期刊
NATURE BIOTECHNOLOGY
卷 35, 期 12, 页码 1188-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.4004
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资金
- US National Institutes of Health (NIH) [P01 CA18029-40, R01 CA033084-32, NIH CA178844]
- Guillot Family Fund
- Jose Carreras International Leukemia Foundation
Many promising targets for T-cell-based cancer immunotherapies are self-antigens. During thymic selection, T cells bearing T cell receptors (TCRs) with high affinity for self-antigen are eliminated. The affinity of the remaining low-avidity TCRs can be improved to increase their antitumor efficacy, but conventional saturation mutagenesis approaches are labor intensive, and the resulting TCRs may be cross-reactive. Here we describe the in vitro maturation and selection of mouse and human T cells on antigen-expressing feeder cells to develop higher-affinity TCRs. The approach takes advantage of natural Tcrb gene rearrangement to generate diversity in the length and composition of CDR3 beta. In vitro differentiation of progenitors transduced with a known Tcra gene in the presence of antigen drives differentiation of cells with a distinct agonist-selected phenotype. We purified these cells to generate TCR beta chain libraries pre-enriched for target antigen specificity. Several TCRb chains paired with a transgenic TCR alpha chain to produce a TCR with higher affinity than the parental TCR for target antigen, without evidence of cross-reactivity.
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