肿瘤细胞治疗研究
英文原题：Emerging precision medicine in multiple myeloma: clinical and preclinical landscape of T cell, natural killer cell, and macrophages engaging multi-specific antibodies.
多发性骨髓瘤（MM）是全球第三大常见的血液系统恶性肿瘤。
多发性骨髓瘤（MM）是全球第三常见的血液系统恶性肿瘤。尽管现有治疗手段不断进步，MM对大多数患者仍不可治愈，主要原因是早期复发和最终对治疗产生耐药，这凸显了对新药的需求。其中，多特异性抗体（MsAbs）已成为有前景的药物。多特异性免疫细胞衔接抗体，如双特异性和三特异性抗体，被设计用于识别同一细胞或不同细胞上的两种或更多抗原。这些抗体可通过衔接骨髓瘤细胞与细胞毒性免疫细胞（如T细胞、自然杀伤（NK）细胞和巨噬细胞（M））来促进癌细胞清除。目前，已有四种双特异性T细胞衔接器（teclistamab、elranatamab、talquetamab和linvoseltamab）获批用于难治性或复发性MM患者（RRMM）。尽管这些疗法在使RRMM患者获得深度缓解方面已显示出有前景的结果，但约三分之一患者会出现原发性耐药。最初，免疫衔接器研究仅聚焦于T细胞，因为其具有关键的抗癌作用，但最近，兴趣已扩展至NK细胞和M，以寻求更广泛的治疗潜力。迄今为止，已有若干NK和M衔接MsAbs，主要以双特异性和三特异性形式，正在临床或临床前评估中，用于改善MM患者的缓解并减少治疗相关毒性。本综述讨论了T、NK和M衔接MsAbs在治疗MM中的最新进展，包括免疫学背景、作用机制、相关临床和临床前进展及挑战。此外，我们还讨论了不同免疫细胞衔接器的优势和缺点。此外，我们回顾了近期研究，这些研究探讨了耐药的临床和分子决定因素，以及针对MsAbs反应的最新预测或预后生物标志物。最后，我们探索了增强MsAbs疗效并降低其毒性的新策略，从而为MM患者提供长期疾病控制并改善生存。
Multiple Myeloma (MM) is the third most common hematological malignancy worldwide. Despite advancements in available therapies, MM remains incurable for most patients, mainly due to the early relapse and eventual resistance to therapy, underlining the need for novel drugs. Among these, multi-specific antibodies (MsAbs) have emerged as promising agents. Multi-specific immune cell-engaging antibodies, such as bi-specific, and tri-specific are designed to recognize two or more antigens on the same or distinct cells. These antibodies could promote cancer cell clearance by engaging both myeloma cells and cytotoxic immune cells such as T and Natural killer (NK) cells and macrophages (M). Currently, four bi-specific T cell engagers (teclistamab, elranatamab, talquetamab and linvoseltamab) are approved for refractory or relapsed MM patients (RRMM). While these therapies have demonstrated promising results in achieving deep remissions in RRMM, primary resistance occurs in about one-third of patients. Initially, immune engager research focused only on T cells due to their crucial anti-cancer role, but more recently, interest has expanded to NK cells and M for broader therapeutic potential. To date, several NK and M engaging MsAbs with mainly bi-specific and tri-specific formats are in clinical or preclinical evaluation for improving MM patients' response and reduce treatment related toxicity. This review discusses the recent advancement in T, NK and M engaging MsAbs in treating MM, including immunological background, mechanisms of action, relevant clinical and preclinical advancements and challenges. Moreover, we discuss the advantages and drawbacks of the different immune cell engagers. Furthermore, we review recent studies investigating the clinical and molecular determinants of resistance along with the latest predictive or prognostic biomarkers of response to MsAbs. Finally, we explore novel strategies to enhance MsAbs efficacy and reduce their toxicity, providing long-term disease control and improving survival in MM patients.
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