免疫检查点激动剂治疗实体瘤的研究进展

国际肿瘤学杂志››2023,Vol. 50››Issue (5): 290-293.doi:10.3760/cma.j.cn371439-20220726-00058

免疫检查点激动剂治疗实体瘤的研究进展

岳红云¹, 张百红²()

¹中国人民解放军联勤保障部队第九四〇医院眼科，兰州 730050
²中国人民解放军联勤保障部队第九四〇医院肿瘤科，兰州 730050

收稿日期:2022-07-26修回日期:2022-11-16出版日期:2023-05-08发布日期:2023-06-27
通讯作者:张百红 E-mail:bhzhang1999@126.com
基金资助:
甘肃省自然科学基金(22JR5RA007)

Research progress of immune checkpoint agonist for solid tumor treatments

Yue Hongyun¹, Zhang Baihong²()

¹Department of Ophthalmology， 940th Hospital of Joint Logistics Support Force of People's Liberation Army， Lanzhou 730050， China
²Department of Oncology， 940th Hospital of Joint Logistics Support Force of People's Liberation Army， Lanzhou 730050， China

Received:2022-07-26Revised:2022-11-16Online:2023-05-08Published:2023-06-27
Contact:Zhang Baihong E-mail:bhzhang1999@126.com
Supported by:
Natural Science Foundation of Gansu Province of China(22JR5RA007)

摘要/Abstract

摘要：

免疫检查点由抑制性和刺激性分子组成，抑制性检查点程序性死亡蛋白1（PD-1）和细胞毒性T淋巴细胞抗原4（CTLA-4）抑制剂已经广泛用于肿瘤临床治疗，刺激性检查点GITR、OX40、4-1BB、ICOS、CD40和STING激动剂正在进行临床试验。影响刺激性检查点分子的免疫检查点激动剂发展迅速，免疫激动剂抗体将成为治疗实体瘤的重要药物。

关键词:肿瘤,刺激性检查点分子,免疫激动剂抗体,治疗

Abstract:

Immune checkpoint consists of inhibitory and stimulatory molecules. Drugs blocking inhibitory checkpoint programmed cell death receptor-1 （PD-1） and cytotoxic T lymphocyte-associated molecule-4 （CTLA-4） are currently utilized for wide variety of human cancers. Agonists of stimulatory checkpoints such as GITR， OX40， 4-1BB， ICOS， CD40 and STING are undergoing critical clinical trials. Immune checkpoint agonists that affect stimulatory checkpoint molecules develop rapidly， and immune agonist antibodies thus represent an important approach for solid tumor treatments.

Key words:Neoplasms,Stimulatory checkpoint molecules,Immune agonist antibody,Therapy

岳红云, 张百红. 免疫检查点激动剂治疗实体瘤的研究进展[J]. 国际肿瘤学杂志, 2023, 50(5): 290-293.

Yue Hongyun, Zhang Baihong. Research progress of immune checkpoint agonist for solid tumor treatments[J]. Journal of International Oncology, 2023, 50(5): 290-293.

图/表1

表1

常见免疫检查点分子及激动剂"

受体和配体	作用机制	试验阶段	代表药物
GITR-GITRL	促进Teff细胞激活和增殖，减少Treg细胞	Ⅱ期	TRX518、MK-1248^{[ 5 , 7 ]}
OX40-OX40L	促进Teff细胞和记忆T细胞存活	Ⅱ期	MEDI6469^{[ 9 ]}
4-1BB-4-1BBL	促进T细胞增殖和提高线粒体功能	Ⅰ期	乌托鲁单抗、乌瑞芦单抗^{[ 11 - 12 ]}
ICOS-ICOSL	促进TCR共刺激和Treg细胞激活	Ⅰ期	GSK3359609^{[ 17 ]}
CD40-CD40L	促进T细胞激活和浸润	Ⅰ期	CP-870893、Sotigalimab^{[ 21 - 22 ]}
cGAS-STING	提高抗肿瘤免疫反应	临床前研究	MSA-2^{[ 26 - 27 ]}

表1

参考文献29

[1]	Ribas A. Releasing the brakes on cancer immunotherapy[J]. N Engl J Med, 2015, 373(16): 1490-1492. DOI: 10.1056/NEJMp1510079. doi:10.1056/NEJMp1510079
[2]	Mayes PA, Hance KW, Hoos A. The promise and challenges of immune agonist antibody development in cancer[J]. Nat Rev Drug Discov, 2018, 17(7): 509-527. DOI: 10.1038/nrd.2018.75. doi:10.1038/nrd.2018.75pmid:29904196
[3]	Flemming A. Bispecific agonist boosts anti-tumour T cells via GITR[J]. Nat Rev Immunol, 2022, 22(4): 208. DOI: 10.1038/s41577-022-00708-1. doi:10.1038/s41577-022-00708-1
[4]	Chan S, Belmar N, Ho S, et al. An anti-PD-1-GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy[J]. Nat Cancer, 2022, 3(3): 337-354. DOI: 10.1038/s43018-022-00334-9. doi:10.1038/s43018-022-00334-9
[5]	Killock D. GITR agonism—combination is key[J]. Nat Rev Clin Oncol, 2019, 16(7): 402. DOI: 10.1038/s41571-019-0221-5. doi:10.1038/s41571-019-0221-5pmid:31065053
[6]	He C, Maniyar RR, Avraham Y, et al. Therapeutic antibody activation of the glucocorticoid-induced TNF receptor by a clustering mechanism[J]. Sci Adv, 2022, 8(8): eabm4552. DOI: 10.1126/sciadv.abm4552. doi:10.1126/sciadv.abm4552
[7]	Geva R, Voskoboynik M, Dobrenkov K, et al. First-in-human phase 1 study of MK-1248, an anti-glucocorticoid-induced tumor necrosis factor receptor agonist monoclonal antibody, as monotherapy or with pembrolizumab in patients with advanced solid tumors[J]. Cancer, 2020, 126(22): 4926-4935. DOI: 10.1002/cncr.33133. doi:10.1002/cncr.33133
[8]	Morad G, Helmink BA, Sharma P, et al. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade[J]. Cell, 2021, 184(21): 5309-5337. DOI: 10.1016/j.cell.2021.09.020. doi:10.1016/j.cell.2021.09.020pmid:34624224
[9]	Duhen R, Ballesteros-Merino C, Frye AK, et al. Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells[J]. Nat Commun, 2021, 12(1): 1047. DOI: 10.1038/s41467-021-21383-1. doi:10.1038/s41467-021-21383-1pmid:33594075
[10]	Sagiv-Barfi I, Czerwinski DK, Shree T, et al. Intratumoral immunotherapy relies on B and T cell collaboration[J]. Sci Immunol, 2022, 7(71): eabn5859. DOI: 10.1126/sciimmunol.abn5859. doi:10.1126/sciimmunol.abn5859
[11]	Chin SM, Kimberlin CR, Roe-Zurz Z, et al. Structure of the 4-1BB/4-1BBL complex and distinct binding and functional properties of utomilumab and urelumab[J]. Nat Commun, 2018, 9(1): 4679. DOI: 10.1038/s41467-018-07136-7. doi:10.1038/s41467-018-07136-7pmid:30410017
[12]	Segal NH, He AR, Doi T, et al. Phase Ⅰ study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer[J]. Clin Cancer Res, 2018, 24(8): 1816-1823. DOI: 10.1158/1078-0432.CCR-17-1922. doi:10.1158/1078-0432.CCR-17-1922pmid:29549159
[13]	You G, Lee Y, Kang YW, et al. B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8⁺tumor-infiltrating lymphocytes[J]. Sci Adv, 2021, 7(3): eaax3160. DOI: 10.1126/sciadv.aax3160. doi:10.1126/sciadv.aax3160
[14]	Geuijen C, Tacken P, Wang LC, et al. A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade[J]. Nat Commun, 2021, 12(1): 4445. DOI: 10.1038/s41467-021-24767-5. doi:10.1038/s41467-021-24767-5pmid:34290245
[15]	Claus C, Ferrara C, Xu W, et al. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy[J]. Sci Transl Med, 2019, 11(496): eaav5989. DOI: 10.1126/scitranslmed.aav5989. doi:10.1126/scitranslmed.aav5989
[16]	Peng CW, Huggins MA, Wanhainen KM, et al. Engagement of the costimulatory molecule ICOS in tissues promotes establishment of CD8⁺tissue-resident memory T cells[J]. Immunity, 2022, 55(1): 98-114.e5. DOI: 10.1016/j.immuni.2021.11.017. doi:10.1016/j.immuni.2021.11.017
[17]	Garber K. Immune agonist antibodies face critical test[J]. Nat Rev Drug Discov, 2020, 19(1): 3-5. DOI: 10.1038/d41573-019-00214-5. doi:10.1038/d41573-019-00214-5pmid:31907434
[18]	Kvedaraite E, Ginhoux F. Human dendritic cells in cancer[J]. Sci Immunol, 2022, 7(70): eabm9409. DOI: 10.1126/sciimmunol.abm9409. doi:10.1126/sciimmunol.abm9409
[19]	Choi Y, Shi Y, Haymaker CL, et al. T-cell agonists in cancer immunotherapy[J]. J Immunother Cancer, 2020, 8(2): e000966. DOI: 10.1136/jitc-2020-000966. doi:10.1136/jitc-2020-000966
[20]	Carmona J. Immunity boost against pancreatic cancer[J/OL]. Nat Med. [2021-03-03][2022-05-01]. https://pubmed.ncbi.nlm.nih.gov/33658709/. DOI: 10.1038/d41591-021-00012-w. doi:10.1038/d41591-021-00012-w
[21]	O'Hara MH, O'Reilly EM, Varadhachary G, et al. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study[J]. Lancet Oncol, 2021, 22(1): 118-131. DOI: 10.1016/S1470-2045(20)30532-5. doi:10.1016/S1470-2045(20)30532-5pmid:33387490
[22]	Bajor DL, Mick R, Riese MJ, et al. Long-term outcomes of a phase Ⅰ study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma[J]. Oncoimmunology, 2018, 7(10): e1468956. DOI: 10.1080/2162402X.2018.1468956. doi:10.1080/2162402X.2018.1468956
[23]	Salomon R, Rotem H, Katzenelenbogen Y, et al. Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting[J]. Nat Cancer, 2022, 3(3): 287-302. DOI: 10.1038/s43018-022-00329-6. doi:10.1038/s43018-022-00329-6
[24]	Maskalenko NA, Zhigarev D, Campbell KS. Harnessing natural killer cells for cancer immunotherapy: dispatching the first responders[J]. Nat Rev Drug Discov, 2022, 21(8): 559-577. DOI: 10.1038/s41573-022-00413-7. doi:10.1038/s41573-022-00413-7pmid:35314852
[25]	Wolf NK, Blaj C, Picton LK, et al. Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC Ⅰ-deficient and MHC Ⅰ⁺tumors[J]. Proc Natl Acad Sci U S A, 2022, 119(22): e2200568119. DOI: 10.1073/pnas.2200568119. doi:10.1073/pnas.2200568119
[26]	Pan BS, Perera SA, Piesvaux JA, et al. An orally available non-nucleotide STING agonist with antitumor activity[J]. Science, 2020, 369(6506): eaba6098. DOI: 10.1126/science.aba6098. doi:10.1126/science.aba6098
[27]	Gajewski TF, Higgs EF. Immunotherapy with a sting[J]. Science, 2020, 369(6506): 921-922. DOI: 10.1126/science.abc6622. doi:10.1126/science.abc6622pmid:32820113
[28]	Gong N, Mitchell MJ. Lipid nanodiscs give cancer a STING[J]. Nat Mater, 2022, 21(6): 616-617. DOI: 10.1038/s41563-022-01270-w. doi:10.1038/s41563-022-01270-w
[29]	Dane EL, Belessiotis-Richards A, Backlund C, et al. STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity[J]. Nat Mater, 2022, 21(6): 710-720. DOI: 10.1038/s41563-022-01251-z. doi:10.1038/s41563-022-01251-z