过继性 T 细胞疗法 (ACT) 是将确定的 T 细胞免疫力转移给患者，在对抗包括难以治疗的病毒感染在内的不同人类疾病方面具有巨大潜力，但细胞的持久性和寿命是令人担忧的领域。极早期分化的干细胞记忆T细胞（TSCM）具有优异的自我更新、植入、持久性和抗癌功效，但其抗病毒ACT的潜力仍然未知。在这里，我们开发了一种临床可扩展的方案，用于扩展 Epstein-Barr 病毒 (EBV) 特异性 TSCM 富集 T 细胞，具有高比例的 CD4 T 细胞和广泛的 EBV 抗原覆盖率。这些细胞在 EBV 诱导的淋巴瘤异种移植模型中显示出肿瘤控制，并且在肿瘤浸润、体内增殖、持久性、功能性 CD4 T 细胞比例和 EBV 抗原特异性多样性方面优于之前的 ACT 方案。因此，我们的方案可能为下一代有效的未经修饰的抗原特异性细胞疗法治疗 EBV 相关疾病（包括肿瘤和其他适应症）铺平道路。

Adoptive T cell therapy (ACT), the therapeutic transfer of defined T cell immunity to patients, offers great potential in the fight against different human diseases including difficult-to-treat viral infections, but persistence and longevity of the cells are areas of concern. Very-early-differentiated stem cell memory T cells (TSCMs) have superior self-renewal, engraftment, persistence, and anticancer efficacy, but their potential for antiviral ACT remains unknown. Here, we developed a clinically scalable protocol for expanding Epstein-Barr virus (EBV)-specific TSCM-enriched T cells with high proportions of CD4+ T cells and broad EBV antigen coverage. These cells showed tumor control in a xenograft model of EBV-induced lymphoma and were superior to previous ACT protocols in terms of tumor infiltration, in vivo proliferation, persistence, proportion of functional CD4+ T cells, and diversity of EBV antigen specificity. Thus, our protocol may pave the way for the next generation of potent unmodified antigen-specific cell therapies for EBV-associated diseases, including tumors, and other indications.