摘要
肉瘤是最严重的儿科癌症之一，目前的治疗方法 - 化疗和手术 - 在一半患者中未能根除这种疾病。结合新治疗方法的临床前研究可用于设计更好的疗法。一方面，已知CXCR4表达与横纹肌肉瘤进展有关，因此我们分析了来自儿科患者的复发和化疗耐药性横纹肌肉瘤肿瘤，发现它们具有特别高水平的CXCR4表达。此外，在体外测定中，抗CXCR4阻断抗体（MDX1338）有效地减少肺泡横纹肌肉瘤RH30细胞的迁移和侵袭。另一方面，活化和扩增的自然杀伤（NKAE）细胞疗法在体外显示出对肉瘤细胞的高细胞毒性并且在体内完全抑制RH30肿瘤植入。只有MDX1338和NKAE治疗的组合才能完全抑制小鼠的转移。在这项研究中，我们提出了一种新的治疗方法，基于抗CXCR4阻断抗体与NKAE细胞疗法相结合，以防止横纹肌肉瘤肿瘤植入和肺转移。这些结果为该联合免疫疗法预防肉瘤疾病传播的功效提供了第一个证据。
Front Immunol. Aug 2;10:1814. doi: 10.3389/fimmu..01814. eCollection .
Anti-CXCR4 Antibody Combined With Activated and Expanded Natural Killer Cells for Sarcoma Immunotherapy.
Vela M1,Bueno D2,González-Navarro P1,Brito A1,Fernández L3,Escudero A4,Valentín J1,Mestre-Durán C1,Arranz-Álvarez M5,Pérez de Diego R6,7,8,Mendiola M9,10,Pozo-Kreilinger JJ9,11,Pérez-Martínez A2,12.
Impact Factor:4.716Abstract
Sarcoma is one of the most severe forms of pediatric cancer and current therapies -chemotherapy and surgery- fail to eradicate the disease in half of patients. Preclinical studies combining new therapeutic approaches can be useful to design better therapies. On one hand, it is known that CXCR4 expression is implicated in rhabdomyosarcoma progression, so we analyzed relapses and chemotherapy-resistant rhabdomyosarcoma tumors from pediatric patients and found that they had particularly high levels of CXCR4 expression. Moreover, in assaysin vitro, anti-CXCR4 blocking antibody (MDX1338) efficiently reduced migration and invasion of alveolar rhabdomyosarcoma RH30 cells. On the other hand, activated and expanded natural killer (NKAE) cell therapy showed high cytotoxicity against sarcoma cellsin vitroand completely inhibited RH30 tumor implantationin vivo. Only the combination of MDX1338 and NKAE treatments completely suppressed metastasis in mice. In this study, we propose a novel therapeutic approach based on anti-CXCR4 blocking antibody in combination with NKAE cell therapy to prevent rhabdomyosarcoma tumor implantation and lung metastasis. These results provide the first evidence for the efficacy of this combined immunotherapy for preventing sarcoma disease dissemination.
KEYWORDS:
activated and expanded natural killer (NKAE) cells; chemokine C-X-C receptor 4 (CXCR4); immunotherapy; metastasis; sarcoma; therapeutic antibody
PMID:31428099
PMCID:PMC6688426
DOI:10.3389/fimmu..01814
