biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2019-19-4-206-214biopreparat-259Research ArticleОБЗОРЫREVIEWSПрименение биомедицинских клеточных продуктов для лечения онкологических заболеванийThe Current Use of Biomedical Cell Products for Cancer Treatmenthttps://orcid.org/0000-0001-6553-5303УстюговаЕ. А.UstyugovaE. A.

Устюгова Екатерина Александровна, канд. биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Ekaterina A. Ustyugova, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

ustugova@expmed.ruhttps://orcid.org/0000-0002-8527-2157СавкинаМ. В.SavkinaM. V.

Савкина Мария Владимировна, канд. биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Maria V. Savkina, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

savkina@expmed.ruhttps://orcid.org/0000-0003-1620-6233ГоряевА. А.GoryaevA. A.

Горяев Артем Анатольевич, канд. биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Artem A. Goryaev, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

goryaev@expmed.ruhttps://orcid.org/0000-0001-6472-6386БондаревВ. П.BondarevV. P.

Бондарев Владимир Петрович, д-р мед. наук, проф.

Петровский б-р, д. 8, стр. 2, Москва, 127051

Vladimir P. Bondarev, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

bondarev@expmed.ruhttps://orcid.org/0000-0003-4891-973XМеркуловВ. А.MerkulovV. A.

Меркулов Вадим Анатольевич, д-р мед. наук, проф.

Петровский б-р, д. 8, стр. 2, Москва, 127051;Трубецкая ул., д. 8, стр. 2, Москва, 119991

Vadim A. Merkulov, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation;8/2 Trubetskaya St., Moscow 119991, Russian Federation

merkulov@expmed.ruhttps://orcid.org/0000-0002-9585-3545МельниковаЕ. В.MelnikovaE. V.

Мельникова Екатерина Валерьевна, канд. биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Ekaterina V. Melnikova, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

melnikovaEV@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской Федерации; Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И. М. Сеченова» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal Products; I. M. Sechenov First Moscow State Medical UniversityRussian Federation201930102019194206214Copyright © Устюгова Е.А., Савкина М.В., Горяев А.А., Бондарев В.П., Меркулов В.А., Мельникова Е.В., 20192019Устюгова Е.А., Савкина М.В., Горяев А.А., Бондарев В.П., Меркулов В.А., Мельникова Е.В.Ustyugova E.A., Savkina M.V., Goryaev A.A., Bondarev V.P., Merkulov V.A., Melnikova E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/259

В настоящее время онкологические заболевания продолжают оставаться одной из причин смертности населения. Стандартные методы терапии, включая лучевую и химиотерапию, имеют ограниченную эффективность. В связи с этим разработка принципиально новых методов терапии онкологических заболеваний является актуальной задачей. Перспективным и многообещающим подходом считается лечение онкологии с помощью биомедицинских клеточных продуктов (БМКП), к которым можно отнести адоптивную клеточную терапию и терапию вакцинами на основе дендритных клеток. Цель работы — обзор современных представлений о принципах терапии, а также имеющегося клинического опыта применения клеточных продуктов для лечения онкологических заболеваний. В работе представлены данные клинического применения опухоль-инфильтрирующих лимфоцитов (TIL-терапия), генетически модифицированных T-клеток, экспрессирующих специфичные к опухолевым антигенам рецепторы (TCR/CAR-T-терапия), а также дендритно-клеточных вакцин. Применение ex vivo модифицированных клеток иммунной системы человека является новым подходом и имеет большие перспективы для лечения онкологических заболеваний. Представленные основные направления адоптивной клеточной терапии, базирующиеся на использовании генетически модифицированных Т-лимфоцитов, имеют различные преимущества и недостатки. В работе рассмотрены способы получения БМКП, приведены данные по эффективности применения адоптивной клеточной терапии и вакцин на основе дендритных клеток. Отдельное внимание уделено проблемам, связанным с безопасностью каждого метода терапии, а также другим факторам, ограничивающим применение данных терапевтических подходов в клинической практике. Ожидается, что дальнейшие исследования будут направлены на повышение эффективности и снижение побочных реакций при терапии БМКП.

Cancer remains one of the leading causes of death. Conventional treatment methods, including radiation and chemotherapy, have limited effectiveness. Therefore, the development of novel approaches to cancer treatment is an urgent challenge. Biomedical cell products (BMCPs) which include adoptive cell therapy (ACT) and dendritic cells vaccines (DCVs) are considered a promising area of research. The aim of the study was to review current ideas about the principles of BMCP therapy, as well as clinical experience with cell-based products used for cancer treatment. The paper summarises the results of clinical use of tumor-infiltrating lymphocytes (TIL-therapy), genetically modified T-cells that express tumour antigen-specific receptors (TCR/CAR T-therapy), as well as DCVs. The use of human immune cells genetically modified ex vivo is a novel and promising approach to cancer treatment. The main analysed ACT approaches which are based on the use of genetically modified T-lymphocytes have some benefits and drawbacks. The paper discusses the methods of BMCP production, provides data on the effectiveness of ACT and DCVs. It pays special attention to safety concerns associated with each treatment method, as well as to other factors limiting their clinical use. It is expected that the main areas of further research will be aimed at increasing BMCP efficacy and reducing adverse reactions.

биомедицинские клеточные продуктыклеточная терапияонкологические заболеванияадоптивная клеточная терапиядендритные клеткимодифицированные Т-клеткихимерный антигенный рецептордендритно-клеточная вакцинаbiomedical cell productscell-based therapycanceradoptive cell therapydendritic cellsgenetically modified T cellschimeric antigen receptordendritic cell vaccineРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00154-19-00 на проведение прикладных научных исследований (номер государственного учета НИР AAAAA18-118021590045-2).The study reported in this publication was carried out as a part of publicly funded research project № 056-00154-19-00 and was supported by Scientific Center for Expert Evaluation of Medicinal Products (R&D public accounting No. AAAA-A18-118021590045-2).ReferencesBray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492Каприна АД, Старинский ВВ, Петрова ГВ, ред. Злокачественные новообразования в России в 2017 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2018.Kaprina AD, Starinskiy VV, Petrova GV, eds. Malignant neoplasms in Russia in 2017 (morbidity and mortality). Moscow: Herzen P.A. MNIOI – a branch of the Federal State Budgetary Scientific Radiology Research Center of the Ministry of Health of Russia; 2018 (In Russ.)Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. PNAS. 2005;102(51):18538–43. https://doi.org/10.1073/pnas.0509182102Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. PNAS. 2005;102(51):18538–43. https://doi.org/10.1073/pnas.0509182102Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4. https://doi.org/10.1126/science.1129139Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4. https://doi.org/10.1126/science.1129139Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550–7. https://doi.org/10.1158/1078-0432.CCR-11-0116Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550–7. https://doi.org/10.1158/1078-0432.CCR-11-0116Rohaan MW, Wilgenhof S, Haanen JBAG. Adoptive cellular therapies: the current landscape. Virchows Arch. 2019;474(4):449–61. https://doi.org/10.1007/s00428-018-2484-0Rohaan MW, Wilgenhof S, Haanen JBAG. Adoptive cellular therapies: the current landscape. Virchows Arch. 2019;474(4):449–61. https://doi.org/10.1007/s00428-018-2484-0Salas-Benito D, Casares N, Sarobe P, Lasarte JJ, Hervas-Stubbs S. Pre-selection of PD-1+ tumor-infiltrating CD8+ T cells improves the efficacy of adoptive T-cell therapy. J Immunol Sci. 2018;2(1):55–9.Salas-Benito D, Casares N, Sarobe P, Lasarte JJ, Hervas-Stubbs S. Pre-selection of PD-1+ tumor-infiltrating CD8+ T cells improves the efficacy of adoptive T-cell therapy. J Immunol Sci. 2018;2(1):55–9.Met Ö, Jensen K.M, Chamberlain CA, Donia M, Svane IM. Principles of adoptive T cell therapy in cancer. Semin Immunopathol. 2019;41(1):49–58. https://doi.org/10.1007/s00281-018-0703-zMet Ö, Jensen K.M, Chamberlain CA, Donia M, Svane IM. Principles of adoptive T cell therapy in cancer. Semin Immunopathol. 2019;41(1):49–58. https://doi.org/10.1007/s00281-018-0703-zLu YC, Yao X, Li YF, El-Gamil M, Dudley ME, Yang JC, et al. Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J Immunol. 2013;190(12):6034–42. https://doi.org/10.4049/jimmunol.1202830Lu YC, Yao X, Li YF, El-Gamil M, Dudley ME, Yang JC, et al. Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J Immunol. 2013;190(12):6034–42. https://doi.org/10.4049/jimmunol.1202830Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641–5. https://doi.org/10.1126/science.1251102Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641–5. https://doi.org/10.1126/science.1251102Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26(4):332–42.Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26(4):332–42.Andersen R, Borch TH, Draghi A, Gokuldass A, Rana MAH, Pedersen M, et al. T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression. Ann Oncol. 2018;29(7):1575–81. https://doi.org/10.1093/annonc/mdy139Andersen R, Borch TH, Draghi A, Gokuldass A, Rana MAH, Pedersen M, et al. T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression. Ann Oncol. 2018;29(7):1575–81. https://doi.org/10.1093/annonc/mdy139Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2010;16(9):2646–55. https://doi.org/10.1158/1078-0432. CCR-10-0041Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2010;16(9):2646–55. https://doi.org/10.1158/1078-0432. CCR-10-0041Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzaki O, Schalmach E, et al. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients. J Immunother. 2009;32(4):415–23. https://doi.org/10.1097/CJI.0b013e31819c8bdaBesser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzaki O, Schalmach E, et al. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients. J Immunother. 2009;32(4):415–23. https://doi.org/10.1097/CJI.0b013e31819c8bdaCohen IJ, Blasberg R. Impact of the tumor microenvironment on tumor-infiltrating lymphocytes: focus on breast cancer. Breast Cancer (Auckl). 2017;11: 1178223417731565. https://doi.org/10.1177/1178223417731565Cohen IJ, Blasberg R. Impact of the tumor microenvironment on tumor-infiltrating lymphocytes: focus on breast cancer. Breast Cancer (Auckl). 2017;11: 1178223417731565. https://doi.org/10.1177/1178223417731565Andersen R, Donia M, Ellebaek E, Borch TH, Kongsted P, Iversen TZ, et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumorinfiltrating lymphocytes and an attenuated IL2 regimen. Clin Cancer Res. 2016;22(15):3734–45. https://doi.org/10.1158/1078-0432.CCR-15-1879Andersen R, Donia M, Ellebaek E, Borch TH, Kongsted P, Iversen TZ, et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumorinfiltrating lymphocytes and an attenuated IL2 regimen. Clin Cancer Res. 2016;22(15):3734–45. https://doi.org/10.1158/1078-0432.CCR-15-1879Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother. 2012;35(8):615–20. https://doi.org/10.1097/CJI.0b013e31826e8f5fPilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, et al. Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. J Immunother. 2012;35(8):615–20. https://doi.org/10.1097/CJI.0b013e31826e8f5fLarkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. https://doi.org/10.1056/NEJMoa1504030Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. https://doi.org/10.1056/NEJMoa1504030Stevanović S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus targeted tumor-infiltrating T cells. J Clin Oncol. 2015;33(14):1543–50. https://doi.org/10.1200/JCO.2014.58.9093Stevanović S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus targeted tumor-infiltrating T cells. J Clin Oncol. 2015;33(14):1543–50. https://doi.org/10.1200/JCO.2014.58.9093Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009;114(3):535–46. https://doi.org/10.1182/blood-2009-03-211714Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009;114(3):535–46. https://doi.org/10.1182/blood-2009-03-211714Chodon T, Comin-Anduix B, Chmielowski B, Koya RC, Wu Z, Auerbach M, et al. Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res. 2014;20(9):2457–65. https://doi.org/10.1158/1078-0432.CCR-13-3017Chodon T, Comin-Anduix B, Chmielowski B, Koya RC, Wu Z, Auerbach M, et al. Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin Cancer Res. 2014;20(9):2457–65. https://doi.org/10.1158/1078-0432.CCR-13-3017Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19(3):620–6. https://doi.org/10.1038/mt.2010.272Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011;19(3):620–6. https://doi.org/10.1038/mt.2010.272Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013; 36(2):133–51. https://doi.org/10.1097/CJI.0b013e3182829903Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013; 36(2):133–51. https://doi.org/10.1097/CJI.0b013e3182829903Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914–21. https://doi.org/10.1038/nm.3910Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 2015;21(8):914–21. https://doi.org/10.1038/nm.3910Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917–24. https://doi.org/10.1200/JCO.2010.32.2537Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917–24. https://doi.org/10.1200/JCO.2010.32.2537Wolf B, Zimmermann S, Arber C, Irving M, Trueb L, Coukos G. Safety and tolerability of adoptive cell therapy in cancer. Drug Saf. 2019;42(2):315–34. https://doi.org/10.1007/s40264-018-0779-3Wolf B, Zimmermann S, Arber C, Irving M, Trueb L, Coukos G. Safety and tolerability of adoptive cell therapy in cancer. Drug Saf. 2019;42(2):315–34. https://doi.org/10.1007/s40264-018-0779-3Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863–71. https://doi.org/10.1182/blood-2013-03-490565Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863–71. https://doi.org/10.1182/blood-2013-03-490565Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017;9(9):1183–97. https://doi.org/10.15252/emmm.201607485Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017;9(9):1183–97. https://doi.org/10.15252/emmm.201607485Arabi F, Torabi-Rahvar M, Shariati A, Ahmadbeigi N, Naderi M. Antigenic targets of CAR T cell therapy. A retrospective view on clinical trials. Exp Cell Res. 2018;369(1):1–10. https://doi.org/10.1016/j.yexcr.2018.05.009Arabi F, Torabi-Rahvar M, Shariati A, Ahmadbeigi N, Naderi M. Antigenic targets of CAR T cell therapy. A retrospective view on clinical trials. Exp Cell Res. 2018;369(1):1–10. https://doi.org/10.1016/j.yexcr.2018.05.009Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116(20):4099–102. https://doi.org/10.1182/blood-2010-04-281931Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116(20):4099–102. https://doi.org/10.1182/blood-2010-04-281931Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18. https://doi.org/10.1056/NEJMoa1215134Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18. https://doi.org/10.1056/NEJMoa1215134Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. https://doi.org/10.1056/NEJMoa1103849Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. https://doi.org/10.1056/NEJMoa1103849Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10(1):53. https://doi.org/10.1186/s13045-017-0423-1Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol. 2017;10(1):53. https://doi.org/10.1186/s13045-017-0423-1Charrot S, Hallam S. CAR-T cells: future perspectives. HemaSphere. 2019;3(2):e188. https://doi.org/10.1097/HS9.0000000000000188Charrot S, Hallam S. CAR-T cells: future perspectives. HemaSphere. 2019;3(2):e188. https://doi.org/10.1097/HS9.0000000000000188Long KB, Young RM, Boesteanu AC, Davis MM, Melenhorst JJ, Lacey SF, et al. CAR T cell therapy of non-hematopoietic malignancies: detours on the road to clinical success. Front Immunol. 2018;9:2740. https://doi.org/10.3389/fimmu.2018.02740Long KB, Young RM, Boesteanu AC, Davis MM, Melenhorst JJ, Lacey SF, et al. CAR T cell therapy of non-hematopoietic malignancies: detours on the road to clinical success. Front Immunol. 2018;9:2740. https://doi.org/10.3389/fimmu.2018.02740Dudek AM, Martin S, Garg AD, Agostinis P. Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells interface that augments anticancer immunity. Front Immunol. 2013;4:438. https://doi.org/10.3389/fimmu.2013.00438Dudek AM, Martin S, Garg AD, Agostinis P. Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells interface that augments anticancer immunity. Front Immunol. 2013;4:438. https://doi.org/10.3389/fimmu.2013.00438Garg AD, Vara Perez M, Schaaf M, Agostinis P, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: dendritic cell-based anticancer immunotherapy. Oncoimmunology. 2017;6(7):e1328341. https://doi.org/10.1080/2162402X.2017.1328341Garg AD, Vara Perez M, Schaaf M, Agostinis P, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: dendritic cell-based anticancer immunotherapy. Oncoimmunology. 2017;6(7):e1328341. https://doi.org/10.1080/2162402X.2017.1328341Sabado RL, Balan S, Bhardwaj N. Dendritic cell-based immunotherapy. Cell Res. 2017;27(1):74–95. https://doi.org/10.1038/cr.2016.157Sabado RL, Balan S, Bhardwaj N. Dendritic cell-based immunotherapy. Cell Res. 2017;27(1):74–95. https://doi.org/10.1038/cr.2016.157Anguille S, Smits EL, Bryant C, Van Acker HH, Goossens H, Lion E, et al. Dendritic cells as pharmacological tools for cancer immunotherapy. Pharmacol Rev. 2015;67(4):731–53. https://doi.org/10.1124/pr.114.009456Anguille S, Smits EL, Bryant C, Van Acker HH, Goossens H, Lion E, et al. Dendritic cells as pharmacological tools for cancer immunotherapy. Pharmacol Rev. 2015;67(4):731–53. https://doi.org/10.1124/pr.114.009456Cohn L, Delamarre L. Dendritic cell-targeted vaccines. Front Immunol. 2014;5:255. https://doi.org/10.3389/fimmu.2014.00255Cohn L, Delamarre L. Dendritic cell-targeted vaccines. Front Immunol. 2014;5:255. https://doi.org/10.3389/fimmu.2014.00255Decker WK, Xing D, Li S, Robinson SN, Yang H, Yao X, et al. Double loading of dendritic cell MHC class I and MHC class II with an AML antigen repertoire enhances correlates of T-cell immunity in vitro via amplification of T-cell help. Vaccine. 2006;24(16):3203–16. https://doi.org/10.1016/j.vaccine.2006.01.029Decker WK, Xing D, Li S, Robinson SN, Yang H, Yao X, et al. Double loading of dendritic cell MHC class I and MHC class II with an AML antigen repertoire enhances correlates of T-cell immunity in vitro via amplification of T-cell help. Vaccine. 2006;24(16):3203–16. https://doi.org/10.1016/j.vaccine.2006.01.029Draube A, Klein-González N, Mattheus S, Brillant C, Hellmich M, Engert A, von Bergwelt-Baildon M. Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. PLoS One. 2011;6(4):e18801. https://doi.org/10.1371/journal.pone.0018801Draube A, Klein-González N, Mattheus S, Brillant C, Hellmich M, Engert A, von Bergwelt-Baildon M. Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. PLoS One. 2011;6(4):e18801. https://doi.org/10.1371/journal.pone.0018801Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014;15(7):e257–67. https://doi.org/10.1016/S1470-2045(13)70585-0Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014;15(7):e257–67. https://doi.org/10.1016/S1470-2045(13)70585-0Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22. https://doi.org/10.1056/NEJMoa1001294Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22. https://doi.org/10.1056/NEJMoa1001294Vandenberk L, Belmans J, Van Woensel M, Riva M, Van Gool SW. Eхploiting the immunogenic potential of cancer cells for improved dendric cells vaccines. Front Immunol. 2016;6:663. https://doi.org/10.3389/fimmu.2015.00663Vandenberk L, Belmans J, Van Woensel M, Riva M, Van Gool SW. Eхploiting the immunogenic potential of cancer cells for improved dendric cells vaccines. Front Immunol. 2016;6:663. https://doi.org/10.3389/fimmu.2015.00663Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16(1):142. https://doi.org/10.1186/s12967-018-1507-6Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, et al. First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16(1):142. https://doi.org/10.1186/s12967-018-1507-6Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. https://doi.org/10.1056/NEJMoa043330Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96. https://doi.org/10.1056/NEJMoa043330

The authors declare that there are no conflicts of interest present.