肿瘤细胞治疗研究
英文原题：Engineering TCR-directed T-cells for the treatment of multiple myeloma.
多发性骨髓瘤（MM）是一种几乎无法治愈的浆细胞恶性肿瘤，其特征是恶性细胞在允许肿瘤生长的骨髓（BM）微环境中扩增。
多发性骨髓瘤（MM）是一种几乎无法治愈的浆细胞恶性肿瘤，其特征是恶性细胞在允许肿瘤生长的骨髓（BM）微环境中扩增。迫切需要新的策略来改善难以治疗和难治性疾病患者的预后。基因操纵T细胞的能力以及过继性细胞疗法（ACTs）的引入改善了复发和/或难治性（RR）MM的治疗。新出现的证据支持ACTs作为癌症早期治疗线的疗效，甚至可能作为自体造血干细胞移植的替代方案。基于基因工程患者来源T细胞的嵌合抗原受体（CAR）T细胞疗法已用于常规临床实践，然而严重的毒性、治疗耐药性、高昂的成本、繁琐的生产工艺和生产物流限制了其更广泛的应用。TIL（肿瘤浸润淋巴细胞）（TILs）也可以介导肿瘤消退并导致持久缓解，但更广泛的疗效受到可及性有限、增殖能力降低和效应功能低下的限制。在此背景下，经工程化表达T细胞受体（TCRs）的自体T细胞代表了一种改善MM治疗的有前景的选择。免疫蛋白酶体是适应性免疫的重要基石，对于MHC I类（MHC-I）分子向细胞毒性CD8+ T淋巴细胞（CTLs）呈递的抗原肽的高效加工是必需的。近期研究表明，免疫蛋白酶体激活增加了肿瘤特异性新抗原的呈递，从而为提高T细胞介导免疫疗法的抗骨髓瘤效果提供了一种潜在策略。在此，我们讨论支持TCR工程化T细胞用于治疗MM的优势和策略。本综述聚焦于免疫蛋白酶体依赖性抗原加工在塑造骨髓瘤免疫肽组和实现基于TCR的免疫治疗中的作用。我们讨论新抗原呈递的调节如何为MM的TCR工程化T细胞及相关免疫治疗策略的设计提供信息。
Multiple myeloma (MM) is a virtually incurable plasma cell malignancy characterized by malignant cells that expand within the tumor-permissive bone marrow (BM) microenvironment. Novel strategies are urgently needed to improve the outcomes of patients with difficult-to-treat and therapy-refractory disease. The ability to genetically manipulate T-cells and the introduction of adoptive cellular therapies (ACTs) has improved the treatment of relapsed and/or refractory (RR)MM. Emerging evidence supports the efficacy of ACTs as early lines of cancer treatment, potentially even as an alternative to autologous hematopoietic stem cell transplantation. Chimeric antigen receptor (CAR) T-cell therapies based upon genetically engineered patient-derived T-cells are utilized in routine clinical practice, however severe toxicities, therapeutic resistance, exorbitant costs, a cumbersome manufacturing process and production logistics limits their broader application. Tumor-infiltrating lymphocytes (TILs) can also mediate tumor regression and lead to durable responses, but wider efficacy is restricted by limited accessibility, reduced proliferative capacity and low effector function. In this context, autologous T-cells engineered to express T-cell receptors (TCRs) represent an intriguing option to improve MM treatment. Immunoproteasomes represent an essential cornerstone of adaptive immunity and are required for the efficient processing of antigenic peptides presented by MHC class I (MHC-I) molecules to cytotoxic CD8 + T-lymphocytes (CTLs). Recent studies have demonstrated that immunoproteasome activation increases the presentation of tumor-specific neo-antigens, thereby offering a potential strategy to improve the antimyeloma effects of T-cell-mediated immunotherapies. Here, we discuss advantages and strategies that support the administration of TCR-engineered T-cells for the treatment of MM. This review focuses on the role of immunoproteasome dependent antigen processing in shaping the myeloma immunopeptidome and enabling TCR-based immunotherapy. We discuss how modulation of neoantigen presentation may inform the design of TCR-engineered T cells and related immunotherapeutic strategies for MM.
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