Center for Molecular Medicine Cologne, and Clinic I for Internal Medicine, University Hospital Cologne, University of Cologne, Robert-Koch-Strasse 21, Cologne, Germany.
Cancer Immunol Immunother. 2012 Aug;61(8):1269-77. doi: 10.1007/s00262-012-1202-z. Epub 2012 Jan 25.
Adoptive T cell therapy recently achieved impressive efficacy in early-phase clinical trials; this significantly raises the profile of immunotherapy in the fight against cancer. A broad variety of tumour cells can specifically be targeted by patients' T cells, which are redirected in an antibody-defined, major histocompatibility complex-unrestricted fashion by endowing them with a chimeric antigen receptor (CAR). Despite promising results for some haematologic malignancies, the stroma of large, established tumours, the broad plethora of infiltrating repressor cells, and cancer cell variants that had lost the target antigen limit their therapeutic efficacy in the long term. This article reviews a newly described strategy for overcoming some of these shortcomings by engineering CAR T cells with inducible or constitutive release of IL-12. Once redirected, these T cells are activated, and released IL-12 accumulates in the tumour lesion where it promotes tumour destruction by at least two mechanisms: (1) induction of an innate immune cell response towards those cancer cells which are invisible to redirected T cells and (2) triggering programmatic changes in immune-suppressive cells. Given the enormous complexity of both tumour progression and immune attack, the upcoming strategies using CAR-redirected T cells for local delivery of immune-modulating payloads exhibited remarkable efficacy in pre-clinical models, suggesting their evaluation in clinical trials.
过继性 T 细胞疗法最近在早期临床试验中取得了令人瞩目的疗效；这显著提高了免疫疗法在抗癌中的地位。患者的 T 细胞可以特异性地靶向广泛的肿瘤细胞，这些 T 细胞通过赋予其嵌合抗原受体 (CAR)，以抗体定义的、主要组织相容性复合体不受限制的方式被重新定向。尽管一些血液恶性肿瘤的结果很有希望，但大型已建立的肿瘤的基质、广泛存在的浸润抑制细胞以及失去靶抗原的癌细胞变体限制了它们的长期治疗效果。本文综述了一种新描述的策略，通过工程化 CAR T 细胞以诱导或组成型释放 IL-12 来克服其中的一些缺点。一旦被重新定向，这些 T 细胞就会被激活，并且释放的 IL-12 在肿瘤病变部位积累，通过至少两种机制促进肿瘤破坏：（1）诱导对那些对重新定向的 T 细胞不可见的癌细胞的先天免疫细胞反应；（2）触发免疫抑制细胞的程序性变化。鉴于肿瘤进展和免疫攻击的巨大复杂性，使用 CAR 重定向 T 细胞局部递送免疫调节有效载荷的即将到来的策略在临床前模型中显示出显著的疗效，这表明它们在临床试验中的评估。
