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Journal Article Review Epublish 48 citations

PubMed: 36156878 DOI: 10.1016/j.omtm.2022.08.008

Applying a clinical lens to animal models of CAR-T cell therapies.

Mol Ther Methods Clin Dev 27:17-31

Authors: Brynn B Duncan, Cynthia E Dunbar, Kazusa Ishii

Affiliations

  • Molecular Hematopoiesis Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Dr. Building 10, Room 13N240, Bethesda, MD 20892, USA.

Abstract

Chimeric antigen receptor (CAR)-T cells have emerged as a promising treatment modality for various hematologic and solid malignancies over the past decade. Animal models remain the cornerstone of pre-clinical evaluation of human CAR-T cell products and are generally required by regulatory agencies prior to clinical translation. However, pharmacokinetics and pharmacodynamics of adoptively transferred T cells are dependent on various recipient factors, posing challenges for accurately predicting human engineered T cell behavior in non-human animal models. For example, murine xenograft models did not forecast now well-established cytokine-driven systemic toxicities of CAR-T cells seen in humans, highlighting the limitations of animal models that do not perfectly recapitulate complex human immune systems. Understanding the concordance as well as discrepancies between existing pre-clinical animal data and human clinical experiences, along with established advantages and limitations of each model, will facilitate investigators' ability to appropriately select and design animal models for optimal evaluation of future CAR-T cell products. We summarize the current state of animal models in this field, and the advantages and disadvantages of each approach depending on the pre-clinical questions being asked.

MeSH

Cells, Therapeutics, T-Lymphocytes, Car-T Cell

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