PO.IM01.16 · 免疫学
利用现货型T细胞增强双特异性T细胞衔接器治疗在T细胞反应欠佳患者中的疗效
Leveraging off-the-shelf T cells to enhance bispecific T cell engager therapy efficacy in patients with suboptimal T cell responses
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
双特异性T细胞衔接器（BiTE）在血液系统恶性肿瘤中已显示出强效的抗肿瘤活性，但常受患者T细胞功能障碍的限制。为克服这一挑战，我们开发了一种现货型免疫治疗平台，使用健康供者来源的多病毒特异性T细胞（mVST）作为BiTE介导重定向的效应细胞。这些记忆来源的mVST识别巨细胞病毒（CMV）和EB病毒（EBV）抗原，表现出中央记忆和效应记忆表型，并携带极小的移植物抗宿主病（GVHD）风险，提供了一种可储备的、有功能的T细胞来源。mVST从CMV/EBV血清阳性供者中扩增，并在多发性骨髓瘤和淋巴瘤模型中进行评估。测试了两种BiTE负载策略：与T细胞预孵育（装载式）或直接添加到共培养中。单独的mVST表现出极小的细胞毒性，而BCMAxCD3 BiTE重定向的mVST在两种方法中均介导了稳健的肿瘤裂解（在72h、E:T为1:4时分别为89.8 ± 1.7%和88.7 ± 0.4%），并相对于无BiTE对照扩增≥3倍。两种负载方法均触发了稳健的活化，CD137和CD25显著上调，效应细胞因子大幅增加。在Raji淋巴瘤模型中，CD19×CD3和CD20×CD3 BiTE与装载式mVST产生48-52%的细胞毒性，而直接添加BiTE进一步将杀伤增强至73-74%，并具有可比的活化谱。总体而言，BiTE重定向的mVST在骨髓瘤和淋巴瘤靶点中表现出强效细胞毒性、稳健活化和强烈的效应细胞因子释放，验证了它们作为一种有效的现货型T细胞平台的功能。单一供者来源的mVST来源可以与多种BiTE配对，以解决肿瘤异质性或抗原丢失复发问题，而无需进行工程改造。这些数据支持将BiTE与健康供者来源的mVST相结合以生成可扩展、非工程化的同种异体T细胞免疫疗法用于多种恶性肿瘤的可行性和转化前景。
查看英文原文 English abstract
Bispecific T cell engagers (BiTEs) have showed potent antitumor activity in hematologic malignancies but are often limited by T-cell dysfunction in patients. To overcome this challenge, we developed an off-the-shelf immunotherapy platform using healthy donor-derived multi-virus-specific T cells (mVSTs) as effectors for BiTE-mediated redirection. These memory-derived mVSTs recognize cytomegalovirus (CMV) and Epstein-Barr virus (EBV) antigens, exhibit central and effector memory phenotypes, and carry minimal graft-versus-host disease (GVHD) risk, providing a bankable, and functional T-cell source.mVSTs were expanded from CMV/EBV-seropositive donors and evaluated in multiple myeloma and lymphoma models. Two BiTE-loading strategies were tested: pre-incubation with T cells (armored) or direct addition to co-culture. mVSTs alone exhibited minimal cytotoxicity, whereas BCMAxCD3 BiTE-redirected mVSTs mediated robust tumor lysis in both approaches (89.8 ± 1.7% and 88.7 ± 0.4%, respectively at 72h and E:T 1:4) and expanded ≥3-fold versus no-BiTE controls. Both loading methods triggered robust activation, with marked upregulation of CD137 and CD25 and substantial increases in effector cytokines. In Raji lymphoma models, CD19×CD3 and CD20×CD3 BiTEs produced 48-52% cytotoxicity with armored mVSTs, and direct BiTE addition further enhanced killing to 73-74% with a comparable activation profile. Collectively, BiTE-redirected mVSTs exhibit potent cytotoxicity, robust activation, and strong effector cytokine release across myeloma and lymphoma targets, validating their function as an effective, off-the-shelf T-cell platform. A single donor-derived mVST source can be paired with multiple BiTEs to address tumor heterogeneity or antigen-loss relapse without engineering. These data support the feasibility and translational promise of combining BiTEs with healthy donor-derived mVSTs to generate scalable, non-engineered allogeneic T-cell immunotherapies for diverse malignancies.
利益披露 Disclosure
S. Pahlavanneshan, None..
S. J. Forman, None..
X. Wang, None.