nodgoРоссийский журнал детской гематологии и онкологии (РЖДГиО)Russian Journal of Pediatric Hematology and Oncology2311-12672413-5496LTD “Graphica”10.21682/2311-1267-2023-10-4-11-34-43nodgo-1000Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL STUDIESПилотное клиническое исследование ДНК-вакцинации против нейробластомы: дизайн исследования и промежуточные результатыPilot clinical trial of DNA vaccination against neuroblastoma: study design and preliminary resultshttps://orcid.org/0000-0002-1145-7263ПролесковскаяИ. В.ProleskovskayaI. V.

к.м.н., доцент, заместитель директора по клинической работе; главный внештатный детский онкогематолог Министерства здравоохранения Республики Беларусь

223053, Минская область, Минский район, Боровлянский с/с, д. Боровляны, ул. Фрунзенская, 43

Cand. of Sci. (Med.), Docent, Deputy Director of Clinical Work; Chief Supernumerary Pediatric Oncohematologist of the Ministry of Health of the Republic of Belarus

43 Frunzenskaya St., Borovlyany village, Minsk district, Minsk region, 223053

proleskai@mail.ruhttps://orcid.org/0000-0001-6964-3635МелешкоА. Н.MeleshkoA. N.

к.б.н., ведущий научный сотрудник лаборатории генетических биотехнологий 

223053, Минская область, Минский район, Боровлянский с/с, д. Боровляны, ул. Фрунзенская, 43

Cand. of Sci. (Biol.), Leading Researcher of the Laboratory of Genetic Biotechnologies

43 Frunzenskaya St., Borovlyany village, Minsk district, Minsk region, 223053

meleshko@tut.byhttps://orcid.org/0000-0002-5105-3757ВашкевичЕ. П.VashkevichE. P.

заведующий лабораторией иммунологических исследований

223053, Минская область, Минский район, Боровлянский с/с, д. Боровляны, ул. Фрунзенская, 43

Head of the Laboratory of Immunological Research

43 Frunzenskaya St., Borovlyany village, Minsk district, Minsk region, 223053

katsiaryna.vashkevich@gmail.comhttps://orcid.org/0000-0003-0592-7182КонопляН. Е.KonoplyaN. E.

д.м.н., профессор, главный научный сотрудник группы химиотерапии лаборатории фотодинамической терапии и гипертермии

223040, Минский район, аг. Лесной

Dr. of Sci. (Med.), Professor, Chief Researcher of the Chemotherapy Group of the Laboratory of Photodynamic Therapy and Hyperthermia

ag. Lesnoy, Minsk region, 223040

n.konoplya@mail.ruГУ «Республиканский научно-практический центр детской онкологии, гематологии и иммунологии» Министерства здравоохранения Республики БеларусьБеларусьRepublican Scientific and Practical Center for Pediatric Oncology, Hematology and Immunology, Ministry of Health of the Republic of BelarusBelarusГУ «Республиканский научно-практический центр онкологии и медицинской радиологии имени Н.Н. Александрова» Министерства здравоохранения Республики БеларусьБеларусьRepublican Scientific and Practical Center of Oncology and Medical Radiology named after N.N. Aleksandrov, Ministry of Health of the Republic of BelarusBelarus2023170120241043443Copyright © Пролесковская И.В., Мелешко А.Н., Вашкевич Е.П., Конопля Н.Е., 20242024Пролесковская И.В., Мелешко А.Н., Вашкевич Е.П., Конопля Н.Е.Proleskovskaya I.V., Meleshko A.N., Vashkevich E.P., Konoplya N.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nodgo.org/jour/article/view/1000Введение

Введение. Мы сообщаем промежуточные результаты пилотного клинического испытания терапевтической ДНК-вакцинации пациентов с нейробластомой (НБ) (NCT04049864).

Цель исследования – проверить безопасность и иммуногенность ДНК-вакцинации против НБ.

Материалы и методы

Материалы и методы. В статье приведены данные о 6 больных, закончивших вакцинацию. Определены критерии включения и исключения пациентов. Клинический протокол включает форму и дозы вакцины, временную схему вакцинации и сопроводительную терапию. Для всех пациентов проводился анализ минимальной остаточной болезни методом количественной полимеразной цепной реакции, измерение Т-клеточного иммунного ответа методом ELISpot и антительного ответа методом иммуноферментного анализа.

Результаты

Результаты. Вакцина хорошо переносилась пациентами с минимальными побочными симптомами. Т-клеточный иммунный ответ оценивался через 2 нед после каждого курса вакцинации и был положительным у 5 из 6 больных. Антительный иммунный ответ был выявлен у 1 пациента. Пять из 6 больных живы и находятся в клинической ремиссии на 01.11.2022. Бессобытийная выживаемость вакцинированных пациентов составила 82 ± 18 % против 29 ± 11 % в контрольной группе (p = 0,03).

Introduction

Introduction. We report preliminary results of a pilot clinical trial of therapeutic DNA vaccination of patients with neuroblastoma (NCT04049864).

The aim of the study – is to test the safety and immunogenicity of DNA vaccination against neuroblastoma.

Materials and methods

Materials and methods. The results of 6 patients who completed vaccination are summarized in the article. Inclusion and exclusion criteria for patients are defined. The clinical protocol included vaccine form and doses, timed vaccination regimen, and concomitant therapy. Minimal residual disease was analyzed for all patients by quantitative polymerase chain reaction, measurement of T-cell immune response by ELISpot and antisense response by ELISA.

Results

Results. The vaccine was well tolerated by patients with minimal adverse symptoms. T-cell immune response was evaluated two weeks after each course of vaccination and was positive in 5 of 6 patients. An antisense immune response was detected in 1 patient. 5 out of 6 patients are alive and in clinical remission as of 11/01/2022. Event-free survival of vaccinated patients was 82 ± 18 % vs 29 ± 11 % of controls (p = 0.03).

нейробластомаДНК-вакцинапротивоопухолевый иммунный ответneuroblastomaDNA vaccineantitumor immune responseReferencesJäger E., Jäger D., Knuth A. Antigen-specifi c immunotherapy and cancer vaccines. Int J Cancer 2003;106(6):817–20. doi: 10.1002/ijc.11292.Jäger E., Jäger D., Knuth A. Antigen-specifi c immunotherapy and cancer vaccines. Int J Cancer 2003;106(6):817–20. doi: 10.1002/ijc.11292.Stevenson F.K., Ottensmeier C.H., Rice J. DNA vaccines against cancer come of age. Curr Opin Immunol. 2010;22(2):264–70. doi: 10.1016/j.coi.2010.01.019.Stevenson F.K., Ottensmeier C.H., Rice J. DNA vaccines against cancer come of age. Curr Opin Immunol. 2010;22(2):264–70. doi: 10.1016/j.coi.2010.01.019.Rice J., Ottensmeier C.H., Stevenson F.K. DNA vaccines: precision tools for activating eff ective immunity against cancer. Nat Rev Cancer. 2008;8(2):108–20. doi: 10.1038/nrc2326.Rice J., Ottensmeier C.H., Stevenson F.K. DNA vaccines: precision tools for activating eff ective immunity against cancer. Nat Rev Cancer. 2008;8(2):108–20. doi: 10.1038/nrc2326.Larocca C., Schlom J. Viral Vector-Based Therapeutic Cancer Vaccines. Cancer J. 2011;17(5):359–71. doi: 10.1097/PPO.0b013e3182325e63.Larocca C., Schlom J. Viral Vector-Based Therapeutic Cancer Vaccines. Cancer J. 2011;17(5):359–71. doi: 10.1097/PPO.0b013e3182325e63.Timmerman J.M., Singh G., Hermanson G., Hobart P., Czerwinski D.K., Taidi B., Rajapaksa R., Caspar C.B., Van Beckhoven A., Levy R. Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma. Cancer Res. 2002;62(20):5845–52. PMID: 12384547.Timmerman J.M., Singh G., Hermanson G., Hobart P., Czerwinski D.K., Taidi B., Rajapaksa R., Caspar C.B., Van Beckhoven A., Levy R. Immunogenicity of a plasmid DNA vaccine encoding chimeric idiotype in patients with B-cell lymphoma. Cancer Res. 2002;62(20):5845–52. PMID: 12384547.van den Berg J.H., Nuijen B., Schumacher T.N., Haanen J.B.G., Storm G., Beijnen J.H., Hennink W.E. Synthetic vehicles for DNA vaccination. J Drug Target. 2010;18(1):1–14. doi: 10.3109/10611860903278023.van den Berg J.H., Nuijen B., Schumacher T.N., Haanen J.B.G., Storm G., Beijnen J.H., Hennink W.E. Synthetic vehicles for DNA vaccination. J Drug Target. 2010;18(1):1–14. doi: 10.3109/10611860903278023.Grant E.V., Thomas M., Fortune J., Klibanov A.M., Letvin N.L. Enhancement of plasmid DNA immunogenicity with linear polyethylenimine. Eur J Immunol. 2012;42(11):2937–48. doi: 10.1002/eji.201242410.Grant E.V., Thomas M., Fortune J., Klibanov A.M., Letvin N.L. Enhancement of plasmid DNA immunogenicity with linear polyethylenimine. Eur J Immunol. 2012;42(11):2937–48. doi: 10.1002/eji.201242410.Shen C., Li J., Zhang Y., Li Y., Shen G., Zhu J., Tao J. Polyethylenimine-based micro/nanoparticles as vaccine adjuvants. Int J Nanomedicine. 2017;12:5443–60. doi: 10.2147/IJN.S137980.Shen C., Li J., Zhang Y., Li Y., Shen G., Zhu J., Tao J. Polyethylenimine-based micro/nanoparticles as vaccine adjuvants. Int J Nanomedicine. 2017;12:5443–60. doi: 10.2147/IJN.S137980.Berger E., Soldati R., Huebener N., Hohn O., Stermann A., Durmus T., Lobitz S., Zenclussen A.C., Christiansen H., Lode H.N., Fest S. Salmonella SL7207 application is the most eff ective DNA vaccine delivery method for successful tumor eradication in a murine model for neuroblastoma. Cancer Lett. 2013;331(2):167–73. doi: 10.1016/j.canlet.2012.12.026.Berger E., Soldati R., Huebener N., Hohn O., Stermann A., Durmus T., Lobitz S., Zenclussen A.C., Christiansen H., Lode H.N., Fest S. Salmonella SL7207 application is the most eff ective DNA vaccine delivery method for successful tumor eradication in a murine model for neuroblastoma. Cancer Lett. 2013;331(2):167–73. doi: 10.1016/j.canlet.2012.12.026.Niethammer A.G., Lubenau H., Mikus G., Hohmann N., Leowardi C., Beckhove P., Akhisaroglu M., Ge Y., Springer M., Grenacher L., Buchler M.W., Koch M., Weitz J., Haefeli W.E., Schmitz-Winnenthal F.H. Double-blind, placebo-controlled fi rst in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer. BMC Cancer. 2012;12(1):361. doi: 10.1186/1471-2407-12-361.Niethammer A.G., Lubenau H., Mikus G., Hohmann N., Leowardi C., Beckhove P., Akhisaroglu M., Ge Y., Springer M., Grenacher L., Buchler M.W., Koch M., Weitz J., Haefeli W.E., Schmitz-Winnenthal F.H. Double-blind, placebo-controlled fi rst in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer. BMC Cancer. 2012;12(1):361. doi: 10.1186/1471-2407-12-361.Le D.T., Wang-Gillam A., Picozzi V., Greten T.F., Crocenzi T., Springett G., Morse M., Zeh H., Cohen D., Fine R.L., Onners B., Uram J.N., Laheru D.A., Lutz E.R., Solt S., Murphy A.L., Skoble J., Lemmens E., Grous J., Dubensky T., Brockstedt D.G., Jaff ee E.M. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325–33. doi: 10.1200/JCO.2014.57.4244.Le D.T., Wang-Gillam A., Picozzi V., Greten T.F., Crocenzi T., Springett G., Morse M., Zeh H., Cohen D., Fine R.L., Onners B., Uram J.N., Laheru D.A., Lutz E.R., Solt S., Murphy A.L., Skoble J., Lemmens E., Grous J., Dubensky T., Brockstedt D.G., Jaff ee E.M. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325–33. doi: 10.1200/JCO.2014.57.4244.Stegantseva M.V., Shinkevich V.A, Tumar E.M., Meleshko A.N. Conjugation of new DNA vaccine with polyethylenimine induces cellular immune response and tumor regression in neuroblastoma mouse model. Exp Oncol. 2020;42(2):120–5. doi: 10.32471/exp-oncology.2312-8852.vol-42-no-2.14473.Stegantseva M.V., Shinkevich V.A, Tumar E.M., Meleshko A.N. Conjugation of new DNA vaccine with polyethylenimine induces cellular immune response and tumor regression in neuroblastoma mouse model. Exp Oncol. 2020;42(2):120–5. doi: 10.32471/exp-oncology.2312-8852.vol-42-no-2.14473.Stegantseva M.V., Shinkevich V.A, Tumar E.M., Meleshko A.N. Multi-antigen DNA vaccine delivered by polyethylenimine and Salmonella enterica in neuroblastoma mouse model. Cancer Immunol Immunother. 2020;69(12):2613–22. doi: 10.1007/s00262-020-02652-2.Stegantseva M.V., Shinkevich V.A, Tumar E.M., Meleshko A.N. Multi-antigen DNA vaccine delivered by polyethylenimine and Salmonella enterica in neuroblastoma mouse model. Cancer Immunol Immunother. 2020;69(12):2613–22. doi: 10.1007/s00262-020-02652-2.Meleshko A., Piatrouskaya N., Vashkevich K., Lutskovich D., Wang C., Dormeshkin D., Savelyeva N., Katsin M.. Safety and Immunogenicity of Combined DNA-Polyethylenimine and Oral Bacterial Idiotypic Vaccine for Patients with B-Cell Non-Hodgkin Lymphoma: A Pilot Study. Cancers (Basel). 2022;14(14):3298. doi: 10.3390/cancers14143298.Meleshko A., Piatrouskaya N., Vashkevich K., Lutskovich D., Wang C., Dormeshkin D., Savelyeva N., Katsin M.. Safety and Immunogenicity of Combined DNA-Polyethylenimine and Oral Bacterial Idiotypic Vaccine for Patients with B-Cell Non-Hodgkin Lymphoma: A Pilot Study. Cancers (Basel). 2022;14(14):3298. doi: 10.3390/cancers14143298.Стёганцева М.В., Мелешко А.Н. Противораковая ДНК-вакцинация: принцип и возможности метода. Медицинская иммунология. 2017;19(2):145–56.Stegantseva M.V., Meleshko A.N. Anticancer DNA vaccination: principle and possibilities of the method. Medicinskaya immunologia = Medical Immunology. 2017;19(2):145–56. (In Russ.)].Kunath K., Von Harpe A., Fischer D., Petersen H., Bickel U., Voigt K., Kissel T. Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: Comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecularweight polyethylenimine. J Control Release. 2003;89(1):113–25. doi: 10.1016/S0168-3659(03)00076-2.Kunath K., Von Harpe A., Fischer D., Petersen H., Bickel U., Voigt K., Kissel T. Low-molecular-weight polyethylenimine as a non-viral vector for DNA delivery: Comparison of physicochemical properties, transfection efficiency and in vivo distribution with high-molecularweight polyethylenimine. J Control Release. 2003;89(1):113–25. doi: 10.1016/S0168-3659(03)00076-2.Ma Y.F., Yang Y.W. Delivery of DNA-based cancer vaccine with polyethylenimine. Eur J Pharm Sci. 2010;40(2):75–83. doi: 10.1016/j.ejps.2010.02.009.Ma Y.F., Yang Y.W. Delivery of DNA-based cancer vaccine with polyethylenimine. Eur J Pharm Sci. 2010;40(2):75–83. doi: 10.1016/j.ejps.2010.02.009.Oh Y.K., Kim J.P., Yoon H, Kim J.M., Yang J.S., Kim C.K. Prolonged organ retention and safety of plasmid DNA administered in polyethylenimine complexes. Gene Ther. 2001;8:1587–92. doi: 10.1038/sj.gt.3301516.Oh Y.K., Kim J.P., Yoon H, Kim J.M., Yang J.S., Kim C.K. Prolonged organ retention and safety of plasmid DNA administered in polyethylenimine complexes. Gene Ther. 2001;8:1587–92. doi: 10.1038/sj.gt.3301516.Chen Y., Liu X., Jin C.G., Zhou Y.C., Navab R., Jakobsen K.R., Chen X.Q., Li J., Li T.T., Luo L., Wang X.C. An orally administered DNA vaccine targeting vascular endothelial growth factor receptor-3 inhibits lung carcinoma growth. Tumour Biol. 2016;37(2):2395–404. doi: 10.1007/s13277-015-4061-3.Chen Y., Liu X., Jin C.G., Zhou Y.C., Navab R., Jakobsen K.R., Chen X.Q., Li J., Li T.T., Luo L., Wang X.C. An orally administered DNA vaccine targeting vascular endothelial growth factor receptor-3 inhibits lung carcinoma growth. Tumour Biol. 2016;37(2):2395–404. doi: 10.1007/s13277-015-4061-3.Zuo S.G., Chen Y., Wu Z.P, Liu X., Liu C., Zhou Y.C., Wu C.L., Jin C.G., Gu Y.L., Li J., Chen X.Q., Li Y., Wei H.P., Li L.H., Wang X.C. Orally administered DNA vaccine delivery by attenuated Salmonella typhimurium targeting fetal liver kinase 1 inhibits murine Lewis lung carcinoma growth and metastasis. Biol Pharm Bull. 2010;33(2):174–82. doi: 10.1248/bpb.33.174.Zuo S.G., Chen Y., Wu Z.P, Liu X., Liu C., Zhou Y.C., Wu C.L., Jin C.G., Gu Y.L., Li J., Chen X.Q., Li Y., Wei H.P., Li L.H., Wang X.C. Orally administered DNA vaccine delivery by attenuated Salmonella typhimurium targeting fetal liver kinase 1 inhibits murine Lewis lung carcinoma growth and metastasis. Biol Pharm Bull. 2010;33(2):174–82. doi: 10.1248/bpb.33.174.Schmitz-Winnenthal F.H., Hohmann N., Schmidt T., Podola L., Friedrich T., Lubenau H., Springer M., Wieckowski S., Breiner K.M., Mikus G., Büchler M.W., Keller A.V., Koc R., Springfeld C., Knebel P., Bucur M., Grenacher L., Haefeli W.E., Beckhove P. A phase 1 trial extension to assess immunologic effi cacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer. Oncoimmunology. 2018;7(4):e1303584. doi: 10.1080/2162402X.2017.1303584.Schmitz-Winnenthal F.H., Hohmann N., Schmidt T., Podola L., Friedrich T., Lubenau H., Springer M., Wieckowski S., Breiner K.M., Mikus G., Büchler M.W., Keller A.V., Koc R., Springfeld C., Knebel P., Bucur M., Grenacher L., Haefeli W.E., Beckhove P. A phase 1 trial extension to assess immunologic effi cacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGFR2, in patients with advanced pancreatic cancer. Oncoimmunology. 2018;7(4):e1303584. doi: 10.1080/2162402X.2017.1303584.Le D.T., Picozzi V.J., Ko A.H, Wainberg Z.A., Kindler H., WangGillam A., Oberstein P., Morse M.A., Zeh H.J., Weekes C., Reid T., Borazanci E., Crocenzi T., LoConte N.K., Musher B., Laheru D., Murphy A., Whiting C., Nair N., Enstrom A, Ferber S., Brockstedt D.G., Jaff ee E.M. Results from a phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). Clin Cancer Res. 2019;25(18):5493–502. doi: 10.1158/1078-0432.CCR-18-2992.Le D.T., Picozzi V.J., Ko A.H, Wainberg Z.A., Kindler H., WangGillam A., Oberstein P., Morse M.A., Zeh H.J., Weekes C., Reid T., Borazanci E., Crocenzi T., LoConte N.K., Musher B., Laheru D., Murphy A., Whiting C., Nair N., Enstrom A, Ferber S., Brockstedt D.G., Jaff ee E.M. Results from a phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). Clin Cancer Res. 2019;25(18):5493–502. doi: 10.1158/1078-0432.CCR-18-2992.

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