CAR-T抗肿瘤研究的现状及展望

doi:10.6040/j.issn.1671-7554.0.2016.835

摘要/Abstract

摘要： 嵌合抗原受体修饰的T细胞(CAR-T)是一种安全有效的肿瘤治疗策略。在多种血液肿瘤的临床试验中,CAR-T细胞疗法取得重大突破,在实体瘤的临床试验中也崭露头角。但在获得显著疗效的同时,CAR-T也存在脱靶效应、细胞因子风暴、插入突变、对实体肿瘤疗效有限等问题。现就CAR-T技术的最新进展及该领域有待解决的问题进行综述,为CAR-T疗法的进一步研究和临床应用提供参考。

关键词: 嵌合抗原受体, 嵌合抗原受体修饰的T细胞, 肿瘤, 免疫治疗

Abstract: A lot of remarkable results suggested that the modification of T-cells with CARs(CRA-T)could be a powerful approach for developing safe and effective cancer therapeutics. A novel breakthrough has been made in CAR-T treatment of hematologic tumors and therapeutic potential in clinical studies of solid tumors has been achieved, although there are still many problems for CAR-T on the clinical application such as off-target effects, cytokine storm, insertion mutagenesis, limited effects for solid tumors. Here, we reviewed the recent advances of CAR-T and problems that need to be solved in this field, which provide references for the in-depth study and further clinical immunotherapy.

Key words: Tumor, Immunotherapy, Chimeric antigen receptor, Chimeric antigen receptor T cells

中图分类号:

R730

郑敏,张岚. CAR-T抗肿瘤研究的现状及展望[J]. 山东大学学报（医学版）, 2016, 54(11): 1-6.

ZHENG Min, ZHANG Lan. Current situation and development trend of CAR-T in anti-tumor research[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2016, 54(11): 1-6.

参考文献

[1] Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy[J]. Clin Cancer Res, 2011, 17(13):4550-4557.
[2] Spear P, Barber A, Rynda-Apple A, et al. Chimeric antigen receptor T cells shape myeloid cell function within the tumor microenvironment through IFN-gamma and GM-CSF[J]. J Immunol, 2012, 188(12):6389-6398.
[3] Eshhar Z, Waks T, Bendavid A, et al. Functional expression of chimeric receptor genes in human T cells[J]. J Immunol Methods, 2001, 248(1-2):67-76.
[4] Pule MA, Straathof KC, Dotti G, et al. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells[J]. Mol Ther, 2005, 12(5):933-941.
[5] Jensen MC, Riddell SR. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells[J]. Immunol Rev, 2014, 257(1):127-144.
[6] Carpenito C, Milone MC, Hassan R, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains[J]. Proc Natl Acad Sci U S A, 2009, 106(9):3360-3365.
[7] Chmielewski M, Kopecky C, Hombach AA, et al. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression[J]. Cancer Res, 2011, 71(17):5697-5706.
[8] Zhao Z, Condomines M, van der Stegen SJ, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T Cells[J]. Cancer Cell, 2015, 28(4):415-428.
[9] Xu Y, Zhang M, Ramos CA, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15[J]. Blood, 2014, 123(24):3750-3759.
[10] Dudley ME, Gross CA, Somerville RP, et al. Randomized selection design trial evaluating CD8+-enriched versus unselected tumor-infiltrating lymphocytes for adoptive cell therapy for patients with melanoma[J]. J Clin Oncol, 2013, 31(17):2152-2159.
[11] Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2[J]. Mol Ther, 2010, 18(4):843-851.
[12] Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19[J]. Blood, 2010, 116(20):4099-4102.
[13] Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia[J]. N Engl J Med, 2014, 371(16):1507-1517.
[14] Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia[J]. Sci Transl Med, 2015, 7(303):303ra139. doi: 10.1126/scitranslmed.aac5415.
[15] Garfall AL, Maus MV, Hwang WT, et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma[J]. N Engl J Med, 2015, 373(11):1040-1047.
[16] Ritchie DS, Neeson PJ, Khot A, et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia[J]. Mol Ther, 2013, 21(11):2122-2129.
[17] Wang QS, Wang Y, Lv HY, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia[J]. Mol Ther, 2015, 23(1):184-191.
[18] Dai H, Wang Y, Lu X, et al. Chimeric antigen receptors modified T-cells for cancer therapy[J]. J Natl Cancer Inst, 2016, 108(7). pii: djv439. doi: 10.1093/jnci/djv439.
[19] 克晓燕. 嵌合抗原受体-T细胞免疫治疗在血液系统恶性肿瘤中的应用进展[J].中国全科医学, 2016, 19(12):1361-1366. KE Xiaoyan. Application of CAR-T cell immunotherapy in the treatment of hematological malignancy[J]. Chinese General Practice, 2016, 19(12):1361-1366.
[20] Moon EK, Wang LC, Dolfi DV, et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors[J]. Clin Cancer Res, 2014, 20(16):4262-4273.
[21] Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer[J]. Clin Cancer Res, 2006, 12(20 Pt1):6106-6115.
[22] Koneru M, Purdon TJ, Spriggs D, et al. IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors[J]. Oncoimmunology, 2015, 4(3):e994446. eCollection 2015.
[23] Koneru M, OCearbhaill R, Pendharkar S, et al. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto)directed chimeric antigen receptors for recurrent ovarian cancer[J]. J Transl Med, 2015, 13:102. doi: 10.1186/s12967-015-0460-x.
[24] Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted CARs: driving T cells to solid tumors[J]. Cancer Discov, 2016, 6(2):133-146.
[25] Sun M, Shi H, Liu C, et al. Construction and evaluation of a novel humanized HER2-specific chimeric receptor[J]. Breast Cancer Res, 2014, 16(3):R61. doi: 10.1186/bcr3674.
[26] Hong H, Brown CE, Ostberg JR, et al. L1 Cell adhesion molecule-specific chimeric antigen receptor-redirected human T cells exhibit specific and efficient antitumor activity against human ovarian cancer in mice[J]. PLoS One, 2016, 11(1):e0146885. doi: 10.1371/journal.pone.0146885. eCollection 2016.
[27] Louis CU, Savoldo B, Dotti G, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma[J]. Blood, 2011, 118(23):6050-6056.
[28] Ahmed N, Brawley VS, Hegde M, et al. Human epidermal growth factor receptor 2(HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma[J]. J Clin Oncol, 2015, 33(15):1688-1696.
[29] Grada Z, Hegde M, Byrd T, et al. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy[J]. Mol Ther Nucleic Acids, 2013, 2:e105. doi: 10.1038/mtna.2013.32.
[30] Wilkie S, van Schalkwyk MC, Hobbs S, et al. Dual targeting of ErbB2 and MUC1 in breast cancer using chimeric antigen receptors engineered to provide complementary signaling[J]. J Clin Immunol, 2012, 32(5):1059-1070.
[31] Kakarla S, Chow KK, Mata M, et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma[J]. Mol Ther, 2013, 21(8):1611-1620.
[32] 章浩,叶真龙,钱其军. 降低亲和力提高HER2-CAR-T细胞治疗的安全性[J].药学实践杂志, 2016, 34(3):261-266. ZHANG Hao, YE Zhenlong, QIAN Qijun. Decreasing affinity of CAR-T cells targeting HER2 to increase the therapeutic outcome against tumors[J]. Journal of Pharmaceutical Practice, 2016, 34(3):261-266.
[33] Maude SL, Barrett D, Teachey DT, et al. Managing cytokine release syndrome associated with novel T cell-engaging therapies[J]. Cancer J, 2014, 20(2):119-122.
[34] Wu CY, Roybal KT, Puchner EM, et al. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor[J]. Science, 2015, 350(6258):aab4077. doi: 10.1126/science.aab4077.
[35] Di Stasi A, De Angelis B, Rooney CM, et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model[J]. Blood, 2009, 113(25):6392-6402.
[36] Craddock JA, Lu A, Bear A, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b[J]. J Immunother, 2010, 33(8):780-788.
[37] Beatty GL, Winograd R, Evans RA, et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C(low)F4/80(+)extratumoral macrophages[J]. Gastroenterology, 2015, 149(1):201-210.
[38] Yao X, Ahmadzadeh M, Lu YC, et al. Levels of peripheral CD4(+)FoxP3(+)regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer[J]. Blood, 2012, 119(24):5688-5696.
[39] John LB, Devaud C, Duong CP, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells[J]. Clin Cancer Res, 2013, 19(20):5636-5646.
[40] Cheadle EJ, Gornall H, Baldan V, et al. CAR T cells: driving the road from the laboratory to the clinic[J]. Immunol Rev, 2014, 257(1):91-106.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed