肿瘤细胞治疗研究
英文原题：New Treatment Options for Newly-Diagnosed and Relapsed Chronic Lymphocytic Leukemia.
过去十年间对慢性淋巴细胞白血病（CLL）生物学认识的加深，促成了多种靶向药物的研发与上市，使这一目前无法治愈的疾病的预后得到可证实的改善。
过去十年对慢性淋巴细胞白血病（CLL）生物学认识的加深，推动了多种靶向药物的开发和应用，并显著改善了这一目前仍无法治愈疾病的预后。目前，布鲁顿酪氨酸激酶（BTK）抑制剂、磷脂酰肌醇3激酶（PI3K）抑制剂、维奈克拉和CD20单克隆抗体，是既往未经治疗及复发／难治性CLL患者治疗的主要药物。伊布替尼是首个获准临床使用的BTK抑制剂，疗效显著且安全性可接受。随后，耐受性更好的第二代不可逆BTK抑制剂阿卡替尼和泽布替尼被用于淋巴系统恶性肿瘤治疗，其中阿卡替尼已获批用于CLL。BTK抑制剂单药通常持续使用，直至出现不可接受的毒性或疾病进展；但与维奈克拉和／或CD20抗体联合时，可带来更深缓解，并可采用限时疗程。近期发现的可逆BTK抑制剂吡托布替尼和奈他布替尼前景良好，似乎比不可逆同类药物活性更强、耐受性更好；但它们仍处于早期开发阶段，尚未获批用于CLL。PI3K抑制剂艾德拉利西和度维利西在复发性CLL患者（包括高危患者）中疗效显著，但其主要应用限制是不良事件，多数具有自身免疫性质，如肝炎、肠炎／结肠炎和肺炎。对于BTK抑制剂和维奈克拉治疗失败的患者，异基因造血干细胞移植、嵌合抗原受体（CAR）T细胞等细胞疗法以及双特异性单克隆抗体也显示出希望。未来几年，新型靶向治疗很可能取代大多数患者所接受的免疫化疗方案。
The better understanding of the biology of chronic lymphocytic leukemia (CLL) gained over the past decade has led to the development and introduction of several targeted drugs, with an demonstrable improvement in the prognosis for this currently incurable condition. Currently, Bruton's tyrosine kinase (BTK) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, venetoclax, and CD20 monoclonal antibodies are the key elements in the treatment of both previously untreated and relapsed/refractory CLL patients. Ibrutinib was the first BTK inhibitor approved for clinical use, and showed excellent efficacy and an acceptable safety profile. Following this, the better-tolerated second-generation irreversible BTK inhibitors acalabrutinib and zanubrutinib have been introduced for the treatment of lymphoid malignancies, and acalabrutinib was approved for CLL. When used as single drugs, BTK inhibitors are given continuously until unacceptable toxicity or disease progression; however, when combined with venetoclax and/or CD20 antibodies, they induce deeper response and can be given for a limited time. Recently, promising new reversible BTK inhibitors pirtobrutinib and nemtabrutinib were discovered, and these seem to be more active and better tolerated than their irreversible predecessors. However, they are in an early phase of development and are not currently approved for CLL. The phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib and duvelisib are highly effective in patients with relapsed CLL, including high-risk disease. The major limitations for their use are adverse events, mostly of autoimmune origin (hepatitis, enteritis/colitis, and pneumonitis). Otherwise, cellular therapies like allogeneic hematopoietic stem cell transplantation and chimeric antigen receptor (CAR) T cells and bispecific monoclonal antibodies offer promise for patients who have failed BTK inhibitors and venetoclax treatment. In the coming years, it is likely that novel targeted therapies will replace immunochemotherapy regimens in most patients.
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