Velasco-Sidro Miriam, Arroyo-Ródenas Javier, Díez-Alonso Laura, Ramírez-Fernández Ángel, Álvarez-Vallina Luis
Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre, Madrid, Spain.
Immuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, Spain.
Oncoimmunology. 2025 Dec;14(1):2444701. doi: 10.1080/2162402X.2024.2444701. Epub 2024 Dec 26.
Despite recent advances in immunotherapy against B cell malignancies such as BCMA (B cell maturation antigen) and CD19-targeted treatments using soluble T cell-engaging (TCE) antibodies or chimeric antigen receptor T cells (CAR-T), there is still an important number of patients experiencing refractory/relapsed (R/R) disease. Approaches to avoid tumor-intrinsic mechanisms of resistance such as immune pressure-mediated antigen downmodulation, are being broadly investigated. These strategies include BCMA/CD19 dual-targeting therapies, which may be of particular interest to patients with B cell lymphoma and multiple myeloma, where a specific double-positive immature subpopulation is commonly associated with poor prognosis and poor response to current treatments. In fact, several clinical trials targeting both antigens through different strategies are currently underway. Here, based on the previously validated STAb (in situ secretion of T cell-redirecting bispecific antibodies) concept, we used two different engineering strategies (pool and co-transduction) to generate dual-targeted STAb-T cells simultaneously secreting BCMA TCE and CD19 TCE that outperformed single-targeted STAb-T cells in different models. These promising results encourage further preclinical clinical testing of dual STAb-T cells in R/R B-cell malignancies.
尽管针对B细胞恶性肿瘤的免疫疗法取得了最新进展,如针对B细胞成熟抗原(BCMA)的疗法以及使用可溶性T细胞衔接(TCE)抗体或嵌合抗原受体T细胞(CAR-T)进行的CD19靶向治疗,但仍有相当数量的患者出现难治性/复发性(R/R)疾病。避免肿瘤内在耐药机制(如免疫压力介导的抗原下调)的方法正在广泛研究中。这些策略包括BCMA/CD19双靶向疗法,对于B细胞淋巴瘤和多发性骨髓瘤患者可能特别有意义,在这些疾病中,特定的双阳性未成熟亚群通常与预后不良和对当前治疗反应不佳相关。事实上,目前正在进行多项通过不同策略靶向这两种抗原的临床试验。在此,基于先前验证的原位分泌T细胞重定向双特异性抗体(STAb)概念,我们使用了两种不同的工程策略(汇集和共转导)来生成同时分泌BCMA TCE和CD19 TCE的双靶向STAb-T细胞,在不同模型中其表现优于单靶向STAb-T细胞。这些有前景的结果鼓励在R/R B细胞恶性肿瘤中对双STAb-T细胞进行进一步的临床前临床试验。
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