Enhancing CAR-T cell functionality in a patient-specific manner

David K. Y. Zhang, Kwasi Adu-Berchie, Siddharth Iyer, Yutong Liu, Nicoletta Cieri, Joshua M. Brockman, Donna Neuberg, Catherine J. Wu and David J. Mooney ()
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David K. Y. Zhang: Harvard University
Kwasi Adu-Berchie: Harvard University
Siddharth Iyer: Harvard University
Yutong Liu: Harvard University
Nicoletta Cieri: Dana-Farber Cancer Institute
Joshua M. Brockman: Harvard University
Donna Neuberg: Dana-Farber Cancer Institute
Catherine J. Wu: Dana-Farber Cancer Institute
David J. Mooney: Harvard University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Patient responses to autologous CD19 chimeric antigen receptor (CAR) T-cell therapies are limited by insufficient and inconsistent cellular functionality. Here, we show that controlling the precise level of stimulation during T-cell activation to accommodate individual differences in the donor cells will dictate the functional attributes of CAR-T cell products. The functionality of CAR-T cell products, consisting of a diverse set of blood samples derived from healthy donors, acute lymphoblastic leukemia (ALL), and chronic lymphocytic lymphoma (CLL) patient samples, representing a range of patient health status, is tested upon culturing on artificial antigen-presenting cell scaffolds to deliver T-cell stimulatory ligands (anti-CD3/anti-CD28) at highly defined densities. A clear relationship is observed between the dose of stimulation, the phenotype of the T-cell blood sample prior to T-cell activation, and the functionality of the resulting CAR-T cell products. We present a model, based on this dataset, that predicts the precise stimulation needed to manufacture a desired CAR-T cell product, given the input T-cell attributes in the initial blood sample. These findings demonstrate a simple approach to enhance CAR-T functionality by personalizing the level of stimulation during T-cell activation to enable flexible manufacturing of more consistent and potent CAR-T cells.

Date: 2023
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DOI: 10.1038/s41467-023-36126-7

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