Department of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Med. 2019 May;25(5):814-824. doi: 10.1038/s41591-019-0410-x. Epub 2019 Apr 8.
Indolent non-Hodgkin's lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8 T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial ( NCT01976585 ). Non-responding patients developed a population of PD1CD8 T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.
惰性非霍奇金淋巴瘤（iNHL）无法通过标准疗法治愈，对检查点阻断的反应也很差。尽管淋巴瘤细胞可以被激活的 T 细胞有效杀死，但在体内激活抗淋巴瘤 T 细胞一直难以实现。在这里，我们证明淋巴瘤细胞可以直接激活 T 细胞，但体内免疫仍需要交叉呈递。为了解决这个问题，我们开发了一种原位疫苗（ISV），结合了 Flt3L、放射治疗和 TLR3 激动剂，招募、负载抗原并激活肿瘤内的交叉呈递树突状细胞（DC）。ISV 在一项正在进行的试验（NCT01976585）中诱导了晚期 iNHL 患者的抗肿瘤 CD8 T 细胞反应和全身（远隔）癌症缓解。非应答患者在 ISV 后会产生一群 PD1CD8 T 细胞，而小鼠肿瘤对 PD1 阻断变得新有反应，促使进行联合治疗的后续试验。我们的数据证实，招募和激活肿瘤内的交叉呈递 DC 是可行的，对抗肿瘤 T 细胞反应和 PD1 阻断疗效至关重要。
