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Less is more: reducing the number of administered chimeric antigen receptor T cells in a mouse model using a mathematically guided approach

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Chimeric antigen receptor T cell (CAR-T) therapy is a novel approved treatment for hematological malignancies, still under development for solid tumors. Here, we use a rate equation-based mathematical model to discover regimens and schedules that maintain efficacy while potentially reducing toxicity by decreasing the amount of CAR-T infused. Tested on an in vivo murine model of spontaneous breast cancer, we show that our mathematical model accurately recapitulates in vivo tumor growth results achieved in the previous experiments. Moreover, we use the mathematical model to predict results of new therapy schedules and successfully prospectively validated these predictions in the in vivo. We conclude that using one tenth and even one percent of a full CAR-T dose used in preclinical trials can achieve efficacious results similar to full dose treatment.

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Abbreviations

CAR:

Chimeric antigen receptor

CTX:

Cyclophosphamide

d:

Days

E/T :

Effector/target

Her2tgm:

MMTV.f.huHer2 #5 (Fo5), (Genentech, USA)

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Funding

VV is supported by the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation under Grant Number 41/11.

Author information

Author notes

  1. Anat Globerson Levin and Natalie Kronik have contributed equally.

  2. Zelig Eshhar and Vladimir Vainstein are equal senior authors.

Authors and Affiliations

  1. Tel Aviv Sourasky Medical Center, 6 Weizmann St., 6423906, Tel Aviv, Israel

    Anat Globerson Levin, Tamar Shiloach, Tova Waks & Zelig Eshhar

  2. Department of Hematology, Hadassah Medical Center, Jerusalem, Israel

    Natalie Kronik & Vladimir Vainstein

  3. Weizmann Institute of Science, Rehovot, Israel

    Anat Globerson Levin, Tova Waks & Zelig Eshhar

Authors
  1. Anat Globerson Levin
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  2. Natalie Kronik
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  3. Tamar Shiloach
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  4. Tova Waks
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  5. Zelig Eshhar
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  6. Vladimir Vainstein
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Contributions

AGL was involved in study conception, study design, critical revision of the manuscript, data acquisition, data interpretation, and statistical analysis. NK was involved in study conception, study design, critical revision of the manuscript, data acquisition, data interpretation, and mathematical model development. TS was involved in study design and data interpretation. TW was involved in study conception, study design, critical revision of the manuscript, and data interpretation. ZE was involved in study conception, study design, critical revision of the manuscript, and data interpretation. VV was involved in study conception, study design, critical revision of the manuscript, and data interpretation.

Corresponding author

Correspondence to Anat Globerson Levin.

Ethics declarations

Conflict of interest

Zelig Eshhar is a member of the Scientific Advisory Board of Kite Pharma Inc. All other authors declare no conflict of interests.

Ethical approval and ethical standard

All animal experiments were performed in compliance with the guidelines of the Institutional Animal Care and Use Committee of TASMC. Ethical Approval Number 33-11-13 (2013 for 4 years). FVB and Her2tgm (Genentech, USA) mice were used.

Animal source

MMTV.f.huHer2 #5(Fo5) transgenic male mice (a gift from Genentech, San Francisco, CA). Female mice for mating were purchased from Envigo, Israel.

Cell line authentication

Mouse lymphocytes were obtained from splenocytes of FVB female mice.

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Globerson Levin, A., Kronik, N., Shiloach, T. et al. Less is more: reducing the number of administered chimeric antigen receptor T cells in a mouse model using a mathematically guided approach. Cancer Immunol Immunother 69, 1165–1175 (2020). https://doi.org/10.1007/s00262-020-02516-9

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  • DOI: https://doi.org/10.1007/s00262-020-02516-9

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