cancerspЮжно-Российский онкологический журнал/ South Russian Journal of CancerSouth Russian Journal of Cancer2686-9039АНО "Перспективы онкологии"10.37748/2687-0533-2020-1-1-4cancersp-40Research ArticleОБЗОРЫREVIEWSАДОПТИВНАЯ КЛЕТОЧНАЯ ТЕРАПИЯ: ДОСТИЖЕНИЯ ПОСЛЕДНИХ ЛЕТADOPTIVE CELL THERAPY: CURRENT ADVANCEShttps://orcid.org/0000-0002-4555-8556ШамоваТ. В.ShamovaT. V.

Шамова Татьяна Владимировна — младший научный сотрудник лаборатории клеточных технологий

344037, г. Ростов-на-Дону, ул. 14-я линия, д. 63 

SPIN: 5426-1873

Tatyana V. Shamova — Junior Researcher, Laboratory of Cell Technologies

63 14 line, Rostov-on-Don 344037

SPIN: 5426-1873 

tanyshamova@mail.ruhttps://orcid.org/0000-0002-6035-1756СитковскаяА. О.SitkovskayaA. O.

Ситковская Анастасия Олеговна — заведующая лабораторией клеточных технологий

344037, г. Ростов-на-Дону, ул. 14-я линия, д. 63 

SPIN: 1659-6976

ResearcherID: E-7496-2018

Scopus Author ID: 56381527400

Anastasiya O. Sitkovskaya — Head of the Laboratory of Cell Technologies

63 14 line, Rostov-on-Don 344037

SPIN: 1659-6976

ResearcherID: E-7496-2018

Scopus Author ID: 56381527400

ВащенкоЛ. Н.VashchenkoL. N.

Ващенко Лариса Николаевна — доктор медицинских наук, профессор, заведующая отделением опухолей костей, кожи, мягких тканей и молочной железы

344037, г. Ростов-на-Дону, ул. 14-я линия, д. 63 

SPIN: 5573-4396

Larisa N. Vashchenko — Dr. Sci. (Med.), Professor, Head of the Department of Bone, Skin, Soft Tissue and Breast Tumours

63 14 line, Rostov-on-Don 344037

SPIN: 5573-4396

КечеджиеваЭ. Э.KechedzhievaE. E.

Кечеджиева Эмма Эдуардовна — кандидат медицинских наук, врач-хирург отделения опухолей костей, кожи, мягких тканей и молочной железы

344037, г. Ростов-на-Дону, ул. 14-я линия, д. 63 

SPIN: 6266-4847  

Emma E. Kechedzhieva — Cand. Sci. (Med.), Surgeon, Department of Bone, Skin, Soft Tissue and Breast Tumours

63 14 line, Rostov-on-Don 344037

SPIN: 6266-4847 

ФГБУ «Национальный медицинский исследовательский центр онкологии» Министерства здравоохранения Российской ФедерацииРоссияNational Medical Research Centre for OncologyRussian Federation202007032020114359Copyright © Шамова Т.В., Ситковская А.О., Ващенко Л.Н., Кечеджиева Э.Э., 20202020Шамова Т.В., Ситковская А.О., Ващенко Л.Н., Кечеджиева Э.Э.Shamova T.V., Sitkovskaya A.O., Vashchenko L.N., Kechedzhieva E.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.cancersp.com/jour/article/view/40

Иммунная система играет важную роль в развитии и лечении многих типов рака. На основе этого факта было разработано множество иммунотерапевтичских подходов, одним из которых является адоптивная клеточная терапия (АКТ). В представленной статье освещается суть основных методов адоптивной клеточной терапии рака, возможность их применения на данном этапе и перспективы развития. В начале статьи излагается актуальность проблемы развития иммунотерапии онкозаболеваний и ее современное состояние. Основная часть включает в себя изложение механизмов адоптивного переноса Т-клеток (немодифицированных и модифицированных генетически), создания дендритно-клеточных вакцин и цитокин-индуцированных киллеров (ЦИК), а также обзор современных исследований по внедрению перечисленных методов в клинику. Результатом данного обзора является вывод, что АКТ является одним из перспективных и интенсивно изучаемых в настоящее время методов иммунотерапии рака, а также требует оптимизации для более эффективного применения в лечении онкозаболеваний.

The immune system plays an important role in the development and treatment of many cancer types. This fact determined the emergence of numerous immunotherapeutic approaches, including that of adoptive cell therapy (ACT). In this article, we set out to describe the basic methods of adoptive cell cancer therapy, their application and development prospects. The first part of the article deals with the significance of immunotherapeutic methods for cancer treatment and describes the current state of the problem. The main part of the article provides information on the mechanisms of adoptive T cell (unmodified and genetically modified) transfer, the creation of dendritic cell vaccines and cytokine-induced killers (CIK). In addition, a review of recent achievements in the introduction of the aforementioned methods into the clinical practice is carried out. The conclusion is made that adoptive cell therapy can be considered as one of the most promising methods of cancer immunotherapy, which should be optimized for more effective use in the treatment of cancer.

онкологияиммунотерапия ракаадоптивная клеточная терапияопухоль-инфильтрующие лимфоцитыдендритно-клеточные вакциныцитокин-индуцированные киллерыoncologycancer immunotherapyadoptive cell therapytumour-infiltrating lymphocytesdendritic cells vaccinescytokine-induced killersReferencesChen D. S., Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity. 2013 Jul 25;39(1):1–10. http://doi.org/10.1016/j.immuni.2013.07.012Chen D. S., Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity. 2013 Jul 25;39(1):1–10. http://doi.org/10.1016/j.immuni.2013.07.012Luke J. J., Flaherty K. T., Ribas A., Long G. V. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017 Aug;14(8):463–482. http://doi.org/10.1038/nrclinonc.2017.43Luke J. J., Flaherty K. T., Ribas A., Long G. V. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017 Aug;14(8):463–482. http://doi.org/10.1038/nrclinonc.2017.43Mayor M., Yang N., Sterman D., Jones D. R., Adusumilli P. S. Immunotherapy for non-small cell lung cancer: current concepts and clinical trials. Eur J Cardiothorac Surg. 2016 May 1;49(5):1324–1333. http://doi.org/10.1093/ejcts/ezv371Mayor M., Yang N., Sterman D., Jones D. R., Adusumilli P. S. Immunotherapy for non-small cell lung cancer: current concepts and clinical trials. Eur J Cardiothorac Surg. 2016 May 1;49(5):1324–1333. http://doi.org/10.1093/ejcts/ezv371Златник Е. Ю., Ситковская А. О., Непомнящая Е. М., Джандигова Ф. Р., Ващенко Л. Н. Достижения и перспективы клеточных технологий на основе активированных лимфоцитов в лечении злокачественных опухолей. Казанский медицинский журнал. 2018;99(5):792–801. http://doi.org/10.17816/KMJ2018–792Zlatnik E.Yu., Sitkovskaya A. O., Nepomnyashchaya E. M., Dzhandigova F. R., Vashchenko L. N. Achievements and prospects of cellular technologies based on the activated lymphocytes in the treatment of malignant tumors. Kazan Medical Journal. 2018;99(5):792–801 (In Russian). http://doi.org/10.17816/KMJ2018–792June C. H., Riddell S. R., Schumacher T. N. Adoptive cellular therapy: A race to the finish line. Sci Transl Med. 2015 Mar 25;7(280):280ps7. http://doi.org/10.1126/scitranslmed.aaa3643June C. H., Riddell S. R., Schumacher T. N. Adoptive cellular therapy: A race to the finish line. Sci Transl Med. 2015 Mar 25;7(280):280ps7. http://doi.org/10.1126/scitranslmed.aaa3643Morvan M. G., Lanier L. L. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. 2016 Jan;16(1):7–19. http://doi.org/10.1038/nrc.2015.5Morvan M. G., Lanier L. L. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. 2016 Jan;16(1):7–19. http://doi.org/10.1038/nrc.2015.5Houot R., Schultz L. M., Marabelle A., Kohrt H. T-cell-based Im-munotherapy: Adoptive Cell Transfer and Checkpoint Inhibition. Cancer Immunol Res. 2015 Oct;3(10):1115–1122. http://doi.org/10.1158/2326–6066.CIR-15–0190Houot R., Schultz L. M., Marabelle A., Kohrt H. T-cell-based Immunotherapy: Adoptive Cell Transfer and Checkpoint Inhibition. Cancer Immunol Res. 2015 Oct;3(10):1115–1122. http://doi.org/10.1158/2326–6066.CIR-15–0190Rosenberg S. A., Yang J. C., Sherry R. M., Kammula U. S., Hughes M. S., Phan G. Q., et al. Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550–4557. http://doi.org/10.1158/1078–0432.CCR-11–0116Rosenberg S. A., Yang J. C., Sherry R. M., Kammula U. S., Hughes M. S., Phan G. Q., et al. Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550–4557. http://doi.org/10.1158/1078–0432.CCR-11–0116Rosenberg S. A., Packard B. S., Aebersold P. M., Solomon D., Topalian S. L., Toy S. T., et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988 Dec 22;319(25):1676–1680. http://doi.org/10.1056/NEJM198812223192527Rosenberg S. A., Packard B. S., Aebersold P. M., Solomon D., Topalian S. L., Toy S. T., et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988 Dec 22;319(25):1676–1680. http://doi.org/10.1056/NEJM198812223192527Nguyen L. T., Saibil S. D., Sotov V., Le M. X., Khoja L., Ghazarian D., et al. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol Immunother. 2019 May 1;68(5):773–785. http://doi.org/10.1007/s00262–019–02307-xNguyen L. T., Saibil S. D., Sotov V., Le M. X., Khoja L., Ghazarian D., et al. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol Immunother. 2019 May 1;68(5):773–785. http://doi.org/10.1007/s00262–019–02307-xStevanovic S., Draper L. M., Langhan M. M., Campbell T. E., Kwong M. L., Wunderlich J. R., et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015 May 10;33(14):1543–1550. http://doi.org/10.1200/JCO.2014.58.9093Stevanovic S., Draper L. M., Langhan M. M., Campbell T. E., Kwong M. L., Wunderlich J. R., et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015 May 10;33(14):1543–1550. http://doi.org/10.1200/JCO.2014.58.9093Tran E., Turcotte S., Gros A., Robbins P. F., Lu Y.-C., Dudley M. E., et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014 May 9;344(6184):641–645. http://doi.org/10.1126/science.1251102Tran E., Turcotte S., Gros A., Robbins P. F., Lu Y.-C., Dudley M. E., et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014 May 9;344(6184):641–645. http://doi.org/10.1126/science.1251102Tran E., Robbins P. F., Lu Y.-C., Prickett T. D., Gartner J. J., Jia L., et al. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016 Dec 8;375(23):2255–2262. http://doi.org/10.1056/NEJMoa1609279Tran E., Robbins P. F., Lu Y.-C., Prickett T. D., Gartner J. J., Jia L., et al. T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer. N Engl J Med. 2016 Dec 8;375(23):2255–2262. http://doi.org/10.1056/NEJMoa1609279Turcotte S., Gros A., Tran E., Lee C.-C. R., Wunderlich J. R., Robbins P. F., et al. Tumor-reactive CD8+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy. Clin Cancer Res. 2014 Jan 15;20(2):331–343. http://doi.org/10.1158/1078–0432.CCR-13–1736Turcotte S., Gros A., Tran E., Lee C.-C. R., Wunderlich J. R., Robbins P. F., et al. Tumor-reactive CD8+ T cells in metastatic gastrointestinal cancer refractory to chemotherapy. Clin Cancer Res. 2014 Jan 15;20(2):331–343. http://doi.org/10.1158/1078–0432.CCR-13–1736Lee H. J., Kim Y.-A., Sim C. K., Heo S.-H., Song I. H., Park H. S., et al. Expansion of tumor-infiltrating lymphocytes and their potential for application as adoptive cell transfer therapy in human breast cancer. Oncotarget. 2017 Dec 26;8(69):113345–113359. http://doi.org/10.18632/oncotarget.23007Lee H. J., Kim Y.-A., Sim C. K., Heo S.-H., Song I. H., Park H. S., et al. Expansion of tumor-infiltrating lymphocytes and their potential for application as adoptive cell transfer therapy in human breast cancer. Oncotarget. 2017 Dec 26;8(69):113345–113359. http://doi.org/10.18632/oncotarget.23007Houot R., Schultz L. M., Marabelle A., Kohrt H. T-cell-based Immunotherapy: Adoptive Cell Transfer and Checkpoint Inhibition. Cancer Immunol Res. 2015 Oct;3(10):1115–1122. http://doi.org/10.1158/2326–6066.CIR-15–0190Houot R., Schultz L. M., Marabelle A., Kohrt H. T-cell-based Immunotherapy: Adoptive Cell Transfer and Checkpoint Inhibition. Cancer Immunol Res. 2015 Oct;3(10):1115–1122. http://doi.org/10.1158/2326–6066.CIR-15–0190Morgan R. A., Dudley M. E., Wunderlich J. R., Hughes M. S., Yang J. C., Sherry R. M., et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006 Oct 6;314(5796):126–129. http://doi.org/10.1126/science.1129003Morgan R. A., Dudley M. E., Wunderlich J. R., Hughes M. S., Yang J. C., Sherry R. M., et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006 Oct 6;314(5796):126–129. http://doi.org/10.1126/science.1129003Johnson L. A., Morgan R. A., Dudley M. E., Cassard L., Yang J. C., Hughes M. S., et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009 Jul 16;114(3):535–546. http://doi.org/10.1182/blood-2009–03–211714Johnson L. A., Morgan R. A., Dudley M. E., Cassard L., Yang J. C., Hughes M. S., et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009 Jul 16;114(3):535–546. http://doi.org/10.1182/blood-2009–03–211714Parkhurst M. R., Yang J. C., Langan R. C., Dudley M. E., Nathan D.-A. N., Feldman S. A., et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011 Mar;19(3):620–626. http://doi.org/10.1038/mt.2010.272Parkhurst M. R., Yang J. C., Langan R. C., Dudley M. E., Nathan D.-A. N., Feldman S. A., et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011 Mar;19(3):620–626. http://doi.org/10.1038/mt.2010.272Robbins P. F., Morgan R. A., Feldman S. A., Yang J. C., Sherry R. M., Dudley M. E., et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NYESO-1. J Clin Oncol. 2011 Mar 1;29(7):917–924. http://doi.org/10.1200/jco.2010.32.2537Robbins P. F., Morgan R. A., Feldman S. A., Yang J. C., Sherry R. M., Dudley M. E., et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NYESO-1. J Clin Oncol. 2011 Mar 1;29(7):917–924. http://doi.org/10.1200/jco.2010.32.2537Morgan R. A., Chinnasamy N., Abate-Daga D., Gros A., Robbins P. F., Zheng Z., et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013 Feb;36(2):133–351. http://doi.org/10.1097/CJI.0b013e3182829903Morgan R. A., Chinnasamy N., Abate-Daga D., Gros A., Robbins P. F., Zheng Z., et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013 Feb;36(2):133–351. http://doi.org/10.1097/CJI.0b013e3182829903Parkhurst M. R., Yang J. C., Langan R. C., Dudley M. E., Nathan D.-A. N., Feldman S. A., et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011 Mar;19(3):620–626. http://doi.org/10.1038/mt.2010.272Parkhurst M. R., Yang J. C., Langan R. C., Dudley M. E., Nathan D.-A. N., Feldman S. A., et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011 Mar;19(3):620–626. http://doi.org/10.1038/mt.2010.272Linette G. P., Stadtmauer E. A., Maus M. V., Rapoport A. P., Levine B. L., Emery L., et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013 Aug 8;122(6):863–871. http://doi.org/10.1182/blood-2013–03–490565Linette G. P., Stadtmauer E. A., Maus M. V., Rapoport A. P., Levine B. L., Emery L., et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013 Aug 8;122(6):863–871. http://doi.org/10.1182/blood-2013–03–490565Kochenderfer J. N., Dudley M. E., Kassim S. H., Somerville R. P. T., Carpenter R. O., Stetler-Stevenson M., et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015 Feb 20;33(6):540–549. http://doi.org/10.1200/JCO.2014.56.2025Kochenderfer J. N., Dudley M. E., Kassim S. H., Somerville R. P. T., Carpenter R. O., Stetler-Stevenson M., et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015 Feb 20;33(6):540–549. http://doi.org/10.1200/JCO.2014.56.2025Porter D. L., Frey N. V., Melenhorst J. J., Hwang W.-T., Lacey S. F., Shaw P. A., et al. Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL. JCO. 2016 May 20;34(15_suppl):3009–3009. http://doi.org/10.1200/JCO.2016.34.15_suppl.3009Porter D. L., Frey N. V., Melenhorst J. J., Hwang W.-T., Lacey S. F., Shaw P. A., et al. Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL. JCO. 2016 May 20;34(15_suppl):3009–3009. http://doi.org/10.1200/JCO.2016.34.15_suppl.3009Maude S. L., Frey N., Shaw P. A., Aplenc R., Barrett D. M., Bunin N.J/, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507– 1517. http://doi.org/10.1056/NEJMoa1407222Maude S. L., Frey N., Shaw P. A., Aplenc R., Barrett D. M., Bunin N.J/, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507– 1517. http://doi.org/10.1056/NEJMoa1407222Louis C. U., Savoldo B., Dotti G., Pule M., Yvon E., Myers G. D., et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011 Dec 1;118(23):6050–6056. http://doi.org/10.1182/blood-2011–05–354449Louis C. U., Savoldo B., Dotti G., Pule M., Yvon E., Myers G. D., et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011 Dec 1;118(23):6050–6056. http://doi.org/10.1182/blood-2011–05–354449Pule M. A., Savoldo B., Myers G. D., Rossig C., Russell H. V., Dotti G., et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008 Nov;14(11):1264–1270. http://doi.org/10.1038/nm.1882Pule M. A., Savoldo B., Myers G. D., Rossig C., Russell H. V., Dotti G., et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008 Nov;14(11):1264–1270. http://doi.org/10.1038/nm.1882Morgan R. A., Yang J. C., Kitano M., Dudley M. E., Laurencot C. M., Rosenberg S. A. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010 Apr;18(4):843–851. http://doi.org/10.1038/mt.2010.24Morgan R. A., Yang J. C., Kitano M., Dudley M. E., Laurencot C. M., Rosenberg S. A. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010 Apr;18(4):843–851. http://doi.org/10.1038/mt.2010.24Kershaw M. H., Westwood J. A., Parker L. L., Wang G., Eshhar Z., Mavroukakis S. A., et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6106–6115. http://doi.org/10.1158/1078–0432.CCR-06–1183Kershaw M. H., Westwood J. A., Parker L. L., Wang G., Eshhar Z., Mavroukakis S. A., et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6106–6115. http://doi.org/10.1158/1078–0432.CCR-06–1183Lamers C. H., Sleijfer S., van Steenbergen S., van Elzakker P., van Krimpen B., Groot C., et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013 Apr;21(4):904–912. http://doi.org/10.1038/mt.2013.17Lamers C. H., Sleijfer S., van Steenbergen S., van Elzakker P., van Krimpen B., Groot C., et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013 Apr;21(4):904–912. http://doi.org/10.1038/mt.2013.17Di Stasi A., Tey S.-K., Dotti G., Fujita Y., Kennedy-Nasser A., Martinez C., et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011 Nov 3;365(18):1673– 1683. http://doi.org/10.1056/NEJMoa1106152Di Stasi A., Tey S.-K., Dotti G., Fujita Y., Kennedy-Nasser A., Martinez C., et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011 Nov 3;365(18):1673– 1683. http://doi.org/10.1056/NEJMoa1106152Restifo N. P., Dudley M. E., Rosenberg S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012 Mar 22;12(4):269–281. http://doi.org/10.1038/nri3191Restifo N. P., Dudley M. E., Rosenberg S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012 Mar 22;12(4):269–281. http://doi.org/10.1038/nri3191Wang Z.-X., Cao J.-X., Wang M., Li D., Cui Y.-X., Zhang X.-Y., et al. Adoptive cellular immunotherapy for the treatment of patients with breast cancer: a meta-analysis. Cytotherapy. 2014 Jul;16(7):934–945. http://doi.org/10.1016/j.jcyt.2014.02.011Wang Z.-X., Cao J.-X., Wang M., Li D., Cui Y.-X., Zhang X.-Y., et al. Adoptive cellular immunotherapy for the treatment of patients with breast cancer: a meta-analysis. Cytotherapy. 2014 Jul;16(7):934– 945. http://doi.org/10.1016/j.jcyt.2014.02.011Palucka K., Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012 Mar 22;12(4):265–277. http://doi.org/10.1038/nrc3258Palucka K., Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012 Mar 22;12(4):265–277. http://doi.org/10.1038/nrc3258Draube A., Klein-González N., Mattheus S., Brillant C., Hellmich M., Engert A., et al. Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. PLoS ONE. 2011 Apr 20;6(4): e18801. http://doi.org/10.1371/journal.pone.0018801Draube A., Klein-González N., Mattheus S., Brillant C., Hellmich M., Engert A., et al. Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. PLoS ONE. 2011 Apr 20;6(4): e18801. http://doi.org/10.1371/journal.pone.0018801Widén K., Mozaffari F., Choudhury A., Mellstedt H. Overcoming immunosuppressive mechanisms. Ann Oncol. 2008 Sep;19 Suppl 7: vii241–247. http://doi.org/10.1093/annonc/mdn459Widén K., Mozaffari F., Choudhury A., Mellstedt H. Overcoming immunosuppressive mechanisms. Ann Oncol. 2008 Sep;19 Suppl 7: vii241–247. http://doi.org/10.1093/annonc/mdn459Boudreau J. E., Bridle B. W., Stephenson K. B., Jenkins K. M., Brunellière J., Bramson J. L., et al. Recombinant vesicular stomatitis virus transduction of dendritic cells enhances their ability to prime innate and adaptive antitumor immunity. Mol Ther. 2009 Aug;17(8):1465–1472. http://doi.org/10.1038/mt.2009.95Boudreau J. E., Bridle B. W., Stephenson K. B., Jenkins K. M., Brunellière J., Bramson J. L., et al. Recombinant vesicular stomatitis virus transduction of dendritic cells enhances their ability to prime innate and adaptive antitumor immunity. Mol Ther. 2009 Aug;17(8):1465–1472. http://doi.org/10.1038/mt.2009.95Amos S. M., Duong C. P. M., Westwood J. A., Ritchie D. S., Junghans R. P., Darcy P. K., et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011 Jul 21;118(3):499– 509. http://doi.org/10.1182/blood-2011–01–325266Amos S. M., Duong C. P. M., Westwood J. A., Ritchie D. S., Junghans R. P., Darcy P. K., et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011 Jul 21;118(3):499– 509. http://doi.org/10.1182/blood-2011–01–325266Leonhartsberger N., Ramoner R., Falkensammer C., Rahm A., Gander H., Höltl L., et al. Quality of life during dendritic cell vaccination against metastatic renal cell carcinoma. Cancer Immunol Immunother. 2012 Sep;61(9):1407–1413. http://doi.org/10.1007/s00262–012–1207–7Leonhartsberger N., Ramoner R., Falkensammer C., Rahm A., Gander H., Höltl L., et al. Quality of life during dendritic cell vaccination against metastatic renal cell carcinoma. Cancer Immunol Immunother. 2012 Sep;61(9):1407–1413. http://doi.org/10.1007/s00262–012–1207–7Anguille S., Smits E. L., Lion E., van Tendeloo V. F., Berneman Z. N. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014 Jun;15(7): e257–267. http://doi.org/10.1016/S1470–2045(13)70585–0Anguille S., Smits E. L., Lion E., van Tendeloo V. F., Berneman Z. N. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014 Jun;15(7): e257–267. http://doi.org/10.1016/S1470–2045(13)70585–0Yron I., Wood T. A., Spiess P. J., Rosenberg S. A. In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol. 1980 Jul;125(1):238–245.Yron I., Wood T. A., Spiess P. J., Rosenberg S. A. In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol. 1980 Jul;125(1):238–245.Lotze M. T., Line B. R., Mathisen D. J., Rosenberg S. A. The in vivo distribution of autologous human and murine lymphoid cells grown in T cell growth factor(TCGF): implications for the adoptive immunotherapy of tumors. J Immunol. 1980 Oct;125(4):1487–1493.Lotze M. T., Line B. R., Mathisen D. J., Rosenberg S. A. The in vivo distribution of autologous human and murine lymphoid cells grown in T cell growth factor (TCGF): implications for the adoptive immunotherapy of tumors. J Immunol. 1980 Oct;125(4):1487–1493.Mulé J. J., Shu S., Schwarz S. L., Rosenberg S. A. Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science. 1984 Sep 28;225(4669):1487–1489. http://doi.org/10.1126/science.6332379Mulé J. J., Shu S., Schwarz S. L., Rosenberg S. A. Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science. 1984 Sep 28;225(4669):1487–1489. http://doi.org/10.1126/science.6332379Parkhurst M. R., Riley J. P., Dudley M. E., Rosenberg S. A. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res. 2011 Oct 1;17(19):6287–6297. http://doi.org/10.1158/1078–0432.CCR-11–1347Parkhurst M. R., Riley J. P., Dudley M. E., Rosenberg S. A. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res. 2011 Oct 1;17(19):6287–6297. http://doi.org/10.1158/1078–0432.CCR-11–1347Lotze M. T., Grimm E. A., Mazumder A., Strausser J. L., Rosenberg S. A. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Cancer Res. 1981 Nov;41(11 Pt 1):4420–4425.Lotze M. T., Grimm E. A., Mazumder A., Strausser J. L., Rosenberg S. A. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Cancer Res. 1981 Nov;41(11 Pt 1):4420–4425.Титов К. С., Демидов Л. В., Шубина И. Ж., Хайленко В. А., Киселевский М. В., Вихрова А. С. Технологии клеточной иммунотерапии в лечении больных со злокачественными новообразованиями. Вестник РГМУ. 2014;1:42–47.Titov K. S., Demidov L. V., Shubina I.Zh., Khaylenko V. A., Kiselevsky M. V., Vikhrova A. S. Technologies of Cell Immunotherapy in Treatment of Cancer Patients. Bulletin of RSMU. 2014;1:42–47.Schmidt-Wolf I. G., Negrin R. S., Kiem H. P., Blume K. G., Weissman I. L. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med. 1991 Jul 1;174(1):139–149. http://doi.org/10.1084/jem.174.1.139Schmidt-Wolf I. G., Negrin R. S., Kiem H. P., Blume K. G., Weissman I. L. Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity. J Exp Med. 1991 Jul 1;174(1):139–149. http://doi.org/10.1084/jem.174.1.139Schmidt-Wolf I. G., Lefterova P., Mehta B. A., Fernandez L. P., Huhn D., Blume K. G., et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol. 1993 Dec;21(13):1673–1679.Schmidt-Wolf I. G., Lefterova P., Mehta B. A., Fernandez L. P., Huhn D., Blume K. G., et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp Hematol. 1993 Dec;21(13):1673–1679.Leemhuis T., Wells S., Scheffold C., Edinger M., Negrin R. S. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2005 Mar;11(3):181–187. http://doi.org/10.1016/j.bbmt.2004.11.019Leemhuis T., Wells S., Scheffold C., Edinger M., Negrin R. S. A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2005 Mar;11(3):181– 187. http://doi.org/10.1016/j.bbmt.2004.11.019Sangiolo D., Martinuzzi E., Todorovic M., Vitaggio K., Vallario A., Jordaney N., et al. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers. Int Immunol. 2008 Jul 1;20(7):841–848. http://doi.org/10.1093/intimm/dxn042Sangiolo D., Martinuzzi E., Todorovic M., Vitaggio K., Vallario A., Jordaney N., et al. Alloreactivity and anti-tumor activity segregate within two distinct subsets of cytokine-induced killer (CIK) cells: implications for their infusion across major HLA barriers. Int Immunol. 2008 Jul 1;20(7):841–848. http://doi.org/10.1093/intimm/dxn042Lu P. H., Negrin R. S.. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol. 1994 Aug 15;153(4):1687–1696.Lu P. H., Negrin R. S. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J Immunol. 1994 Aug 15;153(4):1687–1696.Verneris M. R., Ito M., Baker J., Arshi A., Negrin R. S., Shizuru J. A. Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma. Biol Blood Marrow Transplant. 2001; 7(10):532–542. http://doi.org/10.1016/S1083–8791(01)70014–6Verneris M. R., Ito M., Baker J., Arshi A., Negrin R. S., Shizuru J. A. Engineering hematopoietic grafts: purified allogeneic hematopoietic stem cells plus expanded CD8+ NK-T cells in the treatment of lymphoma. Biol Blood Marrow Transplant. 2001; 7(10):532–542. http://doi.org/10.1016/S1083–8791(01)70014–6Thanendrarajan S., Nowak M., Abken H., SchmidtWolf I. G. H. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: more than one plus one? Leuk Res. 2011 Sep;35(9):1136–1142. http://doi.org/10.1016/j.leukres.2011.05.005Thanendrarajan S., Nowak M., Abken H., SchmidtWolf I. G. H. Combining cytokine-induced killer cells with vaccination in cancer immunotherapy: more than one plus one? Leuk Res. 2011 Sep;35(9):1136–1142. http://doi.org/10.1016/j.leukres.2011.05.005Schmidt-Wolf I. G., Finke S., Trojaneck B., Denkena A., Lefterova P., Schwella N., et al. Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. Br J Cancer. 1999 Nov;81(6):1009–1016. http://doi.org/10.1038/sj.bjc.6690800Schmidt-Wolf I. G., Finke S., Trojaneck B., Denkena A., Lefterova P., Schwella N., et al. Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. Br J Cancer. 1999 Nov;81(6):1009–1016. http://doi.org/10.1038/sj.bjc.6690800Introna M., Borleri G., Conti E., Franceschetti M., Barbui A. M., Broady R., et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica. 2007 Jul;92(7):952–959. http://doi.org/10.3324/haematol.11132Introna M., Borleri G., Conti E., Franceschetti M., Barbui A. M., Broady R., et al. Repeated infusions of donor-derived cytokine-induced killer cells in patients relapsing after allogeneic stem cell transplantation: a phase I study. Haematologica. 2007 Jul;92(7):952–959. http://doi.org/10.3324/haematol.11132Laport G. G., Sheehan K., Baker J., Armstrong R., Wong R. M., Lowsky R., et al. Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011 Nov;17(11):1679–1687. http://doi.org/10.1016/j.bbmt.2011.05.012Laport G. G., Sheehan K., Baker J., Armstrong R., Wong R. M., Lowsky R., et al. Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011 Nov;17(11):1679–1687. http://doi.org/10.1016/j.bbmt.2011.05.012Jiang J.-T., Shen Y.-P., Wu C.-P., Zhu Y.-B., Wei W.-X., Chen L.-J., et al. Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients. World J Gastroenterol. 2010 Dec 28;16(48):6155– 6162. http://doi.org/10.3748/wjg.v16.i48.6155Jiang J.-T., Shen Y.-P., Wu C.-P., Zhu Y.-B., Wei W.-X., Chen L.-J., et al. Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients. World J Gastroenterol. 2010 Dec 28;16(48):6155– 6162. http://doi.org/10.3748/wjg.v16.i48.6155Jiang J., Wu C., Lu B. Cytokine-induced killer cells promote antitumor immunity. J Transl Med. 2013 Mar 28;11:83. http://doi.org/10.1186/1479–5876–11–83Jiang J., Wu C., Lu B. Cytokine-induced killer cells promote antitumor immunity. J Transl Med. 2013 Mar 28;11:83. http://doi.org/10.1186/1479–5876–11–83Liu L., Zhang W., Qi X., Li H., Yu J., Wei S., et al. Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res. 2012 Mar 15;18(6):1751–1759. http://doi.org/10.1158/1078–0432.CCR-11–2442Liu L., Zhang W., Qi X., Li H., Yu J., Wei S., et al. Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin Cancer Res. 2012 Mar 15;18(6):1751–1759. http://doi.org/10.1158/1078–0432.CCR-11–2442

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