Current adoptive T cell therapies conducted in an autologous setting are costly, time consuming, and depend on the quality of the patient's T cells. To address these issues, we developed a strategy in which cytotoxic T lymphocytes (CTLs) are regenerated from iPSCs that were originally derived from T cells and succeeded in regenerating CTLs specific for the WT1 antigen, which exhibited therapeutic efficacy in a xenograft model of leukemia. In this study, we extended our strategy to solid tumors. The regenerated WT1-specific CTLs had a strong therapeutic effect in orthotopic xenograft model using a renal cell carcinoma (RCC) cell line. To make our method more generally applicable, we developed an allogeneic approach by transducing HLA-haplotype homozygous iPSCs with WT1-specific TCR α/β genes that had been tested clinically. The regenerated CTLs antigen-specifically suppressed tumor growth in a patient-derived xenograft model of RCC, demonstrating the feasibility of our strategy against solid tumors.

当前在自体环境中进行的过继性T细胞疗法昂贵，耗时，并取决于患者T细胞的质量。为了解决这些问题，我们制定了一种策略，其中从最初源自T细胞的iPSC中再生出细胞毒性T淋巴细胞（CTL），并成功地再生了特异于WT1抗原的CTL，该CTL在白血病异种移植模型中表现出治疗功效。在这项研究中，我们将策略扩展到了实体瘤。再生的WT1特异性CTL在使用肾细胞癌（RCC）细胞系的原位异种移植模型中具有强大的治疗作用。为了使我们的方法更通用，我们通过用WT1特异性TCRα/β转导HLA-单倍型纯合iPSC，开发了一种同种异体方法经过临床测试的基因。在源自患者的RCC异种移植模型中，再生的CTLs抗原特异性抑制了肿瘤的生长，证明了我们针对实体瘤的策略的可行性。