-483. - PMID 38261330 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
Blood advances - 8(2024), 2 vom: 23. Jan., Seite 470-481 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Lingling [VerfasserIn] |
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| Links: |
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| Themen: |
Antibodies, Bispecific |
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| Anmerkungen: |
Date Completed 24.01.2024 Date Revised 08.02.2024 published: Print CommentIn: Blood Adv. 2024 Jan 23;8(2):482-483. - PMID 38261330 Citation Status MEDLINE |
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| doi: |
10.1182/bloodadvances.2023010971 |
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| Förderinstitution / Projekttitel: |
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| 520 | |a ABSTRACT: T-cell bispecific antibodies (T-BsAbs) such as blinatumomab hold great promise for cancer immunotherapy. A better understanding of the in vivo immune response induced by T-BsAbs is crucial to improving their efficacy and safety profile. However, such efforts are hindered by the limitations of current preclinical models. To address this, we developed a syngeneic murine model with humanized CD3 and target antigen (CD20). This model enables the development of disseminated leukemia with a high tumor burden, which mirrors clinical findings in human patients with relapsed/refractory acute lymphoblastic leukemia. Treatment of this model with T-BsAbs results in cytokine release syndrome, with cytokine profiles and levels reflecting observations made in human patients. This model also faithfully recapitulates the dynamics of T-cell activation seen in human patients, including the temporary disappearance of T cells from the bloodstream. During this phase, T cells are sequestered in secondary lymphoid organs and undergo activation. Clinical correlative studies that rely primarily on peripheral blood samples are likely to overlook this critical activation stage, leading to a substantial underestimation of the extent of T-cell activation. Furthermore, we demonstrate that surface expression of the T-BsAb target antigen by leukemia cells triggers a swift immune response, promoting their own rejection. Humanizing the target antigen in the recipient mice is crucial to facilitate tolerance induction and successful establishment of high tumor burden. Our findings underscore the importance of meticulously optimized syngeneic murine models for investigating T-BsAb-induced immune responses and for translational research aimed at improving efficacy and safety | ||
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| 700 | 1 | |a Muthusamy, Natarajan |e verfasserin |4 aut | |
| 700 | 1 | |a Byrd, John |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Meixiao |e verfasserin |4 aut | |
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