Введение

bloodjour

Гематология и трансфузиология

Russian journal of hematology and transfusiology

0234-57302411-3042

ООО Издательский дом «Практика»

10.35754/0234-5730-2021-66-3-322-345

bloodjour-295

Research Article

ПЕРЕДОВАЯ

EDITORIAL

Минорные антигены гистосовместимости как мишени Т-клеточной иммунотерапии

Minor histocompatibility antigens as targets for T-cell immunotherapy

https://orcid.org/0000-0001-5917-7554

Пилунов

А. М.

Pilunov

A. M.

Пилунов Артем Михайлович*, молекулярный иммунолог, лаборатория трансплантационной иммунологии

125167, Москва

Artem M. Pilunov*, Molecular Immunologist, Laboratory of Transplantation Immunology

125167, Moscow

Pilunov.a@blood.ru

https://orcid.org/0000-0002-9423-1269

Романюк

Д. С.

Romaniuk

D. S.

Романюк Дмитрий Сергеевич, научный сотрудник лабораториитрансплантационной иммунологии

125167, Москва

Dmitrii S. Romaniuk, Researcher, Laboratory of Transplantation Immunology

125167, Moscow

https://orcid.org/0000-0001-7129-6062

Ефимов

Г. А.

Efimov

G. A.

Ефимов Григорий Александрович, кандидат биологических наук, заведующий лабораторией трансплантационной иммунологии

125167, Москва

Grigory A. Efimov, Cand. Sci. (Biol.), Head of the Laboratory of Transplantation Immunology

125167, Moscow

gefimov@gmail.com

https://orcid.org/0000-0003-2935-4040

Савченко

В. Г.

Savchenko

V. G.

Савченко Валерий Григорьевич , доктор медицинских наук, профессор, академик РАН, генеральный директор

125167, Москва

Valery G. Savchenko , Dr. Sci. (Med), Full Member of the Russian Academy of Sciences, Director

125167, Moscow

svg@blood.ru

ФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian Federation

2021

22102021

663322345

2021

Пилунов А.М., Романюк Д.С., Ефимов Г.А., Савченко В.Г.

Pilunov A.M., Romaniuk D.S., Efimov G.A., Savchenko V.G.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.htjournal.ru/jour/article/view/295

Введение

Введение. Минорные антигены гистосовместимости (МАГ) — полиморфные пептиды, презентируемые в молекулахHLA, являются продуктами генов, содержащих несинонимичные однонуклеотидные полиморфизмы. При трансплантации аллогенных гемопоэтических стволовых клеток (алло-ТГСК) иммунный ответ, направленный на МАГ, можетприводить как к реакции «трансплантат против хозяина», так и к реакции «трансплантат против опухоли». Некоторые МАГ представляют собой перспективные и безопасные мишени для Т-клеточной иммунотерапии рецидивов лейкозов после алло-ТГСК.

Цель — анализ литературы, описывающей иммунный ответ на различные МАГ, а также клинические исследования, использующие МАГ как мишень иммунотерапии.

Основные сведения

Основные сведения. МАГ являются перспективными мишенями для профилактики или терапии рецидивов лейкозов после алло-ТГСК за счет того, что они обладают преимуществами по сравнению с другими классами мишеней:опухоль-ассоциированными антигенами и неоантигенами. Для того, чтобы быть пригодными для иммунотерапии, МАГ должен удовлетворять ряду параметров: 1) презентироваться распространенным аллелем HLA, 2) иметь оптимальное соотношение частот аллельных вариантов кодирующего полиморфизма, 3) кодироваться геном, преимущественно экспрессирующимся в кроветворной ткани. Это резко ограничивает число применимых мишеней и делает актуальным поиск новых МАГ.

Introduction

Introduction. Minor histocompatibility antigens (MiHAs) — polymorphic peptides presented in HLA molecules that are products of genes containing nonsynonymous single nucleotide polymorphisms. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the immune response directed to MiHA can result both in graft-versus-host and graft-versus-tumor responses.

Some MiHAs are promising and safe targets for T-cell immunotherapy of leukemia relapse after allo-HSCT.

Aim — to analyze the literature describing the immune response to various MiHAs, as well as clinical trials using MiHAs as targets of immunotherapy.

Main findings

Main findings. MiHAs represent promising targets for the prevention or therapy of leukemia relapse after allo-HSCT due to their advantages over tumor-associated antigens and neoantigens. To be suitable for immunotherapy, MiHA must satisfy several parameters: 1) be presented by a common HLA allele, 2) have an optimal frequency of polymorphism-encoding allele, 3) be encoded by a gene that is predominantly expressed in hematopoietic tissue. This drastically limits the number of applicable targets and makes the discovery of new MiHAs highly relevant.

иммунотерапияминорные антигены гистосовместимостиадоптивный перенострансплантация аллогенных гемопоэтических стволовых клетокреакция трансплантат против хозяинареакция трансплантат против лейкоза

immunotherapyhematopoietic minor histocompatibility antigensadoptive transferallogeneic hemopoietic stem cell transplantationgraft-versushost reactiongraft-versus-leukemia reaction

References1

Савченко В.Г., Любимова Л.С., Паровичникова Е.Н., и др. Трансплантации аллогенных и аутологичных гемопоэтических стволовых клеток при острых лейкозах (итоги 20-летнего опыта). Терапевтический архив. 2007; 79(7):30–5.

Savchenko V.G., Lyubimova L.S., Parovichnikova E.N., et al. Transplantations of allogenic and autologous hemopoietic stem cells in acute leukemia (results of 20-year experience). Terapevticheskiy arkhiv. 2007; 79(7): 30–5. (in Russian).

Giebel S., Labopin M., Potter M., et al. Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphiapositive acute lymphoblastic leukaemia in fi rst complete molecular remission: An analysis by the Acute Leukemia Working Party of the EBMT. Eur J Cancer. 2018; 96: 73–81. DOI: 10.1016/j.ejca.2018.03.018.

Schmid C., de Wreede L.C., van Biezen A., et al. Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: A retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society of Blood and Marrow Transplantation. Haematologica. 2018; 103(2): 237–45. DOI: 10.3324/haematol.2017.168716.

Rautenberg C., Germing U., Haas R., et al. Relapse of acute myeloid leukemia after allogeneic stem cell transplantation: Prevention, detection, and treatment. Int J Mol Sci. 2019; 20(1): 228. DOI: 10.3390/ijms20010228.

Schmid C., Labopin M., Nagler A., et al. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood. 2012; 119(6): 1599–606. DOI: 10.1182/blood-2011-08-375840.

McDonald G.B., Sandmaier B.M., Mielcarek M., et al. Survival, nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: Comparing 2003–2007 versus 2013–2017 cohorts. Ann Intern Med. 2020; 172(4): 229–39. DOI: 10.7326/m19-2936.

Kröger N. Hematopoietic stem cell transplantation and cellular therapies. In: Carreras E., Dufour C., Mohty M., Kröger N. (eds) The EBMT Handbook. Springer, Cham. https://doi.org/10.1007/978-3-030-02278-5_58.

Kirtonia A., Pandya G., Sethi G., et al. A comprehensive review of genetic alterations and molecular targeted therapies for the implementation of personalized medicine in acute myeloid leukemia. J Mol Med (Berl). 2020; 98(8): 1069–91.DOI: 10.1007/s00109-020-01944-5.

Савченко В.Г., Менделеева Л.П., Паровичникова Е.Н., и др. Способ лечения рецидива острого миелоидного лейкоза после трансплантации аллогенных гемопоэтических стволовых клеток. Патент № RU 2538799 C1, 2019.

Savchenko V.G., Mendeleeva L.P., Parovichnikova E.N., et al. Method of treating recurrent acute myeloid leukaemia following transplantation of allogenic haemopoietic stem cells. Patent № RU 2538799 C1, 2019. (in Russian).

Butturini A., Bortin M.M., Gale R.P. Graft-versus-leukemia following bone marrow transplantation. Bone Marrow Transpl. 1987; 2(3): 233–42.

Weiden P.L., Flournoy N., Thomas E.D., et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979; 300(19): 1068–73. DOI: 10.1056/nejm197905103001902.

Jones R., Ambinder R., Piantadosi S., Santos G. Evidence of a graft-versuslymphoma effect associated with allogeneic bone marrow transplantation. Blood. 1991; 77(3): 649–53. DOI: 10.1182/blood.V77.3.649.649.

Thomas E.D. A history of haemopoietic cell transplantation. Br J Haematol. 1999; 105(2): 330–9. DOI: 10.1111/j.1365-2141.1999.01337.x.

Slavin R.E., Woodruff J.M. The pathology of bone marrow transplantation. Pathol Annu. 1974; 9(0): 291–344.

Ефимов Г.А., Вдовин А.С., Григорьев А.А. и др. Иммунобиология острой реакции «трансплантат против хозяина». Медицинская иммунология. 2015; 17(6): 499–516. DOI: 10.15789/1563-0625-2015-6-499-516.

Efimov G.A., Vdovin A.S., Grigoryev A.A., et al. Immunobiology of acute graft-versus-host disease. Meditsinskaya Immunologiya. 2015; 17(6): 499–516. DOI: 10.15789/1563-0625-2015-6-499-516. (in Russian).

Lakkis F.G., Lechler R.I. Origin and biology of the allogeneic response. Cold Spring Harb Perspect Med. 2013; 3(8): a014993. DOI: 10.1101/cshperspect.a014993.

D’Orsogna L., Nguyen T., Claas F., et al. Endogenous peptide dependent alloreactivity: New scientifi c insights and clinical implications. Tissue Antigens. 2013; 81(6): 399–407. DOI: 10.1111/tan.12115.

Korngold R., Sprent J. Features of T cells causing H-2-restricted lethal graftvs.-host disease across minor histocompatibility barriers. J Exp Medicine. 1982; 155(3): 872–83. DOI: 10.1084/jem.155.3.872.

Korngold R, Sprent J. Lethal GVHD across minor histocompatibility barriers: Nature of the effector cells and role of the H 2 complex. Immunol Rev. 1983; 71:5–30. DOI: 10.1111/j.1600-065x.1983.tb01066.x.

Goulmy E., Schipper R., Pool J., et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med. 1996; 334(5): 281–5. DOI: 10.1056/NEJM199602013340501.

Bleakley M., Otterud B.E., Richardt J.L., et al. Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells. Blood. 2010; 115(23): 4923–33. DOI: 10.1182/blood-2009-12-260539.

Weiden P.L., Sullivan K.M., Flournoy N., et al. Antileukemic effect of chronic graft-versus-host disease — contribution to improved survival after allogeneic marrow transplantation. N Engl J Med. 1981; 304(25): 1529–33. DOI: 10.1056/nejm198106183042507.

Horowitz M.M., Gale R.P., Sondel P.M., et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990; 75(3): 555–62. DOI: 10.1182/blood.V75.3.555.555.

Inamoto Y., Flowers M.E.D., Lee S.J., et al. Infl uence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation. Blood. 2011; 118(2): 456–63. DOI: 10.1182/blood-2011-01-330217.

Kersey J.H., Weisdorf D., Nesbit M.E., et al. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987; 317(8): 461–7. DOI: 10.1056/nejm198708203170801.

Gratwohl A., Sureda A., Cornelissen J., et al. Alloreactivity: The Janus-face of hematopoietic stem cell transplantation. Leukemia. 2017; 31(8): 1752–9. DOI: 10.1038/leu.2017.79.

Falkenburg J.H.F., Marijt W.A.F., Heemskerk M.H.M., Willemze R. Minor histocompatibility antigens as targets of graft-versus-leukemia reactions. Curr Opin Hematol. 2002; 9(6): 497–502. DOI: 10.1097/00062752-200211000-00005.

Bevan M.J. The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens. J Exp Medicine. 1975; 142(6): 1349–64. DOI: 10.1084/jem.142.6.1349.

Korngold R., Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J Exp Medicine. 1978; 148(6): 1687–98. DOI: 10.1084/jem.148.6.1687.

Hamilton B.L., Bevan M.J., Parkman R. Anti-recipient cytotoxic T lymphocyte precursors are present in the spleens of mice with acute graft versus host disease due to minor histocompatibility a e foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987; 329(6139): 512–8. DOI: 10.1038/329512a0.

Wallny H-J., Rammensee H-G. Identifi cation of classical minor histocompatibility antigen as cell-derived peptide. Nature. 1990; 343(6255): 275–8. DOI: 10.1038/343275a0.

Goulmy E. Human minor histocompatibility antigens: New concepts for marrow transplantation and adoptive immunotherapy. Immunol Rev. 1997; 157: 125–40. DOI: 10.1111/j.1600-065x.1997.tb00978.x.

Kernan N.A., Bartsch G., Ash R.C., et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. New Engl J Med. 1993; 328(9): 593–602. DOI: 10.1056/nejm199303043280901.

Kernan N., Dupont B. Minor histocompatibility antigens and marrow transplantation. N Engl J Med. 1996; 334(5): 323–4. DOI: 10.1056/NEJM199602013340510.

den Haan J., Meadows L., Wang W., et al. The minor histocompatibility antigen HA-1: A diallelic gene with a single amino acid polymorphism. Science. 1998; 279(5353): 1054–7. DOI: 10.1126/science.279.5353.1054.

von Boehmer H., Hafen K. Minor but not major histocompatibility antigens of thymus epithelium tolerize precursors of cytolytic T cells. Nature. 1986; 320(6063): 626–8. DOI: 10.1038/320626a0.

Vincent K., Roy D-C., Perreault C. Next-generation leukemia immunotherapy. Blood. 2011; 118(11): 2951–9. DOI: 10.1182/blood-2011-04-350868.

Goulmy E., Gratama J.W., Blokland E., et al. A minor transplantation antigen detected by MHC-restricted cytotoxic T lymphocytes during graft-versus-host disease. Nature. 1983; 302(5904): 159–61. DOI: 10.1038/302159a0.

Rötzschke O., Falk K., Wallny H., et al. Characterization of naturally occurring minor histocompatibility peptides including H-4 and H-Y. Science. 1990; 249(4966): 283–7. DOI: 10.1126/science.1695760.

van Els C., D’Amaro J., Pool J., et al. Immunogenetics of human minor histocompatibility antigens: Their polymorphism and immunodominance. Immunogenetics. 1992; 35(3): 161–5. DOI: 10.1007/BF00185109.

Rufer N., Wolpert E., Helg C., et al. HA-1 and the SMCY-derived peptide FIDSYICQV (H-Y) are immunodominant minor histocompatibility antigens after bone marrow transplantation. Transplantation. 1998; 66(7): 910–6. DOI: 10.1097/00007890-199810150-00016.

Korngold R., Leighton C., Mobraaten L.E., Berger M.A. Inter-strain graft-vs.-host disease T-cell responses to immunodominant minor histocompatibility antigens. Biol Blood Marrow Transplant. 1997; 3(2): 57–64.

Pion S., Fontaine P., Baron C., et al. Immunodominant minor histocompatibility antigens expressed by mouse leukemic cells can serve as effective targets for T cell immunotherapy. J Clin Invest. 1995; 95(4): 1561–8. DOI: 10.1172/jci117829.

Yewdell J.W., Bennink J.R. Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Ann Rev Immunol. 1999; 17: 51–88. DOI: 10.1146/annurev.immunol.17.1.51.

Wettstein P.J. Immunodominance in the T-cell response to multiple non-H-2 histocompatibility antigens. II. Observation of a hierarchy among dominant antigens. Immunogenetics. 1986; 24(1): 24–31. DOI: 10.1007/bf00372294.

Chen W., Khilko S., Fecondo J., et al. Deteromplex class I-restricted antigenic peptides is explained by class Ipeptide affi nity and is strongly infl uenced by nondominant anchor residues. J Exp Medicine. 1994; 180(4): 1471–83. DOI: 10.1084/jminant selection of major histocompatibility cem.180.4.1471.

Pion S., Fontaine P., Desaulniers M., et al. On the mechanisms of immunodominance in cytotoxic T lymphocyte responses to minor histocompatibility antigens. Eur J Immunol. 1997; 27(2): 421–30. DOI: 10.1002/eji.1830270212.

Mori S., El-Baki H., Mullen C. Analysis of immunodominance among minor histocompatibility antigens in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2003; 31(10): 865–75. DOI: 10.1038/sj.bmt.1704021.

Hobo W., Broen K., van der Velden W., et al. Association of disparities in known minor histocompatibility antigens with relapse-free survival and graftversus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013; 19(2): 274–82. DOI: 10.1016/j.bbmt.2012.09.008.

Korngold R., Wettstein P.J. Immunodominance in the graft-vs-host disease T cell response to minor histocompatibility antigens. J Immunol. 1990; 145(12): 4079–88.

Goulmy E., Termijtelen A., Bradley B.A., Rood J.J.V. Y-antigen killing by T cells of women is restricted by HLA. Nature. 1977; 266(5602): 544–5. DOI: 10.1038/266544a0.

Antón L.C., Yewdell J.W. Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors. J Leukoc Biol. 2014; 95(4): 551–62. DOI: 10.1189/jlb.1113599.

Apcher S., Millot G., Daskalogianni C., et al. Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway. Proc Natl Acad Sci U S A. 2013; 110(44): 17951–6. DOI: 10.1073/pnas.1309956110.

Granados D., Yahyaoui W., Laumont C.M., et al. MHC I-associated peptides preferentially derive from transcripts bearing miRNA response elements. Blood. 2012; 119(26): e181–91. DOI: 10.1182/blood-2012-02-412593.

Laumont C.M., Daouda T., Laverdure J-P., et al. Global proteogenomic analysis of human MHC class I-associated peptides derived from non-canonical reading frames. Nat Commun. 2016; 7: 10238. DOI: 10.1038/ncomms10238.

Hanna J., Guerra-Moreno A., Ang J., Micoogullari Y. Protein degradation and the pathologic basis of disease. Am J Pathology. 2018; 189(1): 94–103. DOI: 10.1016/j.ajpath.2018.09.004.

Kisselev A.F., Akopian T.N., Woo K.M., Goldberg A.L. The sizes of peptides generated from protein by mammalian 26 and 20 S proteasomes implications for understanding the degradative mechanism and antigen presentation. J Biol Chem. 1999; 274(6): 3363–71. DOI: 10.1074/jbc.274.6.3363.

Pearson H., Daouda T., Granados D., et al. MHC class I-associated peptides derive from selective regions of the human genome. J Clin Invest. 2016; 126(12): 4690–701. DOI: 10.1172/JCI88590.

Abele R., Tampé R. Function of the transport complex TAP in cellular immune recognition. Biochim Biophys Acta. 1999; 1461(2): 405–19. DOI: 10.1016/s0005-2736(99)00171-6.

Rock K.L., Goldberg A.L. Degradation of cell proteins and the generation of MHC class I-presented peptides. Annu Rev Immunol. 1999; 17: 739–79. DOI: 10.1146/annurev.immunol.17.1.739.

Bykova N.A., Malko D.B., Efi mov G.A. In silico analysis of the minor histocompatibility antigen landscape based on the 1000 Genomes Project. Front Immunol. 2018; 9: 1819. DOI: 10.3389/fi mmu.2018.01819.

Spierings E., Brickner A.G., Caldwell J.A., et al. The minor histocompatibility antigen HA-3 arises from differential proteasome-mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein. Blood. 2003; 102(2): 621–9. DOI: 10.1182/blood-2003-01-0260.

Brickner A.G., Warren E.H., Caldwell J.A., et al. The immunogenicity of a new human minor histocompatibility antigen results from differential antigen processing. J Exp Med. 2001; 193(2): 195–206. DOI: 10.1084/jem.193.2.195.

Spierings E., Gras S., Reiser J-B., et al. Steric hindrance and fast dissociation explain the lack of immunogenicity of the minor histocompatibility HA-1Arg Null allele. J Immunol. 2009; 182(8): 4809–16. DOI: 10.4049/jimmunol.0803911.

de Rijke B., van Horssen-Zoetbrood A., Beekman J.M., et al. A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia. J Clin Invest. 2005; 115(12): 3506–16. DOI: 10.1172/JCI24832.

Brickner A.G., Evans A.M., Mito J.K., et al. The PANE1 gene encodes a novel human minor histocompatibility antigen that is selectively expressed in B-lymphoid cells and B-CLL. Blood. 2006; 107(9): 3779–86. DOI: 10.1182/blood-2005-08-3501.

Broen K., Levenga H., Vos J., et al. A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR. PLoS ONE. 2011; 6(6): e21699. DOI: 10.1371/journal.pone.0021699.

Kawase T., Akatsuka Y., Torikai H., et al. Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. Blood. 2007; 110(3): 1055–63. DOI: 10.1182/blood-2007-02-075911.

Terakura S., Murata M., Warren E.H., et al. A single minor histocompatibility antigen encoded by UGT2B17 and presented by human leukocyte antigenA*2902 and -B*4403. Transplantation. 2007; 83(9): 1242–8. DOI: 10.1097/01.tp.0000259931.72622.d1.

Griffi oen M., van Bergen C.A., Falkenburg J. Autosomal minor histocompatibility antigens: How genetic variants create diversity in immune targets. Front Immunol. 2016; 7: 100. DOI: 10.3389/fi mmu.2016.00100.

Meadows L., Wang W., den Haan J., et al. The HLA-A*0201-restricted H-Y antigen contains a posttranslationally modifi ed cysteine that signifi cantly affects T cell recognition. Immunity. 1997; 6(3): 273–81. DOI: 10.1016/s1074-7613(00)80330-1.

Granados D.P., Sriranganadane D., Daouda T., et al. Impact of genomic polymorphisms on the repertoire of human MHC class I-associated peptides. Nat Commun. 2014; 5: 3600. DOI: 10.1038/ncomms4600.

Bijen H.M., Hassan C., Kester M.G.D.G., et al. Specifi c T cell responses against minor histocompatibility antigens cannot generally be explained by absence of their allelic counterparts on the cell surface. Proteomics. 2017; 18(12): e1700250. DOI: 10.1002/pmic.201700250.

van Balen P., van Bergen C., van Luxemburg-Heijs S., et al. CD4 donor lymphocyte infusion can cause conversion of chimerism without GVHD by inducing immune responses targeting minor histocompatibility antigens in HLA class II. Front Immunol. 2018; 9: 3016. DOI: 10.3389/fi mmu.2018.03016.

Christopher M.J., Petti A.A., Rettig M.P., et al. Immune escape of relapsed AML cells after allogeneic transplantation. New Engl J Med. 2018; 379(24): 2330–41. DOI: 10.1056/nejmoa1808777.

Toffalori C., Zito L., Gambacorta V., et al. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat Med. 2019; 25(4): 603–11. DOI: 10.1038/s41591-019-0400-z.

Brooks A.G., Boyington J.C., Sun P.D. Natural killer cell recognition of HLA class I molecules. Rev Immunogenet. 2000; 2(3): 433–48.

Fuchs K.J., Honders W.M., van der Meijden E.D., et al. Optimized whole genome association scanning for discovery of HLA class I-restricted minor histocompatibility antigens. Front Immunol. 2020; 11: 659. DOI: 10.3389/fi mmu.2020.00659.

Martin P.J., Levine D.M., Storer B.E., et al. Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood. 2017; 129(6): 791–798. DOI: 10.1182/blood-2016-09-737700.

Roy D.C., Perreault C. Major vs minor histocompatibility antigens. Blood. 2017; 129(6): 664–6. DOI: 10.1182/blood-2016-12-754515.

Hombrink P., Hadrup S.R., Bakker A., et al. High-throughput identifi cation of potential minor histocompatibility antigens by MHC tetramer-based screening: Feasibility and limitations. PLoS ONE. 2011; 6(8): e22523. DOI: 10.1371/journal.pone.0022523.

Oostvogels R., Lokhorst H., Mutis T. Minor histocompatibility Ags: Identifi cation strategies, clinical results and translational perspectives. Bone Marrow Transplant. 2015; 51(2): 163–71. DOI: 10.1038/bmt.2015.256.

Bleakley M., Riddell S.R. Exploiting T cells specifi c for human minor histocompatibility antigens for therapy of leukemia. Immunol Cell Biol. 2011; 89(3): 396–407. DOI: 10.1038/icb.2010.124.

van Bergen C.A., van Luxemburg-Heijs S.A., de Wreede L.C., et al. Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response. J Clin Invest. 2017; 127(2): 517–29. DOI: 10.1172/JCI86175.

Granados D., Rodenbrock A., Laverdure J-P., et al. Proteogenomic-based discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers. Leukemia. 2016; 30(6): 1344–54. DOI: 10.1038/leu.2016.22.

Summers C., Sheth V.S., Bleakley M. Minor histocompatibility antigen-specifi c T cells. Front Pediatr. 2020; 8: 284. DOI: 10.3389/fped.2020.00284.

Romaniuk D.S., Postovskaya A.M., Khmelevskaya A.A., et al. Rapid multiplex genotyping of 20 HLA-A*02:01 restricted minor histocompatibility antigens. Front Immunol. 2019; 10: 1226. DOI: 10.3389/fi mmu.2019.01226.

Chalmers Z.R., Connelly C.F., Fabrizio D., et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017; 9(1): 34. DOI: 10.1186/s13073-017-0424-2.

MacKay M., Afshinnekoo E., Rub J., et al. The therapeutic landscape for cells engineered with chimeric antigen receptors. Nat Biotechnol. 2020; 38(2): 233–44. DOI: 10.1038/s41587-019-0329-2.

Wudhikarn K., Palomba M.L., Pennisi M., et al. Infection during the fi rst year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma. Blood Cancer J. 2020; 10(8): 79. DOI: 10.1038/s41408-020-00346-7

Mardiana S., Gill S. CAR T cells for acute myeloid leukemia: State of the art and future directions. Front Oncol. 2020; 10: 697. DOI: 10.3389/fonc.2020.00697.

Vago L., Perna S., Zanussi M., et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009; 361(5): 478–88. DOI: 10.1056/NEJMoa0811036.

Wilke M., Dolstra H., Maas F., et al. Quantifi cation of the HA-1 gene product at the RNA level; relevance for immunotherapy of hematological malignancies. Hematol J. 2003; 4(5): 315–20. DOI: 10.1038/sj.thj.6200318.

Nicholls S., Piper K.P., Mohammed F., et al. Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition. Proc Natl Acad Sci U S A. 2009; 106(10): 3889–94. DOI: 10.1073/pnas.0900411106.

Fujii N., Hiraki A., Ikeda K., et al. Expression of minor histocompatibility antigen, HA-1, in solid tumor cells. Transplantation. 2002; 73(7): 1137–41. DOI: 10.1097/00007890-200204150-00022.

de Bueger M., Bakker A., Rood V.J., et al. Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defi ned non-MHC antigens. J Immunol. 1992; 149(5): 1788–94.

Dickinson A.M., Wang X-N., Sviland L., et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specifi c for minor histocompatibility antigens. Nat Med. 2002; 8(4): 410–14. DOI: 10.1038/nm0402-410.

Mutis T., Gillespie G., Schrama E., et al. Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specifi c cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat Med. 1999; 5(7): 839–42. DOI: 10.1038/10563.

Marijt E.W., Heemskerk M.H., Kloosterboer F.M., et al. Hematopoiesisrestricted minor histocompatibility antigens HA-1- or HA-2-specifi c T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci U S A. 2003; 100(5): 2742–7. DOI: 10.1073/pnas.0530192100.

100

Tseng L-H., Lin M-T., Hansen J.A., et al. Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graftversus-host disease after allogeneic marrow transplantation. Blood. 1999; 94(8): 2911–4. DOI: 10.1182/blood.v94.8.2911.420k21_2911_2914.

101

Socié G., Loiseau P., Tamouza R., et al. Both genetic and clinical factors predict the development of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplantation. 2001; 72(4): 699–706. DOI: 10.1097/00007890-200108270-00024.

102

Gallardo D., Aróstegui J., Balas A., et al. Disparity for the minor histocompatibility antigen HA 1 is associated with an increased risk of acute graft versus host disease (GvHD) but it does not affect chronic GvHD incidence, disease‐free survival or overall survival after allogeneic human leucocyte antigen identical sibling donor transplantation. Br J Haematol. 2001; 114(4): 931–6. DOI: 10.1046/j.1365-2141.2001.03013.x.

103

Murata M., Emi N., Hirabayashi N., et al. No signifi cant association between HA-1 incompatibility and incidence of acute graft-versus-host disease after HLA-identical sibling bone marrow transplantation in Japanese patients. Int J Hematol. 2000; 72: 371–5.

104

Heinemann F.M., Ferencik S., Ottinger H.D., et al. Impact of disparity of minor histocompatibility antigens HA-1, CD31, and CD49b in hematopoietic stem cell transplantation of patients with chronic myeloid leukemia with sibling and unrelated donors. Transplantation. 2004; 77(7): 1103–6. DOI: 10.1097/01.tp.0000120175.25116.cb.

105

Lin M., Gooley T., Hansen J., et al. Absence of statistically signifi cant correlation between disparity for the minor histocompatibility antigen-HA-1 and outcome after allogeneic hematopoietic cell transplantation. Blood. 2001; 98(10): 3172–3. DOI: 10.1182/blood.v98.10.3172.

106

Spellman S., Warden M.B., Haagenson M., et al. Effects of mismatching for minor histocompatibility antigens on clinical outcomes in HLA-matched, unrelated hematopoietic stem cell transplants. Biol Blood Marrow Transplant. 2009; 15(7): 856–63. DOI: 10.1016/j.bbmt.2009.03.018.

107

Teshima T., Ordemann R., Reddy P., et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med. 2002; 8(6):575–81. DOI: 10.1038/nm0602-575.

108

Matte-Martone C., Liu J., Jain D., et al. CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL. Blood. 2008; 111(7): 3884–92. DOI: 10.1182/blood-2007-11-125294.

109

Miller J.S., Warren E.H., van den Brink M.R.M., et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on the Biology Underlying Recurrence of Malignant Disease following Allogeneic HSCT:Graft-versus-Tumor/Leukemia Reaction. Biol Blood Marrow Transplant. 2010; 16(5): 565–86. DOI: 10.1016/j.bbmt.2010.02.005.

110

Barge R.M.Y., Osanto S., Marijt W.A.F.E., et al. Minimal GVHD following in-vitro T cell-depleted allogeneic stem cell transplantation with reduced-intensity conditioning allowing subsequent infusions of donor lymphocytes in patients with hematological malignancies and solid tumors. Exp Hematol. 2003; 31(10):865–72. DOI: 10.1016/s0301-472x(03)00200-5.

111

Kolb H.-J. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008; 112(12): 4371–83. DOI: 10.1182/blood-2008-03-077974.

112

Epstein F.H., Ferrara J.L.M., Deeg H.J. Graft-versus-host disease. N Engl J Med. 1991; 324(10): 667–74. DOI: 10.1056/nejm199103073241005.

113

Haan D.J., Sherman N.E., Blokland E., et al. Identifi cation of a graft versus host disease-associated human minor histocompatibility antigen. Science. 1995; 268(5216): 1476–80. DOI: 10.1126/science.7539551.

114

Pierce R.A., Field E.D., Mutis T., et al. The HA-2 minor histocompatibility antigen is derived from a diallelic gene encoding a novel human class I myosin protein. J Immunol. 2001; 167(6): 3223–30. DOI: 10.4049/jimmunol.167.6.3223.

115

Spierings E., Kim Y.-H.H., Hendriks M., et al. Multicenter analyses demonstrate signifi cant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013; 19(8): 1244–53. DOI: 10.1016/j.bbmt.2013.06.001.

116

Heemskerk M.H., Hoogeboom M., de Paus R.A., et al. Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specifi c T-cell receptor complexes expressing a conserved alpha joining region. Blood. 2003; 102(10): 3530–40. DOI: 10.1182/blood-2003-05-1524.

117

Heemskerk M.H., Hoogeboom M., Hagedoorn R., et al. Reprogramming of virus-specifi c T cells into leukemia-reactive T cells using T cell receptor gene transfer. J Exp Med. 2004; 199(7): 885–94. DOI: 10.1084/jem.20031110.

118

Bijen H.M., van der Steen D.M., Hagedoorn R.S., et al. Preclinical strategies to identify off-target toxicity of high-affi nity TCRs. Molecul Ther. 2018; 26(5):1206–14. DOI: 10.1016/j.ymthe.2018.02.017.

119

Lio H-Y., Tang J-L., Wu J., et al. Minor histocompatibility antigen HA-1 and HA-2 polymorphisms in Taiwan: Frequency and application in hematopoietic stem cell transplantation. Clin Chem Lab Med. 2010; 48(9): 1287–93. DOI: 10.1515/CCLM.2010.246.

120

Sellami M.H., Ahmed B.A., Kaabi H., et al. HA‐1 and HA‐2 minor histocompatibility antigens in Tunisians. Tissue Antigens. 2010; 75(6): 720–3.DOI: 10.1111/j.1399-0039.2010.01444.x.

121

Akatsuka Y., Nishida T., Kondo E., et al. Identifi cation of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specifi c minor histocompatibility antigens. J Exp Med. 2003; 197(11): 1489–1500. DOI: 10.1084/jem.20021925.

122

Nagy B., Lundán T., Larramendy M.L., et al. Abnormal expression of apoptosis related genes in haematological malignancies: Overexpression of MYC is poor prognostic sign in mantle cell lymphoma. Br J Haematol. 2003; 120(3): 434–41. DOI: 10.1046/j.1365-2141.2003.04121.x.

123

Sochalska M., Schuler F., Weiss J.G., et al. MYC selects against reduced BCL2A1/A1 protein expression during B cell lymphomagenesis. Oncogene. 2017; 36(15): 2066–73. DOI: 10.1038/onc.2016.362.

124

Пилунов А.М., Кучмий А.А., Шитиков С.А., и др. Модификация цитотоксических лимфоцитов рецептором, специфичным к минорному антигену гистосовместимости ACC1-Y. Молекулярная биология. 2019; 53(3): 456–66. DOI: 10.1134/S0026898419030145.

Pilunov A., Kuchmiy A., Sheetikov S., et al. Modifi cation of cytotoxic lymphocytes with T cell receptor specifi c for minor histocompatibility antigen ACC-1Y. Molecularnaya Biologiya. 2019; 53(3): 456–66. DOI: 10.1134/S0026898419030145. (in Russian).

125

Spierings E., Drabbels J., Hendriks M., et al. A uniform genomic minor histocompatibility antigen typing methodology and database designed to facilitate clinical applications. PLoS ONE. 2006; 1(1): e42. DOI: 10.1371/journal.pone.0000042.

126

Torikai H., Akatsuka Y., Yatabe Y., et al. Aberrant expression of BCL2A1-restricted minor histocompatibility antigens in melanoma cells: Application for allogeneic transplantation. Int J Hematol. 2008; 87(5): 467–73. DOI: 10.1007/s12185-008-0076-5.

127

Kloosterboer F.M., van Luxemburg-Heijs S.A.P., van Soest R.A., et al. Upregulated expression in nonhematopoietic tissues of the BCL2A1-derived minor histocompatibility antigens in response to infl ammatory cytokines: Relevance for allogeneic immunotherapy of leukemia. Blood. 2005; 106(12): 3955–7. DOI: 10.1182/blood-2004-09-3749.

128

Nishida T., Akatsuka Y., Morishima Y., et al. Clinical relevance of a newly identifi ed HLA A24 restricted minor histocompatibility antigen epitope derived from BCL2A1, ACC 1, in patients receiving HLA genotypically matched unrelated bone marrow transplant. Brit J Haematol. 2004; 124(5): 629–35. DOI: 10.1111/j.1365-2141.2004.04823.x.

129

Akatsuka Y., Torikai H., Inamoto Y., et al. Bone marrow may be a reservoir of long lived memory T cells specifi c for minor histocompatibility antigen. Br J Haematol. 2006; 135(3): 413–4. DOI: 10.1111/j.1365-2141.2006.06313.x.

130

Roback J.D. Vaccine-enhanced donor lymphocyte infusion (veDLI). Hematology Am Soc Hematol Educ Program. 2006; 2006(1): 486–91. DOI: 10.1182/asheducation-2006.1.486.

131

Fontaine P., Roy-Proulx G., Knafo L., et al. Adoptive transfer of minor histocompatibility antigen-specifi c T lymphocytes eradicates leukemia cells without causing graft-versus-host disease. Nat Med. 2001; 7(7): 789–94. DOI: 10.1038/89907.

132

Kloosterboer F., van Luxemburg-Heijs S., van Soest R., et al. Direct cloning of leukemia-reactive T cells from patients treated with donor lymphocyte infusion shows a relative dominance of hematopoiesis-restricted minor histocompatibility antigen HA-1 and HA-2 specifi c T cells. Leukemia. 2004; 18(4): 798–808. DOI: 10.1038/sj.leu.2403297.

133

Шитиков С.А., Кучмий А.А., Быкова Н.А. и др. In silico анализ последовательностей T-клеточных рецепторов, специфичных к минорному антигену гистосовместимости HA-2. Российский иммунологический журнал. 2019; 13(1): 31–43. DOI: 10.31857/s102872210005018-4.

Sheetikov S., Kuchmiy A., Bykova N., et al. In silico analysis of T-cell receptors specifi c to the minor histocompatibility antigen HA-2. Rossiyskiy Immunologicheskiy Jurnal. 2019; 13(1): 31–43. DOI: 10.31857/s102872210005018-4. (in Russian).

134

Marijt E., Wafelman A., Hoorn M., et al. Phase I/II feasibility study evaluating the generation of leukemia-reactive cytotoxic T lymphocyte lines for treatment of patients with relapsed leukemia after allogeneic stem cell transplantation. Haematologica. 2007; 92(1): 72–80. DOI: 10.3324/haematol.10433.

135

Warren E.H., Fujii N., Akatsuka Y., et al. Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specifi c for minor histocompatibility antigens. Blood. 2010; 115(19): 3869–78. DOI: 10.1182/blood-2009-10-248997.

136

Meij P., Jedema I., van der Hoorn M., et al. Generation and administration of HA-1-specifi c T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: A pilot study. Haematologica. 2012; 97(8): 1205–8. DOI: 10.3324/haematol.2011.053371.

137

Bondanza A., Hambach L., Aghai Z., et al. IL-7 receptor expression identifi es suicide gene-modifi ed allospecifi c CD8+ T cells capable of self-renewal and differentiation into antileukemia effectors. Blood. 2011; 117(24): 6469–78. DOI: 10.1182/blood-2010-11-320366.

138

van der Waart A.B., van de Weem N.M.P., Maas F., et al. Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy. Blood. 2014; 124(23): 3490–3500. DOI: 10.1182/blood-2014-05-578583.

139

Franssen L., Roeven M., Hobo W., et al. A phase I/II minor histocompatibility antigen-loaded dendritic cell vaccination trial to safely improve the effi cacy of donor lymphocyte infusions in myeloma. Bone Marrow Transplant. 2017; 52(10): 1378–83. DOI: 10.1038/bmt.2017.118.

140

Oostvogels R., Kneppers E., Minnema M., et al. Effi cacy of host-dendritic cell vaccinations with or without minor histocompatibility antigen loading, combined with donor lymphocyte infusion in multiple myeloma patients. Bone Marrow Transplant. 2016; 52(2): 228–37. DOI: 10.1038/bmt.2016.250.

141

Calmeiro J., Carrascal M.A., Tavares A.R., et al. Dendritic cell vaccines for cancer immunotherapy: The role of human conventional type 1 dendritic cells.Pharm. 2020; 12(2): 158. DOI: 10.3390/pharmaceutics12020158.

142

Vdovin A.S., Filkin S.Y., Yefi mova P.R., et al. Recombinant MHC tetramers for isolation of virus-specifi c CD8+ cells from healthy donors: Potential approach for cell therapy of posttransplant cytomegalovirus infection. Biochem Mosc. 2016; 81(11): 1371–83. DOI: 10.1134/s0006297916110146.

143

van Loenen M.M., de Boer R., van Liempt E., et al. A Good Manufacturing Practice procedure to engineer donor virus-specifi c T cells into potent antileukemic effector cells. Haematologica. 2014; 99(4): 759–68. DOI: 10.3324/haematol.2013.093690.

144

van Balen P., Jedema I., van Loenen M.M., et al. HA-1H T-Cell receptor gene transfer to redirect virus-specifi c T cells for treatment of hematological malignancies after allogeneic stem cell transplantation: A phase 1 clinical study. Front Immunol. 2020; 11: 1804. DOI: 10.3389/fi mmu.2020.01804.

145

Kretschmer L., Flossdorf M., Mir J., et al. Differential expansion of T central memory precursor and effector subsets is regulated by division speed. Nat Commun. 2020; 11(1): 113. DOI: 10.1038/s41467-019-13788-w.

146

Gamadia L.E., van Leeuwen E.M., Remmerswaal E.B., et al. The size and phenotype of virus-specifi c T cell populations is determined by repetitive antigenic stimulation and environmental cytokines. J Immunol. 2004; 172(10): 6107–14. DOI: 10.4049/jimmunol.172.10.6107.

147

Dossa R.G., Cunningham T., Sommermeyer D., et al. Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse. Blood. 2018; 131(1): 108–20. DOI: 10.1182/blood-2017-07-791608.

148

Романюк Д.С., Хмелевская А.А., Постовская А.М. и др. Клинически значимые минорные антигены гистосовместимости для российских пациентов, получающих трансплантацию стволовых клеток крови. Медицинская иммунология. 2019; 21(5): 847–60. DOI: 10.15789/1563-0625-2019-5-847-860.

Romaniuk D.S., Khmelevskaya A.A., Postovskaya A.M., et al. Clinically relevant minor histocompatibility antigens for Russian patients undergoing hematopoietic stem cell transplantation. Meditsinskaya immunologiya. 2019; 21(5): 847–60. DOI: 10.15789/1563-0625-2019-5-847-860. (in Russian).

149

van Loenen M.M., de Boer R., Amir A.L., et al. Mixed T cell receptor dimers harbor potentially harmful neoreactivity. Proc Natl Acad Sci U S A. 2010;107(24): 10972–7. DOI: 10.1073/pnas.1005802107

150

Morton L.T., Reijmers R.M., Wouters A.K., et al. Simultaneous deletion of endogenous TCRαβ for TCR gene therapy creates an improved and safe cellular therapeutic. Mol Ther. 2020; 28(1): 654–74. DOI: 10.1016/j.ymthe.2019.10.001.

151

Inaguma Y., Akahori Y., Murayama Y., et al. Construction and molecular characterization of a T-cell receptor-like antibody and CAR-T cells specifi c for minor histocompatibility antigen HA-1H. Gene Ther. 2014; 21(6): 575–84. DOI: 10.1038/gt.2014.30.

152

Sommermeyer D., Hudecek M., Kosasih P., et al. Chimeric antigen receptormodifi ed T cells derived from defi ned CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016; 30(2): 492–500. DOI: 10.1038/leu.2015.247.

153

Tantalo D.G., Oliver A.J., von Scheidt B., et al. Understanding T cell phenotype for the design of effective chimeric antigen receptor T cell therapies. J Immunother Cancer. 2021; 9(5): e002555. DOI: 10.1136/jitc-2021-002555.

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