肿瘤细胞治疗研究
英文原题：Enhancing iNKT cell immunotherapy through the integration of optimized CAR endodomains and iNKT engagers.
iNKT细胞正逐渐成为一种极具前景的癌症免疫治疗平台。
iNKT细胞正逐渐成为一种极具前景的癌症免疫治疗平台。为了最大化CAR-iNKT针对血液系统恶性肿瘤多发性骨髓瘤的抗癌活性，我们研究了最佳CAR设计及其与新型iNKT特异性衔接器的联合应用。我们发现，在五种不同的CAR胞内结构域中，BCMA CD28z CAR-iNKT发挥最高的抗骨髓瘤活性，其基础是增强的亲合力以及CAR-iNKT上的Plexin D1与骨髓瘤细胞上的Semaphorin 4 A之间的串扰。值得注意的是，CD28z CAR-iNKT优于其CAR-T对应细胞。为拓展CAR-iNKT的抗骨髓瘤潜力，我们设计并验证了一种高效BCMA iNKT特异性衔接器，其与过继转移的iNKT细胞联合时可发挥显著的抗骨髓瘤活性。最后，FCRL5 CAR-iNKT与BCMA iNKT衔接器联合的双靶点治疗优于FCRL5 CAR-iNKT，并限制了FCRL5阴性骨髓瘤的免疫逃逸。因此，优化的基于iNKT的双靶点、双模式免疫治疗对多发性骨髓瘤以及潜在的其他恶性肿瘤具有增强的抗肿瘤活性。
iNKT cells are emerging as a highly promising immunotherapy platform for the treatment of cancer. To maximise the anti-cancer activity of CAR-iNKT against the blood cancer multiple myeloma we investigated optimal CAR designs and their combination with new iNKT-specific engagers. We find that amongst five different CAR endodomains, underpinned by increased avidity and a cross talk between Plexin D1 on CAR-iNKT and Semaphorin 4 A on myeloma cells, BCMA CD28z CAR-iNKT exert the highest anti-myeloma activity. Notably, CD28z CAR-iNKT outperform their CAR-T counterparts. To expand the anti-myeloma potential of CAR-iNKT, we designed and validated a high efficacy BCMA iNKT-specific engager which exerts significant anti-myeloma activity in conjunction with adoptively transferred iNKT cells. Finally, combined, dual target therapy with FCRL5 CAR-iNKT and BCMA iNKT engagers outperforms FCRL5 CAR-iNKT and limits immune escape of FCRL5-negative myeloma. Thus, optimised iNKT-based, dual-target, dual-modality immunotherapy has enhanced anti-tumor activity against multiple myeloma and potentially other malignancies.
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