CAR-T在食管鳞状细胞癌治疗中的研究进展

doi:10.3760/cma.j.cn371439-20221123-00045

摘要/Abstract

摘要：

嵌合抗原受体T细胞（CAR-T）疗法作为近几年发展迅速的治疗手段，在血液肿瘤治疗中取得了显著的效果，但在食管鳞状细胞癌等实体瘤的治疗中因多种因素而受到限制。明确CAR-T疗法受限制的原因并寻求其应对方法，可为食管鳞状细胞癌的治疗提供新的思路和见解。

关键词: 食道鳞癌, 嵌合抗原受体, 肿瘤微环境, 免疫疗法

Abstract:

Chimeric antigen receptor T cell （CAR-T） therapy， an emerging immunotherapy， has achieved remarkable results in the treatment of hematologic tumors. However， it's limited in the treatment of solid tumors such as esophageal squamous cell carcinoma due to various factors. Clarifying the reasons for the limitation of CAR-T therapy and exploring the corresponding solutions can provide new ideas and insights for the treatment of esophageal squamous cell carcinoma.

Key words: Esophageal squamous cell carcinoma, Receptors, chimeric antigen, Tumor microenvironment, Immunotherapy

丁浩, 应劲涛, 付茂勇. CAR-T在食管鳞状细胞癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2023, 50(4): 231-235.

Ding Hao, Ying Jintao, Fu Maoyong. Research progress of CAR-T in the treatment of esophageal squamous cell carcinoma[J]. Journal of International Oncology, 2023, 50(4): 231-235.

图/表 1

参考文献 45

[1]	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660. doi: 10.3322/caac.21660
[2]	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1): 7-30. DOI: 10.3322/caac.21590. doi: 10.3322/caac.21590
[3]	Li R, Ma C, Cai H, et al. The CAR T-cell mechanoimmunology at a glance[J]. Adv Sci (Weinh), 2020, 7(24): 2002628. DOI: 10. 1002/advs.202002628. doi: 10. 1002/advs.202002628
[4]	Larson RC, Kann MC, Bailey SR, et al. CAR T cell killing requires the IFNγR pathway in solid but not liquid tumours[J]. Nature, 2022, 604(7906): 563-570. DOI: 10.1038/s41586-022-04585-5. doi: 10.1038/s41586-022-04585-5
[5]	Timmers M, Roex G, Wang Y, et al. Chimeric antigen receptor-modified T cell therapy in multiple myeloma: beyond B cell maturation antigen[J]. Front Immunol, 2019, 10: 1613. DOI: 10.3389/fimmu.2019.01613. doi: 10.3389/fimmu.2019.01613 pmid: 31379824
[6]	Abate-Daga D, Davila ML. CAR models: next-generation CAR modifications for enhanced T-cell function[J]. Mol Ther Oncolytics, 2016, 3: 16014. DOI: 10.1038/mto.2016.14. doi: 10.1038/mto.2016.14
[7]	Asmamaw Dejenie T, Tiruneh G/Medhin M, Dessie Terefe G, et al. Current updates on generations, approvals, and clinical trials of CAR T-cell therapy[J]. Hum Vaccin Immunother, 2022, 18(6): 2114254. DOI: 10.1080/21645515.2022.2114254. doi: 10.1080/21645515.2022.2114254
[8]	Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia[J]. N Engl J Med, 2018, 378(5): 449-459. DOI: 10.1056/NEJMoa1709919. doi: 10.1056/NEJMoa1709919
[9]	Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma[J]. N Engl J Med, 2019, 380(1): 45-56. DOI: 10.1056/NEJMoa1804980. doi: 10.1056/NEJMoa1804980
[10]	Siddiqui RS, Sardar M. A systematic review of the role of chimeric antigen receptor T (CAR-T) cell therapy in the treatment of solid tumors[J]. Cureus, 2021, 13(4): e14494. DOI: 10.7759/cureus.14494. doi: 10.7759/cureus.14494
[11]	Yang S, Wei W, Zhao Q. B7-H3, a checkpoint molecule, as a target for cancer immunotherapy[J]. Int J Biol Sci, 2020, 16(11): 1767-1773. DOI: 10.7150/ijbs.41105. doi: 10.7150/ijbs.41105 pmid: 32398947
[12]	Chen L, Chen J, Xu B, et al. B7-H3 expression associates with tumor invasion and patient's poor survival in human esophageal cancer[J]. Am J Transl Res, 2015, 7(12): 2646-2660. pmid: 26885263
[13]	Xuan Y, Sheng Y, Zhang D, et al. Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models[J]. Transl Oncol, 2021, 14(8): 101138. DOI: 10.1016/j.tranon.2021.101138. doi: 10.1016/j.tranon.2021.101138
[14]	Yue G, Tang J, Zhang L, et al. CD276 suppresses CAR-T cell function by promoting tumor cell glycolysis in esophageal squamous cell carcinoma[J]. J Gastrointest Oncol, 2021, 12(1): 38-51. DOI: 10.21037/jgo-21-50. doi: 10.21037/jgo-21-50 pmid: 33708423
[15]	Bicyclic peptide makes targeting EphA2 possible[J]. Cancer Discov, 2021, 11(12): 2951-2952. DOI: 10.1158/2159-8290.CD-NB2021-0393. doi: 10.1158/2159-8290.CD-NB2021-0393 pmid: 34666990
[16]	Syed N, Barbhuiya MA, Pinto SM, et al. Phosphotyrosine profiling identifies ephrin receptor A2 as a potential therapeutic target in esophageal squamous-cell carcinoma[J]. Proteomics, 2015, 15(2/3): 374-382. DOI: 10.1002/pmic.201400379. doi: 10.1002/pmic.201400379
[17]	Shi H, Yu F, Mao Y, et al. EphA2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma[J]. J Thorac Dis, 2018, 10(5): 2779-2788. DOI: 10.21037/jtd.2018.04.91. doi: 10.21037/jtd.2018.04.91 pmid: 29997940
[18]	Rong L, Wang B, Guo L, et al. HER2 expression and relevant clinicopathological features in esophageal squamous cell carcinoma in a Chinese population[J]. Diagn Pathol, 2020, 15(1): 27. DOI: 10.1186/s13000-020-00950-y. doi: 10.1186/s13000-020-00950-y pmid: 32209107
[19]	Yu F, Wang X, Shi H, et al. Development of chimeric antigen receptor-modified T cells for the treatment of esophageal cancer[J]. Tumori, 2021, 107(4): 341-352. DOI: 10.1177/030089 1620960223. doi: 10.1177/030089 1620960223
[20]	Pataskar A, Champagne J, Nagel R, et al. Tryptophan depletion results in tryptophan-to-phenylalanine substitutants[J]. Nature, 2022, 603(7902): 721-727. DOI: 10.1038/s41586-022-04499-2. doi: 10.1038/s41586-022-04499-2
[21]	Zhang T, Zhang Z, Li F, et al. miR-143 regulates memory T cell differentiation by reprogramming T cell metabolism[J]. J Immunol, 2018, 201(7): 2165-2175. DOI: 10.4049/jimmunol.1800230. doi: 10.4049/jimmunol.1800230 pmid: 30150287
[22]	ClinicalTrials. gov. A first in human phase Ⅰ trial of binary oncolytic adenovirus in combination with HER2-specific autologous CAR T cells in patients with advanced HER2 positive solid tumors[EB/OL]. (2018-11-14)[2022-09-13]. https://clinicaltrials.gov/ct2/show/NCT03740256?term=NCT03740256&draw=2&rank=1.
[23]	Moentenich V, Comut E, Gebauer F, et al. Mesothelin expression in esophageal adenocarcinoma and squamous cell carcinoma and its possible impact on future treatment strategies[J]. Ther Adv Med Oncol, 2020, 12: 1758835920917571. DOI: 10.1177/1758835920917571. doi: 10.1177/1758835920917571
[24]	Shao J, Hou L, Liu J, et al. Indoleamine 2,3-dioxygenase 1 inhibitor-loaded nanosheets enhance CAR-T cell function in esophageal squamous cell carcinoma[J]. Front Immunol, 2021, 12: 661357. DOI: 10.3389/fimmu.2021.661357. doi: 10.3389/fimmu.2021.661357
[25]	ClinicalTrials. gov. EGFRvIII/Dr5/NY-ESO-1/mesothelin CAR-T/TCR-T cells immunotherapy for solid malignancies[EB/OL]. (2021-02-04)[2022-09-04]. https://clinicaltrials.gov/ct2/show/NCT03941626?term=NCT03941626&draw=2&rank=1.
[26]	Wang Y, Liao X, Ye Q, et al. Clinic implication of MUC1 O-glycosylation and C1GALT1 in esophagus squamous cell carcinoma[J]. Sci China Life Sci, 2018, 61(11): 1389-1395. DOI: 10.1007/s11427-017-9345-7. doi: 10.1007/s11427-017-9345-7 pmid: 30076562
[27]	Zhang H, Zhao H, He X, et al. JAK-STAT domain enhanced MUC1-CAR-T cells induced esophageal cancer elimination[J]. Cancer Manag Res, 2020, 12: 9813-9824. DOI: 10.2147/CMAR.S264358. doi: 10.2147/CMAR.S264358 pmid: 33116840
[28]	ClinicalTrials. gov. Autologous immunotherapy with multi-target gene-modified CAR-T/TCR-T cell for malignancies[EB/OL]. (2019-12-11)[2022-09-04]. https://clinicaltrials.gov/ct2/show/NCT03638206?term=NCT03638206&draw=2&rank=1.
[29]	ClinicalTrials. gov. A phase Ⅰ clinical study of anti-CEA CAR-T therapy in the treatment of CEA-positive advanced malignant solid tumors[EB/OL]. (2022-06-02)[2022-09-07]. https://clinicaltrials.gov/ct2/show/NCT05396300?term=NCT05396300&draw=2&rank=1.
[30]	ClinicalTrials. gov. A safety and efficacy clinical study of CEA-targeted CAR-T therapy for CEA-positive advanced malignant solid tumors[EB/OL]. (2022-07-22)[2022-09-06]. https://clinicaltrials.gov/ct2/show/NCT05415475?term=NCT05415475&draw=2&rank=1.
[31]	ClinicalTrials. gov. Chimeric antigen receptor T lymphocytes (CAR-T) targeting CEA in the treatment of CEA positive clinical study of advanced malignant solid tumors[EB/OL]. (2022-09-13)[2022-09-16]. https://clinicaltrials.gov/ct2/show/NCT05538195?term=NCT05538195&draw=2&rank=1.
[32]	ClinicalTrials. gov. A clinical research of CAR T cells targeting EpCAM positive cancer[EB/OL]. (2017-01-06)[2022-09-06]. https://clinicaltrials.gov/ct2/show/NCT03013712?term=NCT0301 3712&draw=2&rank=1.
[33]	ClinicalTrials. gov. Combination therapy of anti-MUC1 CAR T cells and PD-1 knockout engineered T cells for advanced esophageal cancer[EB/OL]. (2018-10-16)[2022-09-10]. https://clinicaltrials.gov/ct2/show/NCT03706326?term=NCT03706326&draw=2&rank=1.
[34]	Ding XC, Wang LL, Zhang XD, et al. The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia[J]. J Hematol Oncol, 2021, 14(1): 92. DOI: 10.1186/s13045-021-01102-5. doi: 10.1186/s13045-021-01102-5
[35]	Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy[J]. Nature, 2015, 527(7577): 249-253. DOI: 10.1038/nature15520. doi: 10.1038/nature15520
[36]	Pang N, Shi J, Qin L, et al. IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin[J]. J Hematol Oncol, 2021, 14(1): 118. DOI: 10.1186/s13045-021-01128-9. doi: 10.1186/s13045-021-01128-9
[37]	Jo Y, Ali LA, Shim JA, et al. Innovative CAR-T cell therapy for solid tumor; current duel between CAR-T spear and tumor shield[J]. Cancers (Basel), 2020, 12(8): 2087. DOI: 10.3390/cancers12082087. doi: 10.3390/cancers12082087
[38]	Xie G, Ivica NA, Jia B, et al. CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia[J]. Nat Biomed Eng, 2021, 5(5): 399-413. DOI: 10.1038/s41551-020-00625-5. doi: 10.1038/s41551-020-00625-5
[39]	Navai SA, Ahmed N. Targeting the tumour profile using broad spectrum chimaeric antigen receptor T-cells[J]. Biochem Soc Trans, 2016, 44(2): 391-396. DOI: 10.1042/BST20150266. doi: 10.1042/BST20150266
[40]	Yang M, Tang X, Zhang Z, et al. Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors[J]. Theranostics, 2020, 10(17): 7622-7634. DOI: 10.7150/thno.43991. doi: 10.7150/thno.43991 pmid: 32685008
[41]	Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy-assessment and management of toxicities[J]. Nat Rev Clin Oncol, 2018, 15(1): 47-62. DOI: 10.1038/nrclinonc.2017.148. doi: 10.1038/nrclinonc.2017.148 pmid: 28925994
[42]	Liu S, Deng B, Yin Z, et al. Corticosteroids do not influence the efficacy and kinetics of CAR-T cells for B-cell acute lymphoblastic leukemia[J]. Blood Cancer J, 2020, 10(2): 15. DOI: 10.1038/s41408-020-0280-y. doi: 10.1038/s41408-020-0280-y pmid: 32029707
[43]	Hong R, Zhao H, Wang Y, et al. Clinical characterization and risk factors associated with cytokine release syndrome induced by COVID-19 and chimeric antigen receptor T-cell therapy[J]. Bone Marrow Transplant, 2021, 56(3): 570-580. DOI: 10.1038/s41409-020-01060-5. doi: 10.1038/s41409-020-01060-5
[44]	Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial[J]. Lancet, 2013, 381(9877): 1541-1550. DOI: 10.1016/S0140-6736(13)60250-0. doi: 10.1016/S0140-6736(13)60250-0 pmid: 23515142
[45]	ClinicalTrials. gov. A phase Ⅱ pilot study to evaluate the role of siltuximab in treatment of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) related to chimeric antigen receptor T-cell therapy (CAR-T) in hematological malignancies[EB/OL]. (2022-12-20)[2023-02-24]. https://clinicaltrials.gov/ct2/show/NCT04975555?term=NCT04975555&draw=2&rank=1.

注册号	临床试验名称	靶点	研究机构	开始日期	状态
NCT03638206^[28]	Ⅰ~Ⅱ期临床研究，多靶点基因修饰CAR-T治疗食管癌的安全性和有效性	NY-ESO-1	郑州大学第一附属医院	2018.3.1	招募中
NCT05396300^[29]	Ⅰ期临床研究，评估CAR-T在晚期食管癌患者中的安全性和耐受性	CEA	浙江大学第一附属医院	2022.5.25	招募中
NCT05415475^[30]	Ⅰ期临床研究，验证CAR-T治疗晚期食管癌的安全性和有效性	CEA	山东省第二人民医院	2021.9.10	招募中
NCT05538195^[31]	Ⅰ~Ⅱ期临床研究，评估CAR-T治疗食管癌的安全性和有效性	CEA	河南省肿瘤医院	2022.6.7	招募中
NCT03013712^[32]	Ⅰ~Ⅱ期临床研究，评估CAR-T治疗食管癌的安全性和有效性	EpCAM	成都医学院	2017.1.6	招募中
NCT03706326^[33]	Ⅰ~Ⅱ期临床研究，评估CAR-T治疗食管癌患者的安全性和有效性	MUC1	广东药科大学附属医院	2018.9.28	招募中