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

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

Research output: Contribution to journalArticlepeer-review

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 doubleknockout 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.

Original languageEnglish
Pages (from-to)926-936
Number of pages11
JournalCancer Immunology Research
Volume8
Issue number7
DOIs
Publication statusPublished - 2020 Jul 1
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this