Toxicity management for patients receiving novel T-cell engaging therapies.
Toxicity management for patients receiving novel T-cell engaging therapies.
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DOI：
10.1097/mop.0000000000000043
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发表时间：
2014-02
影响因子：
3.6
通讯作者：
Grupp SA
中科院分区：
文献类型：
--
作者：
Barrett DM;Teachey DT;Grupp SA
最近的临床试验使用T细胞接合免疫疗法，如靶向T细胞和肿瘤细胞的双特异性抗体，以及表达靶向和活化分子（称为嵌合抗原受体）的工程化T细胞，已经证明了概念的有力证明。这些疗法导致患者中显著程度的免疫激活，这与大大增加的功效相关，但也与显著的毒性相关。这些疗法产生非生理性T细胞活化，这是这些新的高活性治疗的标志。我们和其他人已经注意到细胞因子激活谱与接受T细胞参与疗法的患者的毒性和功效相关。效应细胞因子如干扰素-γ升高，但与巨噬细胞活化综合征/噬血细胞性淋巴组织细胞增多症相关的细胞因子如白细胞介素（IL）-10和IL-6也升高。虽然皮质类固醇可以控制这些毒性中的一些，但靶向方法可以产生上级毒性控制而不干扰疗效。我们已经开发的一种方法使用IL-6受体拮抗剂托珠单抗靶向IL-6，这是毒性反应中的关键细胞因子。对这些新疗法产生的T细胞活化的详细研究导致了更具针对性的方法，这些方法有可能在保持疗效的同时控制毒性。
Recent clinical trials using T-cell engaging immunotherapies such as bispecific antibodies which target T cells and tumor cells, as well as engineered T cells that express targeting and activation molecules known as chimeric antigen receptors, have demonstrated powerful proof of concept. These therapies result in a significant degree of immune activation in the patient, which has correlated with greatly increased efficacy but also with notable toxicity. These therapies produce nonphysiologic T-cell activation, which is the hallmark of these new, highly active treatments. We and others have noted cytokine activation profiles that correlate with both toxicity and efficacy in patients receiving T-cell engaging therapies. Effector cytokines such as interferon-γ are elevated, but so are cytokines that are associated with macrophage activation syndrome/hemophagocytic lymphohistiocytosis, such as interleukin (IL)-10 and IL-6. Although corticosteroids can control some of these toxicities, a targeted approach may produce superior toxicity control without interfering with efficacy. One approach we have developed targets IL-6, a key cytokine in the toxicity response, using the IL-6 receptor antagonist tocilizumab. Detailed studies of the T-cell activation produced by these novel therapies has led to more targeted approaches that have the potential to control toxicity while maintaining efficacy.