分泌αB7-H3-αCD3双特异性衔接子的工程化T细胞增强对B7-H3阳性多发性骨髓瘤的抗肿瘤活性：一种新的治疗方法。
Engineered T cells secreting αB7-H3-αCD3 bispecific engagers for enhanced anti-tumor activity against B7-H3 positive multiple myeloma: a novel therapeutic approach.
作者信息
Rujirachaivej Punchita, Siriboonpiputtana Teerapong, Choomee Kornkan, Supimon Kamonlapat, Sangsuwannukul Thanich, Songprakhon Pucharee, Natungnuy Krissada, Luangwattananun Piriya, Yuti Pornpimon, Junking Mutita, Yenchitsomanus Pa-Thai
机构信息
Graduate Program in Clinical Pathology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
出版信息
J Transl Med. 2025 Jan 13;23(1):54. doi: 10.1186/s12967-024-05923-z.
BACKGROUND
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.
METHODS
To address these issues, we developed a lentiviral system to engineer T cells that secrete αB7-H3-αCD3 bispecific engager molecules (αB7-H3-αCD3 ENG-T cells). We evaluated their effectiveness against MM cells with varying B7-H3 expression levels, from B7-H3 to B7-H3.
RESULTS
The αB7-H3-αCD3 ENG-T cells demonstrated significant anti-tumor activity against MM cell lines expressing B7-H3. SupT-1 cells (B7-H3) served as controls and exhibited minimal cytotoxicity from αB7-H3-αCD3 ENG T cells. In contrast, these engineered T cells showed dose-dependent killing of B7-H3-expressing MM cells: NCI-H929 (B7-H3), L-363 (B7-H3), and KMS-12-PE (B7-H3). 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.
CONCLUSIONS
These results indicate that αB7-H3-αCD3 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.
背景
多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性肿瘤，全球发病率呈上升趋势。靶向B细胞成熟抗原（BCMA）的嵌合抗原受体（CAR）T细胞疗法在复发或难治性MM中显示出疗效，但由于抗原丢失和肿瘤微环境而面临耐药性。双特异性T细胞衔接（BITE）抗体也遇到临床挑战，包括半衰期短需要持续输注以及潜在的毒性。
方法
为了解决这些问题，我们开发了一种慢病毒系统来改造T细胞，使其分泌αB7-H3-αCD3双特异性衔接分子（αB7-H3-αCD3 ENG-T细胞）。我们评估了它们对不同B7-H3表达水平（从低到高）的MM细胞的有效性。
结果
αB7-H3-αCD3 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（低B7-H3表达）用作对照，αB7-H3-αCD3 ENG-T细胞对其细胞毒性极小。相比之下，这些改造后的T细胞对表达B7-H3的MM细胞表现出剂量依赖性杀伤：NCI-H929（高B7-H3表达）、L-363（高B7-H3表达）和KMS-12-PE（高B7-H3表达）。对于NCI-H929细胞，在效应细胞与靶细胞（E:T）比例为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）。对于L-363细胞，在E:T比例为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比例为1:1时也观察到显著的细胞毒性效应，在E:T比例为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）。
结论
这些结果表明，αB7-H3-αCD3 ENG-T细胞可能是B7-H3阳性MM的一种有前景的治疗方法。它们可能增强当前的MM治疗并改善总体结果。需要进一步的临床前和临床研究来全面评估其治疗潜力。
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