合成生物学与工程化T细胞治疗

doi:10.12211/2096-8280.2022-063

合成生物学 ›› 2023, Vol. 4 ›› Issue (2): 373-393.DOI: 10.12211/2096-8280.2022-063

合成生物学与工程化T细胞治疗

谢君鸿¹, 何晶晶², 周鹏辉³

^1.广西医科大学，广西生物靶向诊治重点实验室，国家生物靶向诊治国际联合研究中心，广西南宁 530021
^2.广东医学科学院，广东省人民医院医学研究部，广东广州 510055
^3.中山大学肿瘤防治中心，华南肿瘤学国家重点实验室，广东广州 510060

收稿日期:2022-11-17 修回日期:2023-02-01 出版日期:2023-04-30 发布日期:2023-04-27
通讯作者: 何晶晶,周鹏辉
作者简介:谢君鸿（1996—），男，硕士研究生，研究方向为肿瘤免疫治疗。E-mail：jhxietw@163.com
何晶晶（1987—），博士，特聘副研究员。主要研究方向为肿瘤免疫学和肿瘤免疫治疗。E-mail：hejingjing@gdph.org.cn
周鹏辉（1974—），男，博士，教授，博士生导师。研究方向为肿瘤免疫学和肿瘤免疫治疗。E-mail：zhouph@sysucc.org.cn
基金资助:
国家自然科学基金(82130086);广东省自然科学基金(2017A030308007);广东省特支计划项目(2016LJ06S464);广东省引进创新创业团队(2016ZT06S638)

Synthetic biology and engineered T cell therapy

XIE Junhong¹, HE Jingjing², ZHOU Penghui³

^1.National Center for International Research of Bio-targeting Theranostics，Guangxi Key Laboratory of Bio-targeting Theranostics，Guangxi Medical University，Nanning 530021，Guangxi，China
^2.Medical Research Department，Guangdong Provincial People’s Hospital，Guangdong Academy of Medical Sciences，Guangzhou 510055，Guangdong，China
^3.State Key Laboratory of Oncology in Southern China，Sun Yat-sen University Cancer Center，Guangzhou 510060，Guangdong，China

Received:2022-11-17 Revised:2023-02-01 Online:2023-04-30 Published:2023-04-27
Contact: HE Jingjing, ZHOU Penghui

摘要/Abstract

摘要：

关键词: 合成生物学, 工程化T细胞疗法, TCR-T, CAR-T, 肿瘤免疫治疗

Abstract:

In recent years, engineering T cell therapy has made great progress in tumor immunotherapy, which mainly includes T-cell receptor-engineered T cell (TCR-T) therapy and chimeric antigen receptor T cell (CAR-T) therapy. Due to their structure difference, TCR-T and CAR-T cells show different characteristics in signal activation and antigen recognition. CAR has scFv derived from antibody, containing CD3ζ and costimulatory domain(s), making engineered CAR able to recognize specific tumor associated antigens. Therefore, CAR has an ability to bind unprocessed tumor surface antigens without MHC processing, while TCR engages with both tumor intracellular and surface antigens embedded in MHC. While CAR-T cell therapy has demonstrated a significant clinical effect against malignant blood tumors, TCR-T cell therapies have been tested in hematological and solid tumors. Even though clinical results are encouraging for both approaches, several major challenges have been identified, including: target antigen selection such as less tumor toxicity and antigen escape, T cell homing to the tumor, T cell infiltration into the tumor, T cell persistence, and local immunosuppression in the tumor microenvironment. Synthetic biology technologies have enabled flexible reprogramming of engineered T cells to overcome the aforementioned limitations, bringing new opportunities for improving their safety and effectiveness, but the choice of a suitable target antigen is still a key for success. Moreover, improved preclinical TCR/CAR screening is likely to enhance the safety of engineered T cell therapies, and additional T cell engineering to further enhance engineered T cells at various levels has generated promising results, including: (1) modulation of affinity, (2) safety control elements, and (3) targeting TME components. Future developments will likely harness combinatorial strategies to overcome challenges posed by the tumors. In this article, we address structure and signal activation, target selection, affinity optimization, safety modification and gene editing strategies for engineered T cells, and also review the potential synthetic biological approaches and latest progress of engineered T cell therapy in the application of tumor immunotherapy.

Key words: synthetic biology, engineering T cell therapy, TCR-T, CAR-T, tumor immunotherapy

中图分类号:

R318

谢君鸿, 何晶晶, 周鹏辉. 合成生物学与工程化T细胞治疗[J]. 合成生物学, 2023, 4(2): 373-393.

XIE Junhong, HE Jingjing, ZHOU Penghui. Synthetic biology and engineered T cell therapy[J]. Synthetic Biology Journal, 2023, 4(2): 373-393.

图/表 4

图1 TCR复合物以及T细胞激活信号

Fig. 1 TCR complex and T cell activation

图2 CAR的结构以及发展过程

Fig. 2 CAR structure and develoment process

图3 工程化T细胞的安全控制系统

Fig. 3 Safety control systems for engineered T cells

图4 工程化T细胞的基因编辑策略RES—白藜芦醇；β2M—β2-微球蛋白

Fig. 4 Genome editing strategies for engineered T cellsRES—Resveratrol; β2M—β2-microglobulin

参考文献 132

133	SU S, HU B, SHAO J, et al. CRISPR-Cas9 mediated efficient PD-1 disruption on human primary T cells from cancer patients[J]. Scientific Reports, 2016, 6: 20070.
134	MAROTTE L, SIMON S, VIGNARD V, et al. Increased antitumor efficacy of PD-1-deficient melanoma-specific human lymphocytes[J]. Journal for Immunotherapy of Cancer, 2020, 8(1): e000311.
135	EYQUEM J, MANSILLA-SOTO J, GIAVRIDIS T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection[J]. Nature, 2017, 543(7643): 113-117.
136	ROTH T L, PUIG-SAUS C, YU R, et al. Reprogramming human T cell function and specificity with non-viral genome targeting[J]. Nature, 2018, 559(7714): 405-409.
137	MATTHEW B, DONG, DONG M B, WANG G C, CHOW R D, et al. Systematic immunotherapy target discovery using genome-scale in vivo CRISPR screens in CD8 T cells[J]. Cell, 2019, 178(5): 1189-1204.e23.
138	MASTAGLIO S, GENOVESE P, MAGNANI Z, et al. NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease[J]. Blood, 2017, 130(5): 606-618.
139	BERDIEN B, MOCK U, ATANACKOVIC D, et al. TALEN-mediated editing of endogenous T-cell receptors facilitates efficient reprogramming of T lymphocytes by lentiviral gene transfer[J]. Gene Therapy, 2014, 21(6): 539-548.
140	POIROT L, PHILIP B, SCHIFFER-MANNIOUI C, et al. Multiplex genome-edited T-cell manufacturing platform for "off-the-shelf" adoptive T-cell immunotherapies[J]. Cancer Research, 2015, 75(18): 3853-3864.
141	OSBORN M J, WEBBER B R, KNIPPING F, et al. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases[J]. Molecular Therapy, 2016, 24(3): 570-581.
142	LEGUT M, DOLTON G, MAIN A A, et al. CRISPR-mediated TCR replacement generates superior anticancer transgenic T cells[J]. Blood, 2018, 131(3): 311-322.
143	REN J T, LIU X J, FANG C Y, et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition[J]. Clinical Cancer Research, 2017, 23(9): 2255-2266.
144	SHI L, MENG T Y, ZHANG Z L, et al. CRISPR knock out CTLA-4 enhances the anti-tumor activity of cytotoxic T lymphocytes[J]. Gene, 2017, 636: 36-41.
145	STADTMAUER E A, FRAIETTA J A, DAVIS M M, et al. CRISPR-engineered T cells in patients with refractory cancer[J]. Science, 2020, 367(6481): eaba7365.
146	WANG D, ZHANG F, GAO, G P. CRISPR-based therapeutic genome editing: strategies and in vivo delivery by AAV vectors[J]. Cell, 2020, 181(1): 136-150.
147	SATHER B D, ROMANO IBARRA G S, SOMMER K, et al. Efficient modification of CCR5 in primary human hematopoietic cells using a megaTAL nuclease and AAV donor template[J]. Science Translational Medicine, 2015, 7(307): 307ra156.
148	HALE M, LEE B, HONAKER Y, et al. Homology-directed recombination for enhanced engineering of chimeric antigen receptor T cells[J]. Molecular Therapy Methods & Clinical Development, 2017, 4: 192-203.
149	SACHDEVA M, BUSSER B W, TEMBURNI S, et al. Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality[J]. Nature Communications, 2019, 10: 5100.
150	YANG L F, YIN J L, WU J L, et al. Engineering genetic devices for in vivo control of therapeutic T cell activity triggered by the dietary molecule resveratrol[J]. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118(34): e2106612118.
151	KOBAYASHI A, NOBILI A, NEIER S C, et al. Light-controllable binary switch activation of CAR T cells[J]. ChemMedChem, 2022, 17(12): e202100722.
152	NOBLES C L, SHERRILL-MIX S, EVERETT J K, et al. CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration[J]. The Journal of Clinical Investigation, 2020, 130(2): 673-685.
153	FRAIETTA J A, NOBLES C L, SAMMONS M A, et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells[J]. Nature, 2018, 558(7709): 307-312.
154	SHIFRUT E, CARNEVALE J, TOBIN V, et al. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function[J]. Cell, 2018, 175(7): 1958-1971.e15.
155	GRUPP S A, PRAK E L, BOYER J, et al. Adoptive transfer of autologous T cells improves T-cell repertoire diversity and long-term B-cell function in pediatric patients with neuroblastoma[J]. Clinical Cancer Research, 2012, 18(24): 6732-6741.
156	KALOS M, LEVINE B L, PORTER D L, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia[J]. Science Translational Medicine, 2011, 3(95): 95ra73.
1	ROSENBERG S A, PACKARD B S, AEBERSOLD P M, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report[J]. The New England Journal of Medicine, 1988, 319(25): 1676-1680.
2	WATANABE K, NISHIKAWA H. Engineering strategies for broad application of TCR-T- and CAR-T-cell therapies[J]. International Immunology, 2021, 33(11): 551-562.
3	WEBER E W, MAUS M V, MACKALL C L. The emerging landscape of immune cell therapies[J]. Cell, 2020, 181(1): 46-62.
4	GRUPP S A, KALOS M, BARRETT D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia[J]. The New England Journal of Medicine, 2013, 368(16): 1509-1518.
5	KERSTEN M J, SPANJAART A M, THIEBLEMONT C. CD19-directed CAR T-cell therapy in B-cell NHL[J]. Current Opinion in Oncology, 2020, 32(5): 408-417.
6	MULLARD A. FDA approves fourth CAR-T cell therapy[J]. Nature Reviews Drug Discovery, 2021, 20(3): 166.
7	ANDERSON, A K, STROMNES I M, GREENBERG P D. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies[J]. Cancer Cell, 2017, 31(3): 311-325.
8	LARSON R C, MAUS M V. Recent advances and discoveries in the mechanisms and functions of CAR T cells[J]. Nature Reviews Cancer, 2021, 21(3): 145-161.
9	NISHIKAWA H, MAEDA Y, ISHIDA T, et al. Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma[J]. Blood, 2012, 119(13): 3097-3104.
10	JUNGBLUTH A A, ANTONESCU C R, BUSAM K J, et al. Monophasic and biphasic synovial sarcomas abundantly express cancer/testis antigen NY-ESO-1 but not MAGE-A1 or CT7[J]. International Journal of Cancer, 2001, 94(2): 252-256.
11	D'ANGELO S P, MELCHIORI L, MERCHANT M S, et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 ^c259T cells in synovial sarcoma[J]. Cancer Discovery, 2018, 8(8): 944-957.
12	CHEN L P, FLIES D B. Molecular mechanisms of T cell co-stimulation and co-inhibition[J]. Nature Reviews Immunology, 2013, 13(4): 227-242.
13	RAEBER M E, ZURBUCHEN Y, IMPELLIZZIERI D, et al. The role of cytokines in T-cell memory in health and disease[J]. Immunological Reviews, 2018, 283(1): 176-193.
14	DRIESSENS G, KLINE J, GAJEWSKI T F. Costimulatory and coinhibitory receptors in anti-tumor immunity[J]. Immunological Reviews, 2009, 229(1): 126-144.
15	GLOBERSON LEVIN A, RIVIÈRE I, ESHHAR Z, et al. CAR T cells: building on the CD19 paradigm[J]. European Journal of Immunology, 2021, 51(9): 2151-2163.
16	STERNER R C, STERNER R M. CAR-T cell therapy: current limitations and potential strategies[J]. Blood Cancer Journal, 2021, 11: 69.
17	JAYARAMAN J, MELLODY M P, HOU A J, et al. CAR-T design: elements and their synergistic function[J]. EBioMedicine, 2020, 58: 102931.
18	CHEEVER M A, ALLISON J P, FERRIS A S, et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research[J]. Clinical Cancer Research, 2009, 15(17): 5323-5337.
19	COULIE P G, VAN DEN EYNDE B J, VAN DER BRUGGEN P, et al. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy[J]. Nature Reviews Cancer, 2014, 14(2): 135-146.
20	GUBIN M M, ARTYOMOV M N, MARDIS E R, et al. Tumor neoantigens: building a framework for personalized cancer immunotherapy[J]. The Journal of Clinical Investigation, 2015, 125(9): 3413-3421.
21	SMITH C C, SELITSKY S R, CHAI S J, et al. Alternative tumour-specific antigens[J]. Nature Reviews Cancer, 2019, 19(8): 465-478.
22	RAPOPORT A P, STADTMAUER E A, BINDER-SCHOLL G K, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma[J]. Nature Medicine, 2015, 21(8): 914-921.
23	KAGEYAMA S, IKEDA H, MIYAHARA Y, et al. Adoptive transfer of MAGE-A4 T-cell receptor gene-transduced lymphocytes in patients with recurrent esophageal cancer[J]. Clinical Cancer Research, 2015, 21(10): 2268-2277.
24	MORGAN R A, CHINNASAMY N, ABATE-DAGA D, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy[J]. Journal of Immunotherapy, 2013, 36(2): 133-151.
25	MORGAN R A, DUDLEY M E, WUNDERLICH J R, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes[J]. Science, 2006, 314(5796): 126-129.
26	HE J J, XIONG X X, YANG H, et al. Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response[J]. Cell Research, 2022, 32(6): 530-542.
27	PARKHURST M R, YANG J C, LANGAN R C, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis[J]. Molecular Therapy, 2011, 19(3): 620-626.
28	SHAH N, CHARI A, SCOTT E, et al. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches[J]. Leukemia, 2020, 34(4): 985-1005.
29	HAN Z W, LYV Z W, CUI B, et al. The old CEACAMs find their new role in tumor immunotherapy[J]. Investigational New Drugs, 2020, 38(6): 1888-1898.
30	YAMASHITA N, KUFE D. Addiction of cancer stem cells to MUC1-C in triple-negative breast cancer progression[J]. International Journal of Molecular Sciences, 2022, 23(15): 8219.
31	KARSCHNIA P, TESKE N, THON N, et al. Chimeric antigen receptor T cells for glioblastoma: current concepts, challenges, and future perspectives[J]. Neurology, 2021, 97(5): 218-230.
32	CAO W J, XING H Z, LI Y M, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy[J]. Biomarker Research, 2022, 10(1): 38.
33	HONG M H, CLUBB J D, CHEN Y Y. Engineering CAR-T cells for next-generation cancer therapy[J]. Cancer Cell, 2020, 38(4): 473-488.
34	STONE J D, CHERVIN A S, KRANZ D M. T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity[J]. Immunology, 2009, 126(2): 165-176.
35	ALEKSIC M, LIDDY N, MOLLOY P E, et al. Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies[J]. European Journal of Immunology, 2012, 42(12): 3174-3179.
36	SCHUMACHER T N, SCHREIBER R D. Neoantigens in cancer immunotherapy[J]. Science, 2015, 348(6230): 69-74.
37	STONE J D, KRANZ D M. Role of T cell receptor affinity in the efficacy and specificity of adoptive T cell therapies[J]. Frontiers in Immunology, 2013, 4: 244.
38	WILLIAMS C M, SCHONNESEN A A, ZHANG S Q, et al. Normalized synergy predicts that CD8 co-receptor contribution to T cell receptor (TCR) and pMHC binding decreases as TCR affinity increases in human viral-specific T cells[J]. Frontiers in Immunology, 2017, 8: 894.
39	SHARMA P, HARRIS D T, STONE J D, et al. T-cell receptors engineered de novo for peptide specificity can mediate optimal T-cell activity without self cross-reactivity[J]. Cancer Immunology Research, 2019, 7(12): 2025-2035.
40	TAN M P, GERRY A B, BREWER J E, et al. T cell receptor binding affinity governs the functional profile of cancer-specific CD8⁺ T cells[J]. Clinical and Experimental Immunology, 2015, 180(2): 255-270.
41	SCHMID D A, IRVING M B, POSEVITZ V, et al. Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function[J]. Journal of Immunology, 2010, 184(9): 4936-4946.
42	HOLLER P D, HOLMAN P O, SHUSTA E V, et al. In vitro evolution of a T cell receptor with high affinity for peptide/MHC[J]. Proceedings of the National Academy of Sciences of the United States of America, 2000, 97(10): 5387-5392.
43	LI Y, MOYSEY R, MOLLOY P E, et al. Directed evolution of human T-cell receptors with picomolar affinities by phage display[J]. Nature Biotechnology, 2005, 23(3): 349-354.
44	DUNN S M, RIZKALLAH P J, BASTON E, et al. Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing apparent cross-reactivity[J]. Protein Science, 2006, 15(4): 710-721.
45	ZOETE V, IRVING M, FERBER M, et al. Structure-based, rational design of T cell receptors[J]. Frontiers in Immunology, 2013, 4: 268.
46	PIERCE B G, HELLMAN L M, HOSSAIN M, et al. Computational design of the affinity and specificity of a therapeutic T cell receptor[J]. PLoS Computational Biology, 2014, 10(2): e1003478.
47	HARRIS D T, WANG N Y, RILEY T P, et al. Deep mutational scans as a guide to engineering high affinity T cell receptor interactions with peptide-bound major histocompatibility complex[J]. The Journal of Biological Chemistry, 2016, 291(47): 24566-24578.
48	LINETTE G P, STADTMAUER E A, MAUS M V, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma[J]. Blood, 2013, 122(6): 863-871.
49	SANDERSON J P, CROWLEY D J, WIEDERMANN G E, et al. Preclinical evaluation of an affinity-enhanced MAGE-A4-specific T-cell receptor for adoptive T-cell therapy[J]. OncoImmunology, 2020, 9(1): 1682381.
50	THOMAS S, MOHAMMED F, REIJMERS R M, et al. Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function[J]. Nature Communications, 2019, 10: 4451.
51	WATSON H A, DURAIRAJ R R P, OHME J, et al. L-selectin enhanced T cells improve the efficacy of cancer immunotherapy[J]. Frontiers in Immunology, 2019, 10: 1321.
52	AHMADI M, KING J W, XUE S A, et al. CD3 limits the efficacy of TCR gene therapy in vivo [J]. Blood, 2011, 118(13): 3528-3537.
53	WATANABE K, TERAKURA S, MARTENS A C, et al. Target antigen density governs the efficacy of anti-CD20-CD28-CD3 ζ chimeric antigen receptor-modified effector CD8⁺ T cells[J]. Journal of Immunology, 2015, 194(3): 911-920.
54	IRVINE D J, PURBHOO M A, KROGSGAARD M, et al. Direct observation of ligand recognition by T cells[J]. Nature, 2002, 419(6909): 845-849.
55	HUANG J, BRAMESHUBER M, ZENG X, et al. A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4⁺ T cells[J]. Immunity, 2013, 39(5): 846-857.
56	LIU X J, JIANG S G, FANG C Y, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice[J]. Cancer Research, 2015, 75(17): 3596-3607.
57	CASTELLARIN M, SANDS C, DA T, et al. A rational mouse model to detect on-target, off-tumor CAR T cell toxicity[J]. JCI Insight, 2020, 5(14): e136012.
58	CARUSO H G, HURTON L V, NAJJAR A, et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity[J]. Cancer Research, 2015, 75(17): 3505-3518.
59	AHMED N, SALSMAN V S, KEW Y, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors[J]. Clinical Cancer Research, 2010, 16(2): 474-485.
60	SZÖŐR, Á, TÓTH G, ZSEBIK B, et al. Trastuzumab derived HER2-specific CARs for the treatment of trastuzumab-resistant breast cancer: CAR T cells penetrate and eradicate tumors that are not accessible to antibodies[J]. Cancer Letters, 2020, 484: 1-8.
61	AHMED N, SALSMAN V S, YVON E, et al. Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression[J]. Molecular, 2009, 17(10): 1779-1787
62	HUSZNO J, LEŚ D, SARZYCZNY-SŁOTA D, et al. Cardiac side effects of trastuzumab in breast cancer patients-single centere experiences[J]. Contemporary Oncology, 2013, 17(2): 190-195.
63	SUJJITJOON J, SAYOUR E, TSAO S T, et al. GD2-specific chimeric antigen receptor-modified T cells targeting retinoblastoma-assessing tumor and T cell interaction[J]. Translational Oncology, 2021, 14(2): 100971.
64	GOLINELLI G, GRISENDI G, PRAPA M, et al. Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors[J]. Cancer Gene Therapy, 2020, 27(7): 558-570.
65	YU A L, GILMAN A L, OZKAYNAK F M, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma[J]. The New England Journal of Medicine, 2010, 363(14): 1324-1334.
66	ARI P, KARS M, MEANY H, et al. Treatment of transient peripheral neuropathy during chimeric 14.18 antibody therapy in children with neuroblastoma: a case series[J]. Journal of Pediatric Hematology/Oncology, 2018, 40(2): e113-e116.
67	NAZHA B, INAL C, OWONIKOKO T K. Disialoganglioside GD2 expression in solid tumors and role as a target for cancer therapy[J]. Frontiers in Oncology, 2020, 10: 1000.
68	RICHMAN S A, NUNEZ-CRUZ S, MOGHIMI B, et al. High-affinity GD2-specific CAR T cells induce fatal encephalitis in a preclinical neuroblastoma model[J]. Cancer Immunology Research, 2018, 6(1): 36-46.
69	KE E E, WU Y L. EGFR as a pharmacological target in EGFR-mutant non-small-cell lung cancer: where do we stand now?[J]. Trends in Pharmacological Sciences, 2016, 37(11): 887-903.
70	LI H, HUANG Y, JIANG D Q, et al. Antitumor activity of EGFR-specific CAR T cells against non-small-cell lung cancer cells in vitro and in mice[J]. Cell Death & Disease, 2018, 9: 177.
71	GUO Y L, FENG K C, LIU Y, et al. Phase I study of chimeric antigen receptor-modified T cells in patients with EGFR-positive advanced biliary tract cancers[J]. Clinical Cancer Research, 2018, 24(6): 1277-1286.
72	LIU Y, GUO Y L, WU Z Q, et al. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: a phase I clinical trial[J]. Cytotherapy, 2020, 22(10): 573-580.
73	PEREZ R, MORENO E, GARRIDO G, et al. EGFR-targeting as a biological therapy: understanding nimotuzumab's clinical effects[J]. Cancers, 2011, 3(2): 2014-2031.
74	HERNANDEZ-LOPEZ R A, YU W, CABRAL K A, et al. T cell circuits that sense antigen density with an ultrasensitive threshold[J]. Science, 2021, 371(6534): 1166-1171.
75	HYRENIUS-WITTSTEN A, SU Y, PARK M, et al. SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models[J]. Science Translational Medicine, 2021, 13(591): eabd8836.
76	BONINI C, FERRARI G, VERZELETTI S, et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia[J]. Science, 1997, 276(5319): 1719-1724.
77	TRAVERSARI C, MARKTEL S, MAGNANI Z, et al. The potential immunogenicity of the TK suicide gene does not prevent full clinical benefit associated with the use of TK-transduced donor lymphocytes in HSCT for hematologic malignancies[J]. Blood, 2007, 109(11): 4708-4715.
78	GRECO R, OLIVEIRA G, STANGHELLINI M T L, et al. Improving the safety of cell therapy with the TK-suicide gene[J]. Frontiers in Pharmacology, 2015, 6: 95.
79	STRAATHOF K C, PULÈ M A, YOTNDA P, et al. An inducible caspase 9 safety switch for T-cell therapy[J]. Blood, 2005, 105(11): 4247-4254.
80	DI STASI A, TEY S K, DOTTI G, et al. Inducible apoptosis as a safety switch for adoptive cell therapy[J]. The New England Journal of Medicine, 2011, 365(18): 1673-1683.
81	ZHOU X O, DOTTI G, KRANCE R A, et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation[J]. Blood, 2015, 125(26): 4103-4113.
82	VOGLER I, NEWRZELA S, HARTMANN S, et al. An improved bicistronic CD20/tCD34 vector for efficient purification and in vivo depletion of gene-modified T cells for adoptive immunotherapy[J]. Molecular Therapy, 2010, 18(7): 1330-1338.
83	PHILIP B, KOKALAKI E, MEKKAOUI L, et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy[J]. Blood, 2014, 124(8): 1277-1287.
84	BINNEWIES M, ROBERTS E W, KERSTEN K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy[J]. Nature Medicine, 2018, 24(5): 541-550.
85	D'ALOIA M M, ZIZZARI I G, SACCHETTI B, et al. CAR-T cells: the long and winding road to solid tumors[J]. Cell Death & Disease, 2018, 9: 282.
86	LANITIS E, DANGAJ D, IRVING M, et al. Mechanisms regulating T-cell infiltration and activity in solid tumors[J]. Annals of Oncology, 2017, 28(): xii18-xii32.
87	NAGARSHETH N, WICHA M S, ZOU W P. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy[J]. Nature Reviews Immunology, 2017, 17(9): 559-572.
88	MAHER J, BRENTJENS R J, GUNSET G, et al. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor[J]. Nature Biotechnology, 2002, 20(1): 70-75.
89	KAWALEKAR O U, O'CONNER R S, FRAIETTA J A, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells[J]. Immunity, 2016, 44(2): 380-390.
90	WEINKOVE R, GEORGE P, DASYAM N, et al. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations[J]. Clinical & Translational Immunology, 2019, 8(5): e1049.
91	GROSSER R, CHERKASSKY L, CHINTALAN, et al. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors[J]. Cancer Cell, 2019, 36(5): 471-482.
92	HARLIN H, MENG Y R, PETERSON A C, et al. Chemokine expression in melanoma metastases associated with CD8⁺ T-cell recruitment[J]. Cancer Research, 2009, 69(7): 3077-3085.
93	IDORN M, SKADBORG S K, KELLERMANN L, et al. Chemokine receptor engineering of T cells with CXCR2 improves homing towards subcutaneous human melanomas in xenograft mouse model[J]. OncoImmunology, 2018, 7(8): e1450715.
94	DI STASI A, DE ANGELIS B, ROONEY C M, 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.
95	CRADDOCK J A, LU A, BEAR A, et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b[J]. Journal of Immunotherapy, 2010, 33(8): 780-788.
96	MOON E K, CARPENITO C, SUN J, et al. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor[J]. Clinical Cancer Research, 2011, 17(14): 4719-4730.
97	CARUANA I, SAVOLDO B, HOYOS V, et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes[J]. Nature Medicine, 2015, 21(5): 524-529.
98	SCHUBERTH P C, HAGEDORN C, JENSEN S M, et al. Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells[J]. Journal of Translational Medicine, 2013, 11: 187.
99	WANG L C S, LO A, SCHOLLER J, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity[J]. Cancer Immunology Research, 2014, 2(2): 154-166.
100	GOVERS C, SEBESTYÉN Z, ROSZIK J, et al. TCRs genetically linked to CD28 and CD3ε do not mispair with endogenous TCR chains and mediate enhanced T cell persistence and anti-melanoma activity[J]. Journal of Immunology, 2014, 193(10): 5315-5326.
101	STONE J D, HARRIS D T, SOTO C M, et al. A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control[J]. Cancer Immunology, Immunotherapy, 2014, 63(11): 1163-1176.
102	KLOSS C C, CONDOMINES M, CARTELLIERI M, et al. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells[J]. Nature Biotechnology, 2013, 31(1): 71-75.
103	LANITIS E, POUSSIN M, KLATTENHOFF A W, et al. Chimeric antigen receptor T Cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo [J]. Cancer Immunology Research, 2013, 1(1): 43-53.
104	OMER B, CARDENAS M G, PFEIFFER T, et al. A costimulatory CAR improves TCR-based cancer immunotherapy[J]. Cancer Immunology Research, 2022, 10(4): 512-524.
105	DANIEL-MESHULAM I, HOROVITZ-FRIED M, COHEN C J. Enhanced antitumor activity mediated by human 4-1BB-engineered T cells[J]. International Journal of Cancer, 2013, 133(12): 2903-2913.
106	NISHIMURA C D, BRENNER D A, MUKHERJEEM, et al. c-MPL provides tumor-targeted T-cell receptor-transgenic T cells with costimulation and cytokine signals[J]. Blood, 2017, 130(25): 2739-2749.
107	MÉNDEZ-FERRER S, BONNET D, STEENSMA D P, et al. Bone marrow niches in haematological malignancies[J]. Nature Reviews Cancer, 2020, 20(5): 285-298.
108	WAGNER H J, BOLLARD C M, VIGOUROUX S, et al. A strategy for treatment of Epstein-Barr virus-positive Hodgkin's disease by targeting interleukin 12 to the tumor environment using tumor antigen-specific T cells[J]. Cancer Gene Therapy, 2004, 11(2): 81-91.
109	KERKAR S P, MURANSKI P, KAISER A, et al. Tumor-specific CD8⁺ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts[J]. Cancer Research, 2010, 70(17): 6725-6734.
110	ZHANG L, MORGAN R A, BEANE J D, et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma[J]. Clinical Cancer Research, 2015, 21(10): 2278-2288.
111	DRAKES D J, RAFIQ S, PURDON T J, et al. Optimization of T-cell receptor-modified T cells for cancer therapy[J]. Cancer Immunology Research, 2020, 8(6): 743-755.
112	BATRA S A, RATHI P, GUO L J, et al. Glypican-3-specific CAR T cells coexpressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma[J]. Cancer Immunology Research, 2020, 8(3): 309-320.
113	SHUM T, OMER B, TASHIRO H, et al. Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells[J]. Cancer Discovery, 2017, 7(11): 1238-1247.
114	BOLLARD C M, RÖSSIG C, CALONGE M J, et al. Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity[J]. Blood, 2002, 99(9): 3179-3187.
115	BENDLE G M, LINNEMANN C, BIES L, et al. Blockade of TGF-β signaling greatly enhances the efficacy of TCR gene therapy of cancer[J]. Journal of Immunology, 2013, 191(6): 3232-3239.
116	BOLLARD C M, TRIPIC T, CRUZ C R, et al. Tumor-specific T-cells engineered to overcome tumor immune evasion induce clinical responses in patients with relapsed Hodgkin lymphoma[J]. Journal of Clinical Oncology, 2018, 36(11): 1128-1139.
117	YAMAMOTO T N, LEE P H, VODNALA S K, et al. T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy[J]. The Journal of Clinical Investigation, 2019, 129(4): 1551-1565.
118	ARBER C, YOUNG M, BARTH P. Reprogramming cellular functions with engineered membrane proteins[J]. Current Opinion in Biotechnology, 2017, 47: 92-101.
119	SHIN J H, PARK H B, OH Y M, et al. Positive conversion of negative signaling of CTLA4 potentiates antitumor efficacy of adoptive T-cell therapy in murine tumor models[J]. Blood, 2012, 119(24): 5678-5687.
120	ANKRI C, SHAMALOV K, HOROVITZ-FRIED M, et al. Human T cells engineered to express a programmed death 1/28 costimulatory retargeting molecule display enhanced antitumor activity[J]. Journal of Immunology, 2013, 191(8): 4121-4129.
121	SCHLENKER R, OLGUÍN-CONTRERAS L F, LEISEGANG M, et al. Chimeric PD-1: 28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy[J]. Cancer Research, 2017, 77(13): 3577-3590.
122	HOOGI S, EISENBERG V, MAYER S, et al. A TIGIT-based chimeric co-stimulatory switch receptor improves T-cell anti-tumor function[J]. Journal for Immunotherapy of Cancer, 2019, 7(1): 243.
123	ODA S K, DAMAN A W, GARCIA N M, et al. A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia[J]. Blood, 2017, 130(22): 2410-2419.
124	THEODORE L, ROTH, ROTH T L, LI P J, BLAESCHKE F, et al. Pooled knockin targeting for genome engineering of cellular immunotherapies[J]. Cell, 2020, 181(3): 728-744.e21.
125	WILKIE S, BURBRIDGE S E, CHIAPERO-STANKE L, et al. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4[J]. The Journal of Biological Chemistry, 2010, 285(33): 25538-25544.
126	LEEN A M, SUKUMARAN S, WATANABE N, et al. Reversal of tumor immune inhibition using a chimeric cytokine receptor[J]. Molecular Therapy, 2014, 22(6): 1211-1220.
127	SUKUMARAN S, WATANABE N, BAJGAIN P, et al. Enhancing the potency and specificity of engineered T cells for cancer treatment[J]. Cancer Discovery, 2018, 8(8): 972-987.
128	SINGH N, SHI J W, JUNE C H, et al. Genome-editing technologies in adoptive T cell immunotherapy for cancer[J]. Current Hematologic Malignancy Reports, 2017, 12(6): 522-529.
129	PICKAR-OLIVER A, GERSBACH C A. The next generation of CRISPR-Cas technologies and applications[J]. Nature Reviews Molecular Cell Biology, 2019, 20(8): 490-507.
130	QASIM W, ZHAN H, SAMARASINGHE S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells[J]. Science Translational Medicine, 2017, 9(374): eaaj2013.
131	PROVASI E, GENOVESE P, LOMBARDO A, et al. Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer[J]. Nature Medicine, 2012, 18(5): 807-815.
132	RASAIYAAH J, GEORGIADIS C, PREECE R, et al. TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy[J]. JCI Insight, 2018, 3(13): e99442.

[1]	高歌, 边旗, 王宝俊. 合成基因线路的工程化设计研究进展与展望[J]. 合成生物学, 2025, 6(1): 45-64.
[2]	李冀渊, 吴国盛. 合成生物学视域下有机体的两种隐喻[J]. 合成生物学, 2025, 6(1): 190-202.
[3]	焦洪涛, 齐蒙, 邵滨, 蒋劲松. DNA数据存储技术的法律治理议题[J]. 合成生物学, 2025, 6(1): 177-189.
[4]	唐兴华, 陆钱能, 胡翌霖. 人类世中对合成生物学的哲学反思[J]. 合成生物学, 2025, 6(1): 203-212.
[5]	徐怀胜, 石晓龙, 刘晓光, 徐苗苗. DNA存储的关键技术：编码、纠错、随机访问与安全性[J]. 合成生物学, 2025, 6(1): 157-176.
[6]	石婷, 宋展, 宋世怡, 张以恒. 体外生物转化（ivBT）：生物制造的新前沿[J]. 合成生物学, 2024, 5(6): 1437-1460.
[7]	柴猛, 王风清, 魏东芝. 综合利用木质纤维素生物转化合成有机酸[J]. 合成生物学, 2024, 5(6): 1242-1263.
[8]	邵明威, 孙思勉, 杨时茂, 陈国强. 基于极端微生物的生物制造[J]. 合成生物学, 2024, 5(6): 1419-1436.
[9]	陈雨, 张康, 邱以婧, 程彩云, 殷晶晶, 宋天顺, 谢婧婧. 微生物电合成技术转化二氧化碳研究进展[J]. 合成生物学, 2024, 5(5): 1142-1168.
[10]	郑皓天, 李朝风, 刘良叙, 王嘉伟, 李恒润, 倪俊. 负碳人工光合群落的设计、优化与应用[J]. 合成生物学, 2024, 5(5): 1189-1210.
[11]	夏孔晨, 徐维华, 吴起. 光酶催化混乱性反应的研究进展[J]. 合成生物学, 2024, 5(5): 997-1020.
[12]	陈子苓, 向阳飞. 类器官技术与合成生物学协同研究进展[J]. 合成生物学, 2024, 5(4): 795-812.
[13]	蔡冰玉, 谭象天, 李伟. 合成生物学在干细胞工程化改造中的研究进展[J]. 合成生物学, 2024, 5(4): 782-794.
[14]	谢皇, 郑义蕾, 苏依婷, 阮静怡, 李永泉. 放线菌聚酮类化合物生物合成体系重构研究进展[J]. 合成生物学, 2024, 5(3): 612-630.
[15]	查文龙, 卜兰, 訾佳辰. 中药药效成分群的合成生物学研究进展[J]. 合成生物学, 2024, 5(3): 631-657.

合成生物学与工程化T细胞治疗

Synthetic biology and engineered T cell therapy

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 4

参考文献 132

相关文章 15

编辑推荐

Metrics

本文评价