肿瘤细胞治疗研究
英文原题：Tumor-priming CD8(+) natural killer T-like cells as an efficient novel cell therapy for relapsed/refractory multiple myeloma.
Tumor-priming CD8(+) natural killer T-like cells as an efficient novel cell therapy for relapsed/refractory multiple myeloma.
TPNC 是一种通过肿瘤驱动的致敏产生的新型细胞毒性淋巴细胞产品。
背景：复发/难治性多发性骨髓瘤（RRMM）仍是重大临床挑战，多数患者接受标准治疗后最终复发，后续治疗选择有限。尽管靶向B细胞成熟抗原（BCMA）的CAR-T疗法近期在部分患者中疗效显著，但其依赖自体细胞、制造周期长、成本高且免疫相关毒性严重，阻碍了更广泛应用。因此，亟需更安全、可及且能快速实施的免疫治疗替代方案。方法：在特定细胞因子存在下，将脐带血单个核细胞（CBMC）与RRMM患者经照射的骨髓单个核细胞（BMMC）共同培养，旨在开发一种用于RRMM的新型治疗性免疫细胞产品。通过表面标志物分析、细胞因子分泌检测、体外细胞毒实验、功能和阻断实验，分析其表型和功能特征，包括非MHC限制性和MHC限制性细胞毒机制。使用MM.1S和RPMI-8226细胞建立异种移植小鼠模型评估抗肿瘤活性。结果：通过肿瘤预激活成功生成CD8+ NKT样细胞，这些细胞对多发性骨髓瘤细胞系及RRMM原代样本具有强效细胞毒性，并产生较高水平细胞因子。机制上，肿瘤预激活CD8+ NKT样细胞（TPNC）的细胞毒作用同时由非MHC限制性LFA-1和DNAM-1通路，以及MHC限制性、TCR介导的识别所介导。TPNC可高效形成免疫突触、快速极化细胞毒颗粒，并连续杀伤靶细胞。在异种移植模型中，TPNC显著抑制肿瘤进展、延长生存期，并在血液循环中持续存在，未观察到明显毒性。基于这些结果，研究者将肿瘤预激活策略拓展至急性髓系白血病（AML）和急性淋巴细胞白血病（ALL），并成功制备具有强细胞毒活性的TPNC。在ALL样本中，TPNC的细胞毒性与抗CD19 CAR-NK细胞相当。结论：TPNC是一种通过肿瘤驱动预激活生成的新型细胞毒性淋巴细胞产品。其双重识别能力、功能多样性和良好安全性，提示其有望成为可规模化、个体化治疗血液系统恶性肿瘤的平台。
BACKGROUND: Relapsed and refractory multiple myeloma (RRMM) remains a major clinical challenge, as most patients eventually relapse following standard treatments and are left with limited therapeutic options. Although b-cell maturation antigen (BCMA) CAR-T cell therapy has recently shown remarkable efficacy in select patients, broader implementation is hindered by its reliance on autologous cells, prolonged manufacturing timelines, high costs, and severe immune-related toxicities. These challenges have prompted an urgent demand for safer, more accessible, and rapidly applicable immunotherapeutic alternatives. METHODS: CBMC (cord blood mononuclear cells) were cultured with irradiated BMMC (bone marrow mononuclear cells) from RRMM patients in the presence of defined cytokines, aiming to develop a new therapeutic immune cell product for RRMM. Their phenotypic and functional characteristics, including non-MHC-restricted and MHC-restricted cytotoxicity mechanisms, were analyzed using surface marker profiling, cytokine secretion assays, in vitro cytotoxicity assays, functional and blocking assays. Antitumor activity was evaluated in xenograft mouse models using MM.1 S and RPMI-8226 cells. RESULTS: We successfully generated CD8 + NKT-like cells through tumor priming, which exhibited potent cytotoxicity and elevated cytokine production against multiple myeloma cell lines and primary RRMM samples. Mechanistically, tumor-priming CD8 + NKT-like cells (TPNC) cytotoxicity was mediated by both non-MHC-restricted pathways involving LFA-1 and DNAM-1, and MHC-restricted, TCR-mediated recognition. TPNC efficiently formed immune synapses, rapidly polarized cytotoxic granules, and engaged in serial killing. In xenograft models, TPNC significantly suppressed tumor progression, prolonged survival, and persisted in circulation without observable toxicity. Based on these findings, we extended the tumor-priming strategy to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), successfully generating TPNC with robust cytotoxic activity. In ALL samples, TPNC exhibited cytotoxicity comparable to anti-CD19 CAR-NK cells. CONCLUSIONS: TPNC represents a novel cytotoxic lymphocyte product generated through tumor-driven priming. Their dual recognition capacity, functional versatility, and favorable safety profile highlight their potential as a scalable and personalized immunotherapy platform for hematologic malignancies.
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