Rujirachaivej Punchita, Siriboonpiputtana Teerapong, Choomee Kornkan, Supimon Kamonlapat, Sangsuwannukul Thanich, Songprakhon Pucharee, Natungnuy Krissada, Luangwattananun Piriya, Yuti Pornpimon, Junking Mutita, Yenchitsomanus Pa-Thai
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.
J Transl Med. 2025 Jan 13;23(1):54. doi: 10.1186/s12967-024-05923-z.
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 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.
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.
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.
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。
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。
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）。
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。
