CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：CD138-targeted bispecific protein engager-armed T cells exhibit potent and selective cytotoxicity against multiple myeloma cells.
CD138-targeted bispecific protein engager-armed T cells exhibit potent and selective cytotoxicity against multiple myeloma cells.
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多发性骨髓瘤（MM）是一种血液系统恶性肿瘤，目前仍无法治愈，大多数患者最终会复发或对现有疗法产生耐药性。双特异性T细胞衔接器（BiTEs）通过将T细胞重定向以靶向并杀伤肿瘤细胞而显示出前景；然而，其临床应用受到体内半衰期短、需要高剂量给药以及与治疗相关的毒性的限制。为解决这些局限性，双特异性蛋白衔接器武装的T细胞（BATs）已被开发为一种新型的基于细胞的免疫治疗平台，可增强抗原特异性和体内持久性。
在本研究中，我们评估了靶向CD138的BATs的抗肿瘤疗效，CD138是一种在MM细胞上高表达并与疾病进展相关的硫酸乙酰肝素蛋白聚糖。BATs通过用抗CD138 × 抗CD3双特异性蛋白衔接器（BiPE）武装T细胞而生成，并通过计数微珠技术和流式细胞术评估其抗肿瘤活性。CD138特异性BATs对CD138阳性MM.1R细胞表现出强效的细胞毒性，在共培养48小时后实现高达89.62 ± 2.22%的细胞裂解，显著超过未武装T细胞的活性（33.04 ± 6.57%裂解）。
此外，BATs诱导了白细胞介素-2（IL-2）细胞因子以及细胞溶解介质（包括穿孔素、颗粒酶A/B、可溶性Fas配体（sFasL）和TNF-α）的强劲表达，表明有效的抗原特异性激活。
重要的是，促炎细胞因子如IL-6、IL-10和IFN-γ保持在低水平，提示良好的安全性特征。这些发现支持CD138靶向BATs作为治疗MM的一种有前景且可能更安全的细胞免疫疗法的治疗潜力。
Multiple myeloma (MM) is a hematologic malignancy that remains incurable, with most patients eventually relapsing or developing resistance to available therapies. Bispecific T cell engagers (BiTEs) have shown promise by redirecting T cells to target and kill tumor cells; however, their clinical application is hindered by a short in vivo half-life, the need for high dosing, and treatment-related toxicities. To address these limitations, bispecific protein engager-armed T cells (BATs) have been developed as a novel cell-based immunotherapy platform that enhances antigen specificity and in vivo persistence.
In this study, we evaluated the antitumor efficacy of BATs targeting CD138, a heparan sulfate proteoglycan highly expressed on MM cells and associated with disease progression. BATs were generated by arming T cells with an anti-CD138 × anti-CD3 bispecific protein engager (BiPE), and their antitumor activity was assessed through counting bead technique and flow cytometry.
CD138-specific BATs exhibited potent cytotoxicity against CD138-positive MM. 1R cells, achieving up to 89. 62 ± 2. 22% cell lysis after 48 h of co-culture, significantly surpassing the activity of unarmed T cells (33. 04 ± 6. 57% lysis).
Additionally, BATs induced robust expression of interleukin-2 (IL-2) cytokine and cytolytic mediators, including perforin, granzyme A/B, soluble Fas ligand (sFasL), and TNF-α, indicating effective antigen-specific activation.
Importantly, pro-inflammatory cytokines such as IL-6, IL-10, and IFN-γ remained at low levels, suggesting a favorable safety profile.
These findings support the therapeutic potential of CD138-targeted BATs as a promising and potentially safer cellular immunotherapy for the treatment of MM.
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