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Immune checkpoint inhibitors:breakthroughs in cancer treatment

Cancer Biology & Medicine 2024年第6期21卷 451-472页

作者： Xueqing Kong Jinyi Zhang Shuwei Chen Xianyang Wang Qing Xi Han Shen Rongxin Zhang Laboratory of Immunology and Inflammation School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou 510006China Department of Biology School of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou 510006China

Over the past two decades,immunotherapies have increasingly been considered as first-line treatments for most *** such treatment is immune checkpoint blockade(ICB),which has demonstrated promising results against various solid tumors in clinical *** antibodies(mAbs)are currently available as immune checkpoint inhibitors(icis).These icis target specific immune checkpoints,including cytotoxic T-lymphocyte-associated antigen-4(CTLA-4)and programmed cell death protein 1(PD-1).Clinical trial results strongly support the feasibility of this immunotherapeutic ***,a substantial proportion of patients with cancer develop resistance or tolerance to treatment,owing to tumor immune evasion mechanisms that counteract the host immune ***,substantial research focus has been aimed at identifying additional icis or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1,anti-programmed cell death ligand 1(anti-PD-L1),and anti-CTLA-4 ***,several immune checkpoint molecular targets have been identified,such as T cell immunoreceptor with Ig and ITIM domains(TIGIT),mucin domain containing-3(TIM-3),lymphocyte activation gene-3(LAG-3),V-domain immunoglobulin suppressor of T cell activation(VISTA),B and T lymphocyte attenuator(BTLA),and signal-regulatory proteinα(SIRPα).Functional m Abs targeting these molecules are under ***-4,PD-1/PD-L1,and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of *** review discusses these structures,as well as clinical progress in m Abs targeting these immune checkpoint molecules and their potential applications.

关键词： Immunotherapy cancer icis PD-1 CTLA-4

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The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype,promoting a favorable response to anti-PD-1 therapy via NLRP3 activation

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Cellular & Molecular Immunology 2024年第1期21卷 60-79页

作者： Fan Luo Han Li Wenjuan Ma Jiaxin Cao Qun Chen Feiteng Lu Miaozhen Qiu Penghui Zhou Zengfei Xia Kangmei Zeng Jianhua Zhan Ting Zhou Qiuyun Luo Wentao Pan Lin Zhang Chaozhuo Lin Yan Huang Li Zhang Dajun Yang Hongyun Zhao State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhouChina Ascentage Pharma(Suzhou)Co Ltd 218 Xinghu StreetSuzhouJiangsu ProvinceChina

The main challenges in the use of immune checkpoint inhibitors(icis)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T *** the tumor microenvironment(TME)from“cold”to“hot”and thus more likely to potentiate the effects of icis is a promising strategy for cancer *** found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+mouse *** single-cell RNA sequencing,we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion,restoring T-cell function and promoting a favorable immunotherapy ***,we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling,thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine *** a result,APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment,thus improving tumor immunosuppression and further enhancing antitumor T-cell *** immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86,p-NF-κB p65 and NLRP3 levels,accompanied by lower CD206 expression on ***,these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.

关键词： BCL-2 APG-2575 icis Macrophages NLRP3

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第29届国际影像科学大会(icis’02)和国际影像科学委员会(icis)会议在日本召开

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影像科学与光化学 2002年第4期 317-318页

作者：夏培杰中国科学院理化技术研究所

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icis治疗实体瘤的非常规反应及其疗效评价标准的研究进展

ICIs治疗实体瘤的非常规反应及其疗效评价标准的研究进展

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作者：刘娅重庆医科大学

学位级别：硕士

随着对免疫学及分子生物学的深入研究及理解,以免疫分子生物学为基础的免疫治疗已成为抗肿瘤治疗的新模式。近10年来,免疫检查点抑制剂的广泛获批及逐渐普及于临床,已在多种实体瘤治疗中大放异彩、展现出优良前景,被视为最具有潜力的抗... 详细信息

随着对免疫学及分子生物学的深入研究及理解,以免疫分子生物学为基础的免疫治疗已成为抗肿瘤治疗的新模式。近10年来,免疫检查点抑制剂的广泛获批及逐渐普及于临床,已在多种实体瘤治疗中大放异彩、展现出优良前景,被视为最具有潜力的抗肿瘤治疗方式之一。但同时,越来越多的证据也提示,随着治疗模式的“范式转化”,新的治疗模式也带来了不同于传统应答模式的疗效反应模式,即非常规反应模式,包括假性进展、延迟反应、疾病超进展等。研究证实,传统的实体瘤治疗疗效评价往往无法准确捕捉此类非常规反应,从而难以正确评估免疫治疗疗效,这为临床工作带来了极大困扰与挑战。因此,新的实体瘤免疫治疗疗效评价标准油然而生并亟待发展与完善,导致了一系列免疫相关疗效评价标准被陆续提出。本文就实体瘤免疫治疗,主要是检查点抑制剂治疗的非常规反应模式及相关疗效评价标准的研究发展和应用作一综述。

关键词： icis 实体瘤假性进展超进展疗效评价标准

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第29届国际影像科学大会(icis‘02)将于2002年在日本东京召开

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影像科学与光化学 2001年第3期 237-237页

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晚期实体瘤脑转移放疗联合免疫检查点抑制剂临床疗效及安全性观察

晚期实体瘤脑转移放疗联合免疫检查点抑制剂临床疗效及安全性观察

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第四届全国医药研究论坛

作者：李亚楠陈明红叶志慧阴爱华章毅南通瑞慈医院扬州大学第四临床医学院放疗科

目的研究对于实体瘤脑转移患者单放和放疗联合免疫治疗两种策略下的肿瘤应答情况。方法对42例实体瘤脑转移患者进行回顾性分析,一组为单放组(RT);一组为放疗联合免疫治疗组(RT-icis)。分别统计两组之间的临床数据。结果单放组1、3和6个... 详细信息

目的研究对于实体瘤脑转移患者单放和放疗联合免疫治疗两种策略下的肿瘤应答情况。方法对42例实体瘤脑转移患者进行回顾性分析,一组为单放组(RT);一组为放疗联合免疫治疗组(RT-icis)。分别统计两组之间的临床数据。结果单放组1、3和6个月的DCR率分别为94.5%、94.5%和86.4%,ORR率分别为31.8%、50%和50%。平均i PFS为9.08个月,中位i PFS为8.2个月。RT-icis组1、3和6个月的DCR率分别为84.5%、100%和95.0%,ORR率分别为34.5%、65.0%和70.0%。平均i PFS为12.53个月,中位iPFS为13.0个月(P=0.007)。与单放组相比,RT-icis在1、3和6个月的CD4+T/CD8+T数值分别为1.21±0.87、1.47±0.91和1.74±1.01(p=0.561、0.047、0.023)。脑水肿加重是单放和RT-icis最常见的副反应。RT-icis组的毒副反应整体可控。结论相较于单放,RT-icis能更好地延长i PFS,有着更高的长期局部控制率,且能更好地解除免疫抑制。而联合治疗的毒副反应整体可耐受,安全性可控。

关键词：脑转移放射治疗 icis iPFS 客观缓解率 CD4+T/CD8+T 安全性

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