CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach.
Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach.
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这些结果表明，B7-H3- CD3 ENG T 细胞可能是针对 B7-H3 阳性多发性骨髓瘤的一种有前景的治疗方法。它们可能增强现有的多发性骨髓瘤治疗并改善总体预后。仍需进一步的临床前和临床研究，以全面评估其治疗潜力。
多发性骨髓瘤（MM）是一种不可治愈的浆细胞恶性肿瘤，全球发病率不断上升。靶向BCMA的嵌合抗原受体（CAR）T细胞疗法在复发/难治性MM中显示出疗效，但面临因抗原丢失和肿瘤微环境导致的耐药性。双特异性T细胞衔接（BITE）抗体也面临临床挑战，包括半衰期短需持续输注及潜在毒性。
为解决这些问题，我们开发了一种慢病毒系统，用于工程化T细胞，使其分泌B7-H3-CD3双特异性衔接分子（B7-H3-CD3 ENG-T细胞）。我们评估了这些细胞对具有不同B7-H3表达水平（从B7-H3阴性到B7-H3高表达）的骨髓瘤细胞的效力。
B7-H3- CD3 ENG T细胞对表达B7-H3的MM细胞系表现出显著的抗肿瘤活性。SupT-1细胞（B7-H3阴性）作为对照，B7-H3- CD3 ENG T细胞对其细胞毒性极低。相比之下，这些工程化T细胞对表达B7-H3的MM细胞表现出剂量依赖性杀伤作用：NCI-H929（B7-H3低表达）、L-363（B7-H3中表达）和KMS-12-PE（B7-H3高表达）。对于NCI-H929细胞，在效靶比（E:T）为5:1和10:1时，细胞毒性分别达到38.5±7.4%（p = 0.0212）和54.0±9.2%（p = 0.0317）。针对L-363细胞，在E:T比为5:1和10:1时，细胞毒性分别为56.6±3.2%（p < 0.0001）和71.4±5.2%（p = 0.0002）。对于KMS-12-PE细胞，即使在E:T比为1:1时也观察到显著的细胞毒性效应，在E:T比为1:1、5:1和10:1时，细胞毒性分别为27.2±3.7%（p = 0.0004）、44.4±3.7%（p < 0.0001）和68.6±9.2%（p = 0.0004）。
Multiple myeloma (MM) is an incurable plasma cell malignancy with increasing global incidence. Chimeric antigen receptor (CAR) T-cell therapy targeting BCMA has shown efficacy in relapsed or refractory MM, but it faces resistance due to antigen loss and the tumor microenvironment. Bispecific T-cell engaging (BITE) antibodies also encounter clinical challenges, including short half-lives requiring continuous infusion and potential toxicities.
To address these issues, we developed a lentiviral system to engineer T cells that secrete B7-H3- CD3 bispecific engager molecules ( B7-H3- CD3 ENG-T cells). We evaluated their effectiveness against MM cells with varying B7-H3 expression levels, from B7-H3 neg to B7-H3 high .
The B7-H3- CD3 ENG-T cells demonstrated significant anti-tumor activity against MM cell lines expressing B7-H3. SupT-1 cells (B7-H3 neg ) served as controls and exhibited minimal cytotoxicity from B7-H3- CD3 ENG T cells. In contrast, these engineered T cells showed dose-dependent killing of B7-H3-expressing MM cells: NCI-H929 (B7-H3 low ), L-363 (B7-H3 medium ), and KMS-12-PE (B7-H3 high ). For NCI-H929 cells, cytotoxicity reached 38.5 7.4% (p = 0.0212) and 54.0 9.2% (p = 0.0317) at effector-to-target (E:T) ratios of 5:1 and 10:1, respectively. Against L-363 cells, cytotoxicity was 56.6 3.2% (p < 0.0001) and 71.4 5.2% (p = 0.0002) at E:T ratios of 5:1 and 10:1, respectively. For KMS-12-PE cells, significant cytotoxic effects were observed even at an E:T ratio of 1:1, with 27.2 3.7% (p = 0.0004), 44.4 3.7% (p < 0.0001), and 68.6 9.2% (p = 0.0004) cytotoxicity at E:T ratios of 1:1, 5:1, and 10:1, respectively.
These results indicate that B7-H3- CD3 ENG T cells could be a promising therapy for B7-H3-positive MM. They may enhance current MM treatments and improve overall outcomes. Additional preclinical and clinical research is required to fully assess their therapeutic potential.
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