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Chimeric Antigen Receptor-Engineered T Cells for the Treatment of Metastatic Prostate Cancer Abstract： Cancer immunotherapy was selected as the Breakthrough of the Year 2013 by the editors ofScience, in part because of the successful treatment of refractory hematological malignancies with adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells. Effective treatment of B cell leukemia may pave the road to future treatment of solid tumors, using similar approaches. The prostate expresses many unique proteins and, since the prostate gland is a dispensable organ, CAR T cells can potentially be used to target these tissue-specific antigens. However, the location and composition of prostate cancer metastases complicate the task of treating these tumors. It is therefore likely that more sophisticated CAR T cell approaches are going to be required for prostate metastasis than for B cell malignancies. Two main challenges that need to be resolved are how to increase the migration and infiltration of CAR T cells into prostate cancer bone metastases and how to counteract the immunosuppressive microenvironment found in bone lesions. Inclusion of homing (chemokine) receptors in CAR T cells may improve their recruitment to bone metastases, as may antibody-based combination therapies to normalize the tumor vasculature. Optimal activation of CAR T cells through the introduction of multiple costimulatory domains would help to overcome inhibitory signals from the tumor microenvironment. Likewise, combination therapy with checkpoint inhibitors that can reduce tumor immunosuppression may help improve efficacy. Other elegant approaches such as induced expression of immune stimulatory cytokines upon target recognition may also help to recruit other effector immune cells to metastatic sites. Although toxicities are difficult to predict in prostate cancer, severe on-target/off-tumor toxicities have been observed in clinical trials with use of CAR T cells against hematological malignancies; therefore, the choice of the target antigen is going to be crucial. This review focuses on different means of accomplishing maximal effectiveness of CAR T cell therapy for prostate cancer bone metastases while minimizing side effects and CAR T cell-associated toxicities. CAR T cell based therapies for prostate cancer have the potential to be a therapy model for other solid tumors. 嵌合抗原受体修饰的T细胞治疗前列腺癌的研究 癌症免疫疗法被《科学》杂志评选为2013年度的最大突破之一，部分原因在于使用CAR-T细胞疗法成功治疗了难治性血液系统恶性肿瘤。B淋巴细胞性白血病的有效治疗可能为未来使用类似的方法治疗实体瘤铺平道路。前列腺细胞表达许多独特的蛋白，由于前列腺是一个可有可无的器官，CAR-T细胞治疗有可能被用来靶定这些组织特异性抗原的位置。然而，前列腺癌细胞转移后的位置和结构使得治疗这种肿瘤变得复杂化。因此，很可能，比治疗B淋巴细胞白血病更加需要使用CAR-T细胞来治疗前列腺癌。需要解决的两个主要挑战是：如何增加CAR-T细胞对已经骨转移的前列腺癌细胞的迁移和浸润，以及如何消除骨病变中发现的免疫抑制微环境。CAR-T细胞中自动靶向的受体 也许会增强他们向骨转移癌细胞的聚集，就像以抗体为基础的组合疗法，来使肿瘤的脉管系统正常化。通过引入多刺激域将会帮助克服肿瘤微环境的抑制信号来优化CAR-T细胞的活性。同样的，联合使用免疫检查点抑制剂能够减少肿瘤的免疫抑制，可能会帮助提高治疗效果。其他简洁的方法例如增强目标识别中免疫刺激细胞活素的表达可能也会帮助聚集效应免疫细胞到达肿瘤转移部位。虽然在前列腺癌症的治疗中很难预测会出现的毒副反应，但是严重的靶向/非靶向肿瘤毒副反应已经在CAR-T治疗恶性血液疾病的临床试验中被观察到。因此，靶抗原的选择将是至关重要的。这篇文章着重于不同的手段，来实现CAR-T细胞治疗前列腺癌骨转移的最大治疗效果，同时减少CAR-T治疗相关的毒副反应。CAR-T细胞为基础治疗前列腺癌也有潜力成为一个治疗模式，来治疗其他实体肿瘤。
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发表于 2015-11-8 23:36:39
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