AbstractChimeric antigen receptor (CAR)-T cell therapy is a promising treatment option for relapsed or refractory malignancies, with the potential to achieve complete remission. However, the production of autologous CAR-T cells from individual patients is costly, making its widespread use difficult. In addition, the preparation of CAR-T cell products takes substantial time, with the risk of missing the optimal treatment opportunity. Moreover, the quality of T cells varies among patients, resulting in inconsistent therapeutic outcomes.To address these challenges, the development of "universal CAR-T cells," which can be mass-produced from healthy donors and used for any patient, has been proposed. However, to prevent allogeneic immune response between donors and recipients, the expression of T cell receptors (TCRs) and human leukocyte antigens (HLAs) on infused CAR-T cells need to be suppressed. Although this can be achieved using genome editing technologies such as CRISPR/Cas9 or TALEN, these genome editing technologies raise safety concerns and increase the complexity of the manufacturing process. On the other hand, it is also necessary to avoid natural killer (NK) cell-mediated recognition of HLA-null cells. Recent studies have explored the overexpression of HLA-E to transmit suppressive signals to NK cells. While promising results have been demonstrated at the preclinical level, the efficacy of HLA-E-expressing allogeneic CAR-T cells remains to be established in the clinic.慶應義塾大学医学部先端医科学研究所がん免疫研究部門・教授籠谷 勇紀Yuki KagoyaKeio University― 185 ―In this study, we attempted to incorporate immune evasion mechanisms employed by various pathogenic viruses into allogeneic CAR-T cells to enable escape from allogeneic immune responses. Our findings suggest that a combination of viral-derived proteins can facilitate efficient immune evasion between allogeneic T cells. We also found that HLA-E overexpression does not necessarily suppress NK cell activity due to differential expression levels of its receptor, suggesting that a ゲノム編集を用いない同種免疫細胞療法の開発Development of allogeneic adoptive immunotherapy without genome editing
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