OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal.
OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal.
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DOI：
10.3389/fonc.2015.00034
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发表时间：
2015
影响因子：
4.7
通讯作者：
Redmond WL
中科院分区：
文献类型：
--
作者：
Linch SN;McNamara MJ;Redmond WL
最近的研究强调了免疫疗法的治疗效果，免疫疗法是一类利用患者自身免疫系统破坏癌细胞的癌症治疗方法。在肿瘤内，一个负调节分子家族的存在，统称为“检查点抑制剂”，可以抑制T细胞功能以抑制抗肿瘤免疫。检查点抑制剂，如CTLA-4和PD-1，减弱T细胞增殖和细胞因子产生。用拮抗剂单克隆抗体（mAb）靶向阻断CTLA-4或PD-1释放T细胞上的“制动器”以增强抗肿瘤免疫力。产生最佳的“杀伤”CD 8 T细胞应答还需要T细胞受体活化加上共刺激，这可以通过连接肿瘤坏死因子受体家族成员（包括0X 40（CD 134）和4-1BB（CD 137））来提供。OX 40特别令人感兴趣，因为用激活（激动剂）抗OX 40 mAb治疗可增强T细胞分化和细胞溶解功能，从而增强针对多种肿瘤的抗肿瘤免疫力。当作为单药使用时，这些药物可以在转移性疾病患者中诱导有效的临床和免疫应答。然而，这些药物中的每一种仅使一部分患者受益，突出了对更有效的组合治疗策略的迫切需求。在这篇综述中，我们将讨论我们目前对OX 40激动剂与检查点抑制剂阻断协同作用以增强T细胞介导的抗肿瘤免疫的细胞和分子机制的理解，以及组合免疫策略临床翻译的潜在机会。
Recent studies have highlighted the therapeutic efficacy of immunotherapy, a class of cancer treatments that utilize the patient’s own immune system to destroy cancerous cells. Within a tumor the presence of a family of negative regulatory molecules, collectively known as “checkpoint inhibitors,” can inhibit T cell function to suppress anti-tumor immunity. Checkpoint inhibitors, such as CTLA-4 and PD-1, attenuate T cell proliferation and cytokine production. Targeted blockade of CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAbs) releases the “brakes” on T cells to boost anti-tumor immunity. Generating optimal “killer” CD8 T cell responses also requires T cell receptor activation plus co-stimulation, which can be provided through ligation of tumor necrosis factor receptor family members, including OX40 (CD134) and 4-1BB (CD137). OX40 is of particular interest as treatment with an activating (agonist) anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity against a variety of tumors. When used as single agents, these drugs can induce potent clinical and immunologic responses in patients with metastatic disease. However, each of these agents only benefits a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. In this review, we will discuss our current understanding of the cellular and molecular mechanisms by which OX40 agonists synergize with checkpoint inhibitor blockade to augment T cell-mediated anti-tumor immunity and the potential opportunities for clinical translation of combinatorial immunotherapeutic strategies.
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T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.4
作者：
Cuadros, C;Dominguez, AL;Lustgarten, J
通讯作者：
Lustgarten, J
影响因子：
7.3
作者：
van Bergen J;Trowsdale J
通讯作者：
Trowsdale J
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM
影响因子：
4.4
作者：
Bansal-Pakala, P;Halteman, BS;Croft, M
通讯作者：
Croft, M