American Association for Cancer Research
Browse
23266066cir180508-sup-206033_4_supp_6182516_q8w9ht.pdf (6.47 MB)

Supplementary Figures from Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy

Download (6.47 MB)
journal contribution
posted on 2023-04-04, 01:07 authored by Yuki Kagoya, Tingxi Guo, Brian Yeung, Kayoko Saso, Mark Anczurowski, Chung-Hsi Wang, Kenji Murata, Kenji Sugata, Hiroshi Saijo, Yukiko Matsunaga, Yota Ohashi, Marcus O. Butler, Naoto Hirano

Figures S1-S6

Funding

Ontario Institute for Cancer Research

History

ARTICLE ABSTRACT

Adoptive immunotherapy can induce sustained therapeutic effects in some cancers. Antitumor T-cell grafts are often individually prepared in vitro from autologous T cells, which requires an intensive workload and increased costs. The quality of the generated T cells can also be variable, which affects the therapy's antitumor efficacy and toxicity. Standardized production of antitumor T-cell grafts from third-party donors will enable widespread use of this modality if allogeneic T-cell responses are effectively controlled. Here, we generated HLA class I, HLA class II, and T-cell receptor (TCR) triple-knockout (tKO) T cells by simultaneous knockout of the B2M, CIITA, and TRAC genes through Cas9/sgRNA ribonucleoprotein electroporation. Although HLA-deficient T cells were targeted by natural killer cells, they persisted better than HLA-sufficient T cells in the presence of allogeneic peripheral blood mononuclear cells (PBMC) in immunodeficient mice. When transduced with a CD19 chimeric antigen receptor (CAR) and stimulated by tumor cells, tKO CAR-T cells persisted better when cultured with allogeneic PBMCs compared with TRAC and B2M double-knockout T cells. The CD19 tKO CAR-T cells did not induce graft-versus-host disease but retained antitumor responses. These results demonstrated the benefit of HLA class I, HLA class II, and TCR deletion in enabling allogeneic-sourced T cells to be used for off-the-shelf adoptive immunotherapy.

Usage metrics

    Cancer Immunology Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC