Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA; Eli and Edythe Broad Center for Regenerative Medicine & Stem Cell Research, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA.
Immunol Rev. 2014 Jan;257(1):237-49. doi: 10.1111/imr.12128.
Hematopoietic stem cells (HSCs) provide an attractive target for immunotherapy of cancer and leukemia by the introduction of genes encoding T-cell receptors (TCRs) or chimeric antigen receptors (CARs) directed against tumor-associated antigens. HSCs engraft for long-term blood cell production and could provide a continuous source of targeted anti-cancer effector cells to sustain remissions. T cells produced de novo from HSCs may continuously replenish anti-tumor T cells that have become anergic or exhausted from ex vivo expansion or exposure to the intratumoral microenvironment. In addition, transgenic T cells produced in vivo undergo allelic exclusion, preventing co-expression of an endogenous TCR that could mis-pair with the introduced TCR chains and blunt activity or even cause off-target reactivity. CAR-engineered HSCs may produce myeloid and natural killer cells in addition to T cells expressing the CAR, providing broader anti-tumor activity that arises quickly after transplant and does not solely require de novo thymopoiesis. Use of TCR- or CAR-engineered HSCs would likely require cytoreductive conditioning to achieve long-term engraftment, and this approach may be used in clinical settings where autologous HSC transplant is being performed to add a graft-versus-tumor effect. Results of experimental and preclinical studies performed to date are reviewed.
造血干细胞 (HSCs) 为通过引入针对肿瘤相关抗原的 T 细胞受体 (TCRs) 或嵌合抗原受体 (CARs) 来对癌症和白血病进行免疫治疗提供了一个有吸引力的目标。HSCs 长期植入可用于血细胞的产生，并可提供持续的靶向抗癌效应细胞来源，以维持缓解。从 HSCs 新产生的 T 细胞可不断补充因体外扩增或暴露于肿瘤内微环境而变得无反应或衰竭的抗肿瘤 T 细胞。此外，体内产生的转基因 T 细胞经历等位基因排斥，防止与引入的 TCR 链错误配对的内源性 TCR 的共表达，从而削弱活性甚至导致脱靶反应。CAR 工程化的 HSCs 除了表达 CAR 的 T 细胞外，还可能产生髓样细胞和自然杀伤细胞，提供更广泛的抗肿瘤活性，在移植后迅速出现，并且不仅仅需要新的胸腺生成。TCR 或 CAR 工程化的 HSCs 的使用可能需要细胞减少性调理以实现长期植入，并且这种方法可用于正在进行自体 HSC 移植以增加移植物抗肿瘤效应的临床环境中。对迄今为止进行的实验和临床前研究的结果进行了综述。
