Anti-CS1 x Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines
Anti-CS1 x Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines
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DOI：
10.3389/fonc.2020.00544
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发表时间：
2020-05-05
影响因子：
4.7
通讯作者：
Huang, Manley
中科院分区：
文献类型：
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作者：
Lum, Lawrence G.;Thakur, Archana;Huang, Manley
背景：尽管化疗、靶向治疗和免疫治疗取得了重大进展，但多发性骨髓瘤 (MM) 仍然无法治愈。双特异性抗体 (BiAb) 武装的激活 T 细胞 (BAT) 已被开发用于靶向和治疗实体瘤和血液恶性肿瘤。 BAT 是肿瘤细胞的连环杀手，分泌 Th-1 细胞因子，并诱导患者 (pts) 产生适应性细胞和体液免疫反应。本研究使用双特异性抗 CS1 (elotuzumab) x 抗 CD3 (OKT3) 抗体 (CS1Bi) 武装的活化 T 细胞 (CS1-BAT) 提供临床前数据，为将 CS1-BAT 应用于 MM 患者提供了强有力的理由。方法：CS1-BAT 和非武装活化 T 细胞 (ATC) 与 MM 细胞靶标在定量流中以各种效应物与靶标比率 (E:T) 一起孵育基于细胞计数的测定法，以确定相对于无 ATC 孵育的靶细胞的细胞损失程度。来自最多 8 名正常供体的 ATC 配备了不同浓度的 CS1 BiAb，并针对 5 种骨髓瘤细胞系进行了 CS1-BAT 介导的杀伤和 Th-1 细胞因子、趋化因子和颗粒酶 B 释放的测试。结果：来自正常供体的 CS1-BAT 杀死了 5 种 MM 细胞系中的每一种，其 E:T 比例范围为 1:1 至 10:1，武装浓度为 12.5 至 50 ng/百万 ATC，伴随着 Th-1 细胞因子、趋化因子和颗粒酶 B 的释放。从 MM 患者的外周血单核细胞 (PBMC) 制备的 CS1-BAT 显示出针对 ARH77 MM 细胞的细胞毒性和 T 细胞扩增随着时间的推移而增加。 CS1Bi 的最佳武装剂量是 50 ng/10(6) ATC。结论：这些数据证明了 CS1-BAT 介导的细胞毒性和低 E:T 下 Th-1 细胞因子释放的治疗潜力，并支持推进其在 MM 患者中的临床开发。
Background: Multiple myeloma (MM) remains incurable despite significant advances in chemotherapy, targeted therapies, and immunotherapy. Bispecific antibody (BiAb)-armed activated T cells (BATs) have been developed for targeting and treatment of solid and hematologic malignancies. BATs are serial killers of tumor cells, secrete Th-1 cytokines, and induce adaptive cellular and humoral immune responses in patients (pts). This study provides preclinical data using bispecific anti-CS1 (elotuzumab) x anti-CD3 (OKT3) antibody (CS1Bi)-armed activated T cells (CS1- BATs) that provide a strong rationale for applying CS1-BATs to pts with MM.Methods: CS1-BATs and unarmed activated T cells (ATC) were incubated with MM cell targets at various effector to target ratios (E:T) in a quantitative flow cytometry-based assay to determine the degree of cell loss relative to target cells incubated without ATC. ATC from up to 8 normal donors were armed with various concentrations of CS1 BiAb and tested against 5 myeloma cells lines for CS1-BATs-mediated killing and release of Th-1 cytokines, chemokines and granzyme B.Results: CS1-BATs from normal donors killed each of 5 MM cell lines proportional to E:T ratios ranging between 1:1 and 10:1 and arming concentrations of 12.5 to 50 ng/million ATC, which was accompanied by release of Th-1 cytokines, chemokines and granzyme B. CS1-BATs prepared from MM pts' peripheral blood mononuclear cells (PBMC) showed increasing cytotoxicity and T cell expansion over time against ARH77 MM cells. The optimal arming dose of CS1Bi is 50 ng/10(6) ATC.Conclusions: These data demonstrate the therapeutic potential of CS1-BATs-mediated cytotoxicity and Th-1 cytokines release at low E:T and support advancing their clinical development in pts with MM.