نوع مقاله : مروری
نویسندگان
1 تهران، دانشگاه علوم پزشکی تهران، دانشکده پزشکی، گروه ژنتیک پزشکی
2 کارشناس‌ارشد ژنتیک مولکولی
3 کارشناس ارشد ژنتیک مولکولی
چکیده
سابقه و هدف: با توسعه و پیشرفت روزافزون در زمینة ایمنی‌درمانی تومورها، امروزه توجه خاصی به درمان‌های ایمنی انواع سرطان‌ها معطوف شده است. درمان‌های بر پایة گیرنده‌های کایمری آنتی‌ژن‌ها (CARs)، یکی از انواع درمان‌های مبتنی بر سلول‌های Tی تغییریافته به‌شمار می‌رود که به‌صورت هدف‌مند تنها روی سلول‌های توموری فرد و نه سلول‌های طبیعی اثر می‌گذارد.
مواد و روش‌ها: پژوهش‌ها در دهه‌های اخیر حاکی از این است که درمان‌های بر پایة CAR T-cellها انقلابی را در حوزة درمان انواع سرطان‌ها به‌وجود آورده است و دستاوردهای ارزش‌مندی را در درمان بدخیمی‌های خونی مانند لوسمی‌ها و لنفوماها و تومورهای جامد مشتمل بر نوروبلاستوما و گلیوبلاستوما به‌ارمغان آورده است.
یافته‌ها: در مقالة پیش‌رو، پس از نگاهی اجمالی به ساختار و کارکرد CAR T- cellها، برخی آنتی‌ژن‌های بیان‌شونده در سطح سلول‌های توموری و CAR T- cellهای هدف گیرندة آن‌ها بررسی شده است. در ادامه، چندین نمونه از درمان‌های موفق با کمک این فناوری ارائه و سرانجام، در مورد امنیت این روش‌های درمانی و چالش‌ها و افق‌های پیش رو بحث شده است.
کلیدواژه‌ها
عنوان مقاله [English]
CAR T- cells: Novel targeted therapies in cancer
نویسندگان [English]
- mohamad reza Noori-Daloii 1
- Nazanin Rahimi rad 2
- Saeedeh Kavoosi 3
2 MSc in Molecular Genetics
3 MSc in Molecular Genetics
چکیده [English]
According to the growing developments and improvements of cancer immunotherapies, nowadays, special attention has been paid to the immunotherapies of various types of cancers. Chimeric antigen receptor (CAR) T-cell therapy is one of the T-cell therapies that affects tumor cells, not the normal cells. Research conducted over the past decades suggests that CAR T-cell based therapies has revolutionized cancer therapies, and has provided precious achievements in the treatment of hematologic malignancies such as leukemia and lymphoma, and solid tumors including neuroblastoma and glioblastoma. In this review article, structure, function of CAR T- cells, along with some of the antigens that are expressed on the surface of the tumor cells and the CAR T-cells targeting them are presented. Subsequently, several examples of successful therapies with the help of this technology are presented and finally, the safety of these therapies and the challenges and future perspectives are discussed.
کلیدواژه‌ها [English]
- cancer immunotherapies
- CAR T-cells
- Chimeric Antigen Receptors (CARs)
- targeted therapies
- Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, Vogel AN, Kalos M, Riley JL, Deeks SG, Mitsuyasu RT. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Science Translational Medicine. 2012 May 2; 4(132): 132-53.
- Noori-Daloii MR, Medical molecular genetics in the third millennium. Tehran, Iran: Samer Publication; 2012. [in Persian]
- Noori-Daloii MR, ed. Emery’s elements of medical genetics. 8th ed. Tehran, Iran: Jame-e-negar and Salemi Publication; 2017. [in Persian]
- Zhao Z, Condomines M, van der Stegen SJ, Perna F, Kloss CC, Gunset G, Plotkin J, Sadelain M. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015 Oct 12; 28(4): 415-28.
- Kim MG, Kim D, Suh SK, Park Z, Choi MJ, Oh YK. Current status and regulatory perspective of chimeric antigen receptor-modified T cell therapeutics. Archives of Pharmacal Research. 2016 Apr 1; 39(4): 437-52.
- Frigault MJ, Maus MV. Chimeric antigen receptor-modified T cells strike back. International Immunology. 2016 Mar 28; 28(7): 355-63.
- Xiao L, Tang Y, Zhu X, Chen J, Wu Z. CD19 targeted chimeric antigen receptor T (CAR-T) cell immunotherapy has demonstrated significant anti-leukemia activity in pediatric patients with relapsed/refractory acute lymphocytic leukemia: A multicentre study in China.
- Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, Sakemura R, Goto T, Hanajiri R, Imahashi N, Shimada K. Target Antigen Density Governs the Efficacy of Anti–CD20-CD28-CD3 ζ Chimeric Antigen Receptor–Modified Effector CD8+ T Cells. The Journal of Immunology. 2015 Feb 1; 194(3): 911-20.
- Hombach AA, Görgens A, Chmielewski M, Murke F, Kimpel J, Giebel B, Abken H. Superior Therapeutic Index in Lymphoma Therapy: CD30+ CD34+ Hematopoietic Stem Cells Resist a Chimeric Antigen Receptor T-cell Attack. Molecular Therapy. 2016 Apr 26.
- O’Hear C, Heiber JF, Schubert I, Fey G, Geiger TL. Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. Haematologica. 2015 Mar 1; 100(3): 336-44.
- Gill S, Tasian SK, Ruella M, Shestova O, Li Y, Porter DL, Carroll M, Danet-Desnoyers G, Scholler J, Grupp SA, June CH. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor–modified T cells. Blood. 2014 Apr 10; 123(15): 2343-54.
- Rafiq S, Dao T, Liu C, Scheinberg DA, Brentjens RJ. Engineered T cell receptor-mimic antibody, (TCRm) chimeric antigen receptor (CAR) T cells against the intracellular protein Wilms tumor-1 (WT1) for treatment of hematologic and solid cancers.
- Noori-Daloii MR, Tabarestani S. Molecular Genetics and gene therapy in breast cancer. The Journal of Faculty of Medicine, Sabzevar University of Medical Science. 2010; 17: 74-87. [in Persian]
- Chinnasamy D, Tran E, Yu Z, Morgan RA, Restifo NP, Rosenberg SA. Simultaneous targeting of tumor antigens and the tumor vasculature using T lymphocyte transfer synergize to induce regression of established tumors in mice. Cancer Research. 2013 Jun 1; 73(11): 3371-80.
- Yong CS, Dardalhon V, Devaud C, Taylor N, Darcy PK, Kershaw MH. CAR T-cell therapy of solid tumors. Immunology and Cell Biology. 2016 Dec 22.
- Newick K, O'Brien S, Moon E, Albelda SM. CAR T cell therapy for solid tumors. Annual Review of Medicine. 2017 Jan 14; 68: 139-52.
- Santoro SP, Kim S, Motz GT, Alatzoglou D, Li C, Irving M, Powell DJ, Coukos G. T cells bearing a chimeric antigen receptor against prostate-specific membrane antigen mediate vascular disruption and result in tumor regression. Cancer Immunology Research. 2015 Jan 1; 3(1): 68-84.
- Ruella M, Levine BL. Smart CARS: optimized development of a chimeric antigen receptor (CAR) T cell targeting epidermal growth factor receptor variant III (EGFRvIII) for glioblastoma. Annals of Translational Medicine. 2016 Jan; 4(1).
- Prapa M, Caldrer S, Spano C, Bestagno M, Golinelli G, Grisendi G, Petrachi T, Conte P, Horwitz EM, Campana D, Paolucci P. A novel anti-GD2/4-1BB chimeric antigen receptor triggers neuroblastoma cell killing. Oncotarget. 2015 Sep 22; 6(28): 24884.
- Kowalczuk O, Burzykowski T, Niklinska WE, Kozlowski M, Chyczewski L, Niklinski J. CXCL5 as a potential novel prognostic factor in early stage non-small cell lung cancer: results of a study of expression levels of 23 genes. Tumor Biology. 2014 May 1; 35(5): 4619-28.
- Noori-Daloii MR, Fazilaty H, Tabrizi M. Cancer metastasis, genetic and microenvironmental factors of distant tissue: a review article. Tehran University of Medical Science, 2013. 70(11).
- Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, Ittmann MM, Marchetti D, Dotti G. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nature Medicine. 2015 May 1; 21(5): 524-9.
- Gross G, Eshhar Z. Therapeutic potential of T cell chimeric antigen receptors (CARs) in cancer treatment: counteracting off-tumor toxicities for safe CAR T cell therapy. Annual Review of Pharmacology and Toxicology. 2016 Jan 6; 56: 59-83.
- Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular Therapy. 2010 Apr 30; 18(4): 843-51.
- Jones BS, Lamb LS, Goldman F, Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer. Frontiers in Pharmacology. 2014; 5.
- Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, Vogel AN, Kalos M, Riley JL, Deeks SG, Mitsuyasu RT. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Science Translational Medicine. 2012 May 2; 4(132): 132ra53-.
- Sun N, Liang J, Abil Z, Zhao H. Optimized TAL effector nucleases (TALENs) for use in treatment of sickle cell disease. Molecular BioSystems. 2012; 8(4): 1255-63.
- Noori-Daloii MR, Abdollahzadeh R, Asadollahi K. Targeted genome editing with engineered nucleases-A new approach in gene therapy. 2014: 131-144
- Noori-Daloii MR, Kavoosi S, Rahimi Rad N. CRISPR/Cas9: high throughput genome editing molecular tool. Medical Science Journal of Islamic Azad University-Tehran Medical Branch (under publication, 2017).
- Mirzaei HR, Mirzaei H, Lee SY, Hadjati J, Till BG. Prospects for chimeric antigen receptor (CAR) γδ T cells: A potential game changer for adoptive T cell cancer immunotherapy. Cancer Letters. 2016 Oct 1; 380(2): 413-23.
)