Hematology and Bone Marrow Transplant Unit and Center of Cell Therapy 'G. Lanzani', Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
Department of Pediatrics, M Tettamanti Research Center, Laboratory of Cell therapy 'S. Verri' University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy.
Leukemia. 2015 Jan;29(1):1-10. doi: 10.1038/leu.2014.189. Epub 2014 Jun 12.
When treatment fails, the clinical outcome of acute leukemia patients is usually very poor, particularly when failure occurs after transplantation. A second allogeneic stem cell transplant could be envisaged as an effective and feasible salvage option in younger patients having a late relapse and an available donor. Unmanipulated or minimally manipulated donor T cells may also be effective in a minority of patients but the main limit remains the induction of severe graft-versus-host disease. This clinical complication has brought about a huge research effort that led to the development of leukemia-specific T-cell therapy aiming at the direct recognition of leukemia-specific rather than minor histocompatibility antigens. Despite a great scientific interest, the clinical feasibility of such an approach has proven to be quite problematic. To overcome this limitation, more research has moved toward the choice of targeting commonly expressed hematopoietic specific antigens by the genetic modification of unselected T cells. The best example of this is represented by the anti-CD19 chimeric antigen receptor (CD19.CAR) T cells. As a possible alternative to the genetic manipulation of unselected T cells, specific T-cell subpopulations with in vivo favorable homing and long-term survival properties have been genetically modified by CAR molecules. Finally, the use of naturally cytotoxic effector cells such as natural killer and cytokine-induced killer cells has been proposed in several clinical trials. The clinical development of these latter cells could also be further expanded by additional genetic modifications using the CAR technology.
当治疗失败时，急性白血病患者的临床预后通常非常差，尤其是在移植后失败时。对于有晚期复发且有供体的年轻患者，可以设想进行第二次同种异体造血干细胞移植作为有效且可行的挽救选择。未经处理或轻度处理的供体 T 细胞在少数患者中也可能有效，但主要限制仍然是诱导严重的移植物抗宿主病。这种临床并发症促使人们进行了大量研究，从而开发了针对白血病特异性而非次要组织相容性抗原的白血病特异性 T 细胞疗法。尽管具有很大的科学兴趣，但这种方法的临床可行性已被证明存在相当多的问题。为了克服这一限制，更多的研究转向选择通过遗传修饰未选择的 T 细胞来靶向共同表达的造血特异性抗原。这方面的最佳例子是抗 CD19 嵌合抗原受体 (CD19.CAR) T 细胞。作为未选择的 T 细胞遗传修饰的可能替代方法，具有体内有利归巢和长期存活特性的特定 T 细胞亚群已通过 CAR 分子进行了遗传修饰。最后，在几项临床试验中提出了使用自然细胞毒性效应细胞（如自然杀伤细胞和细胞因子诱导的杀伤细胞）。通过使用 CAR 技术进行额外的遗传修饰，也可以进一步扩展这些后期细胞的临床开发。
