Иммунотерапия злокачественных глиом: современное состояние проблемы и перспективные направления


https://doi.org/10.18027/2224-5057-2015-2-22-39

Полный текст:


Аннотация

Несмотря на агрессивное мультимодальное лечение прогноз при злокачественных глиомах остается плохим. Низкая эффективность традиционной цитостатической терапии вынуждает искать альтернативные подходы к лечению. В данном обзоре рассматриваются вопросы активной иммунотерапии с помощью противоопухолевых вакцин и адоптивной клеточной терапии. Вакцинотерапия может осуществляться с использованием опухолевых лизатов или отдельных пептидов или мРНК. Для улучшения иммуногенности вакцины используются дендритные клетки и различные иммуноадъюванты. При использовании лизатной вакцины при вновь выявленной мультиформной глиобластоме медиана выживаемости без прогрессирования составляет 9,5–18 месяцев, а медиана общей выживаемости 16,25–35,9 месяца, что значительно выше, чем в историческом контроле. Среди пептидных вакцин изучаются вакцины к WT-1, сурвивину, мутированному варианту изоцитратдегидрогеназы (IDHR132H), мутированному варианту рецептора эпидермального фактора роста (EGFRvIII). Перспективными представляются методы вакцинотерапии против антигенов стволовых клеток глиом, цитомегаловирусных антигенов. Активно изучается возможность интеграции иммунотерапии в существующие стандарты лечения, а также комбинация нескольких иммунотерапевтических стратегий.

Об авторах

Константин Евгеньевич Борисов
ГУЗ Республиканский клинический онкологический диспансер Минздрава Республики Башкортостан
Россия
к. м.н., врач-онколог, г. Уфа


Дина Дамировна Сакаева
ГУЗ Республиканский клинический онкологический диспансер Минздрава Республики Башкортостан
Россия
д. м.н., заместитель главного врача по химиотерапии, г. Уфа


Список литературы

1. Stupp R., Hegi M. E., Mason W. P., van den Bent M. J., Taphoorn M. J., Janzer R. C., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009; 10 (5): 459–66.

2. Chinot O. L., Wick W., Mason W., Henriksson R., Saran F., Nishikawa R., et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 2014; 370 (8): 709–22.

3. Cheever M. A., Allison J. P., Ferris A. S., Finn O. J., Hastings B. M., Hecht T. T., Mellman I., Prindiville S. A., Viner J. L., Weiner L. M., Matrisian L. M. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin. Cancer Res. 2009; 15 (17): 5323–37.

4. Reardon D. A., Wucherpfennig K. W., Freeman G., Wu C. J., Chiocca E. A., Wen P. Y., Curry W. T. Jr., Mitchell D. A., Fecci P. E., Sampson J. H., Dranoff G. An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. Expert Rev. Vaccines. 2013; 12 (6): 597–615.

5. Banchereau J., Briere F., Caux C., Davoust J., Lebecque S., Liu Y. J., Pulendran B., Palucka K. Immunobiology of dendritic cells. Annu. Rev. Immunol. 2000; 18: 767–811.

6. Yamanaka R., Homma J., Yajima N., Tsuchiya N., Sano M., Kobayashi T., Yoshida S., Abe T., Narita M., Takahashi M., Tanaka R. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin. Cancer Res. 2005; 11 (11): 4160–7.

7. Palucka K., Banchereau J. Cancer immunotherapy via dendritic cells. Nat. Rev. Cancer. 2012; 12 (4): 265–77.

8. Prins R. M., Craft N., Bruhn K. W., Khan-Farooqi H., Koya R. C., Stripecke R., Miller J. F., Liau L. M. The TLR-7 agonist, imiquimod, enhances dendritic cell survival and promotes tumor antigen-specific T cell priming: relation to central nervous system antitumor immunity. J. Immunol. 2006; 176 (1): 157–64.

9. Ursu R., Carpentier A. F. Immunotherapeutic approach with oligodeoxynucleotides containing CpG motifs (CpG-ODN) in malignant glioma. Adv. Exp. Med. Biol. 2012; 746: 95–108.

10. Zhu X., Nishimura F., Sasaki K., Fujita M., Dusak J. E., Eguchi J., Fellows-Mayle W., Storkus W. J., Walker P. R., Salazar A. M., Okada H. Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. J. Transl. Med. 2007; 5: 10.

11. Herrmann A., Cherryholmes G., Schroeder A., Phallen J. Alizadeh D., Xin H., et al. TLR9 is Critical for Glioma Stem Cell Maintenance and Targeting. Cancer Res. 2014; 74 (18): 5218–28.

12. Linn J. F., Black P., Derksen K., R bben H., Th roff J. W. Keyhole limpet haemocyanin in experimental bladder cancer: literature review and own results. Eur. Urol. 2000; 37 Suppl 3: 34–40.

13. Zhan Y., Xu Y., Lew A. M. The regulation of the development and function of dendritic cell subsets by GM–CSF: more than a hematopoietic growth factor. Mol. Immunol. 2012; 52 (1): 30–7.

14. Clive K. S., Tyler J. A., Clifton G. T., Holmes J. P., Mittendorf E. A., Ponniah S., Peoples G. E. Use of GM–CSF as an adjuvant with cancer vaccines: beneficial or detrimental? Expert Rev. Vaccines. 2010; 9 (5): 519–25.

15. Czerkinsky C. C., Nilsson L. A., Nygren H., Ouchterlony O., Tarkowski A. A Solid-phase Enzyme-Linked Immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J. Immunol. Methods. 1983; 65 (1–2): 109–21.

16. Yu J. S., Wheeler C. J., Zeltzer P. M., Ying H., Finger D. N., Lee P. K., Yong W. H., Incardona F., Thompson R. C., Riedinger M. S., Zhang W., Prins R. M., Black K. L. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res. 2001; 61 (3): 842–7.

17. Yu J. S., Liu G., Ying H., Yong W. H., Black K. L., Wheeler C. J. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004; 64 (14): 4973–9.

18. Rutkowski S., De Vleeschouwer S., Kaempgen E., Wolff J. E., K hl J., Demaerel P., Warmuth-Metz M., Flamen P., Van Calenbergh F., Plets C., S rensen N., Opitz A., Van Gool S. W. Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study. Br. J. Cancer. 2004; 91 (9): 1656–62.

19. Liau L. M., Prins R. M., Kiertscher S. M., Odesa S. K., Kremen T. J., Giovannone A. J., Lin J. W., Chute D. J., Mischel P. S., Cloughesy T. F., Roth M. D. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin. Cancer Res. 2005; 11 (15): 5515–25.

20. Yamanaka R., Abe T., Yajima N., Tsuchiya N., Homma J., Kobayashi T., Narita M., Takahashi M., Tanaka R. Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br.J.Cancer. 2003; 89 (7): 1172–9.

21. Wheeler C. J., Black K. L., Liu G., Mazer M., Zhang X. X., Pepkowitz S., Goldfinger D., Ng H., Irvin D., Yu J. S. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res. 2008; 68 (14): 5955–64.

22. De Vleeschouwer S., Fieuws S., Rutkowski S., Van Calenbergh F., Van Loon J., Goffin J., Sciot R., Wilms G., Demaerel P., Warmuth-Metz M., Soerensen N., Wolff J. E., Wagner S., Kaempgen E., Van Gool S. W. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin. Cancer Res. 2008; 14 (10): 3098–104.

23. Ardon H., Van Gool S., Lopes I. S., Maes W., Sciot R., Wilms G., Demaerel P., Bijttebier P., Claes L., Goffin J., Van Calenbergh F., De Vleeschouwer S. Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study. J. Neurooncol. 2010; 99 (2): 261–72.

24. Ardon H., Van Gool S. W., Verschuere T., Maes W., Fieuws S., Sciot R., Wilms G., Demaerel P., Goffin J., Van Calenbergh F., Menten J., Clement P., Debiec-Rychter M., De Vleeschouwer S. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol. Immunother. 2012; 61 (11): 2033–44.

25. Prins R. M., Soto H., Konkankit V., Odesa S. K., Eskin A., Yong W. H., Nelson S. F., Liau L. M. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin. Cancer Res. 2011; 17 (6): 1603–15.

26. Fadul C. E., Fisher J. L., Hampton T. H., Lallana E. C., Li Z., Gui J., Szczepiorkowski Z. M., Tosteson T. D., Rhodes C. H., Wishart H. A., Lewis L. D., Ernstoff M. S. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J. Immunother. 2011; 34 (4): 382–9.

27. Cho D. Y., Yang W. K., Lee H. C., Hsu D. M., Lin H. L., Lin S. Z., Chen C. C., Harn H. J., Liu C. L., Lee W. Y., Ho L. H. Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: a phase II clinical trial. World Neurosurg. 2012; 77 (5–6): 736–44.

28. Yung W. K., Albright R. E., Olson J., Fredericks R., Fink K., Prados M. D., et al. A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br. J. Cancer. 2000; 83 (5): 588–93.

29. Crane C. A., Han S. J., Ahn B., Oehlke J., Kivett V., Fedoroff A., Butowski N., Chang S. M., Clarke J., Berger M. S., McDermott M.W., Prados M. D., Parsa A. T. Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein. Clin. Cancer res. 2013; 19 (1): 205–14.

30. Bloch O., Crane C. A., Fuks Y., Kaur R., Aghi M. K., Berger M. S., Butowski N. A., Chang S. M., Clarke J. L., McDermott M.W., Prados M. D., Sloan A. E., Bruce J. N., Parsa A. T. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 2014; 16 (2): 274–9.

31. Rausher J., Beschorner R., Gierke M., Bisdas S., Braun C., Ebner F. H., Schittenhelm J. WT1 expression increases with malignancy and indicates unfavourable outcome in astrocytoma. J. Clin. Pathol. 2014; 67 (7): 556–61.

32. Izumoto S., Tsuboi A., Oka Y., Suzuki T., Hashiba T., Kagawa N, et al. Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J. Neorosurg. 2008; 108 (5): 963–71.

33. Ciesielski M. J., Ahluwalia M. S., Munich S. A., Orton M., Barone T., Chanan-Khan A., Fenstermaker R. A. Antitumor cytotoxic T-cell response induced by a survivin peptide mimic. Cancer Immunol. Immunother. 2010; 59 (8): 1211–21.

34. Schumacher T., Bunse L., Pusch S., Sahm F., Wiestler B., Quandt J., et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014; 512 (7514): 324–7.

35. Lowenstein P. R., Castro M. G. The Value of EGFRvIII as the Target for Glioma Vaccines. ASCO Educ. Book. 2014: 42–50.

36. Weller M., Kaulich K., Hentschel B., Felsberg J., Gramatzki D., Pietsch T., et al. Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy. Int. J. Cancer. 2014; 134 (10): 2437–47.

37. Pelloski C. E., Ballman K. V., Furth A. F., Zhang L., Lin E., Sulman E. P., et al. Epidermal growth factor receptor variant III status defines clinically distinct subtypes of glioblastoma. J. Clin. Oncol. 2007; 25 (16): 2288–94.

38. Heimberger A. B., Crotty L. E., Archer G. E., Hess K. R., Wikstrand C. J., Friedman A. H., Friedman H. S., Bigner D. D., Sampson J. H. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin. Cancer Res. 2003; 9 (11): 4247–54.

39. Sampson J. H., Archer G. E., Mitchell D. A., Heimberger A. B., Herndon J. E. 2nd, Lally-Goss D., et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol. Cancer Ther. 2009; 8 (10): 2773–9.

40. Sampson J. H., Heimberger A. B., Archer G. E., Aldape K. D., Friedman A. H., Friedman H. S., et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 2010; 28 (31): 4722–9.

41. Del Vecchio C. A., Li G., Wong A. J. Targeting EGF receptor variant III: tumor-specific peptide vaccination for malignant gliomas. Expert Rev. Vaccines. 2012; 11 (2): 133–44.

42. Sampson J. H., Aldape K. D., Archer G. E., Coan A., Desjardins A., Friedman A. H., et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-Oncol. 2011; 13 (3): 324–33.

43. Schuster J., Lai R. K., Recht L. D., Reardon D. A., Paleologos N. A., Groves M. D., et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 2015.

44. Matsushita H., Vesely M. D., Koboldt D. C., Rickert C. G., Uppaluri R., Magrini V. J., et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012; 482 (7385): 400–4.

45. Okada H., Kalinski P., Ueda R., Hoji A., Kohanbash G., Donegan T. E., et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha} -type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J. Clin. Oncol. 2011; 29 (3): 330–6.

46. Phuphanich S., Wheeler C. J., Rudnick J. D., Mazer M., Wang H., Nu o M. A., Richardson J. E., Fan X., Ji J., Chu R. M., Bender J. G., Hawkins E. S., Patil C. G., Black K. L., Yu J. S. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol. Immunother. 2013; 62 (1): 125–35.

47. Yajima N., Yamanaka R., Mine T., Tsuchiya N., Homma J., Sano M., Kuramoto T., Obata Y., Komatsu N., Arima Y., Yamada A., Shigemori M., Itoh K., Tanaka R. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin. Cancer Res. 2005; 11 (16): 5900–11.

48. Terasaki M., Shibui S., Narita Y., Fujimaki T., Aoki T., Kajiwara K., Sawamura Y., Kurisu K., Mineta T., Yamada A., Itoh K. Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen – A24 with recurrent or progressive glioblastoma multiforme. J. Clin. Oncol. 2011; 29 (3): 337–44.

49. Dutoit V., Herold-Mende C., Hilf N., Schoor O., Beckhove P., Bucher J., Dorsch K., Flohr S., Fritsche J., Lewandrowski P., Lohr J., Rammensee H. G., Stevanovic S., Trautwein C., Vass V., Walter S., Walker P. R., Weinschenk T., Singh-Jasuja H., Dietrich P. Y. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain. 2012; 135 (4): 1042–54.

50. Di Tomaso T., Mazzoleni S., Wang E., Sovena G., Clavenna D., Franzin A., Mortini P., Ferrone S., Doglioni C., Marincola F. M., Galli R., Parmiani G., Maccalli C. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin. Cancer Res. 2010; 16 (3): 800–13.

51. Vik-Mo E.O., Nyakas M., Mikkelsen B. V., Moe M. C., Due-T nnesen P., Suso E. M.,Saeb e-Larssen S., Sandberg C., Brinchmann J. E., Helseth E., Rasmussen A. M., Lote K., Aamdal S., Gaudernack G., Kvalheim G., Langmoen I. A. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma. Cancer Immunol. Immunother. 2013; 62 (9): 1499–509.

52. Cobbs C. S., Harkins L., Samanta M., Gillespie G. Y., Bharara S., King P. H., Nabors L. B., Cobbs C. G., Britt W. J. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 2002; 62 (12): 3347–50.

53. Scheurer M. E., Bondy M. L., Aldape K. D., Albrecht T., El-Zein R. Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol. 2008; 116 (1): 79–86.

54. Soroceanu L., Matlaf L., Bezrookove V., Harkins L., Martinez R., Greene M., Soteropoulos P., Cobbs C. S. Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype. Cancer Res. 2011; 71 (21): 6643–53.

55. Dziurzynski K., Wei J., Qiao W., Hatiboglu M. A., Kong L. Y., Wu A., Wang Y., Cahill D., Levine N., Prabhu S., Rao G., Sawaya R., Heimberger A. B. Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin. Cancer Res. 2011; 17 (14): 4642–9.

56. Prins R. M., Cloughesy T. F., Liau L. M. Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N. Eng. J. Med. 2008; 359 (5): 539–41.

57. Dietrich P., Dutoit V., Walker P. R. Immunotherapy for glioma: from illusion to realistic prospects? ASCO Educ. Book. 2014; 51–9.

58. Neller M. A., Lopez J. A., Schmidt C. W. Antigens for cancer immunotherapy. Semin. Immunol. 2008; 20 (5): 286–95.

59. Prins R. M., Wang X., Soto H., Young E., Lisiero D. N., Fong B., Everson R., Yong W. H., Lai A., Li G., Cloughesy T. F., Liau L. M. Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients. J. Immunother. 2013; 36 (2): 152–7.

60. Sharma S., Yang S. C., Zhu L., Reckamp K., Gardner B., Baratelli F., Huang M., Batra R. K., Dubinett S. M. Tumor cyclooxygenase-2/ prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res. 2005; 65 (12): 5211–20.

61. Ohm J. E., Gabrilovich D. I., Sempowski G. D., Kisseleva E., Parman K. S., Nadaf S., Carbone D. P. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood. 2003; 101 (12): 4878–86.

62. Dixit S. Immunotherapy for high-grade glioma. Future Oncol. 2014; 10 (6): 911–5.

63. De Vleeschouwer S., Ardon H., Van Calenbergh F., Sciot R., Wilms G., van Loon J., Goffin J., Van Gool S. Stratification according to HGG-IMMUNO RPA model predicts outcome in a large group of patients with relapsed malignant glioma treated by adjuvant postoperative dendritic cell vaccination. Cancer Immunol. Immunother. 2012; 61 (11): 2105–12.

64. Eyrich M., Rachor J., Schreiber S. C., W lfl M., Schlegel P. G. Dendritic cell vaccination in pediatric gliomas: lessons learnt and future perspectives. Front. Pediatr. 2013; 1:12.

65. Kennedy B. C., Maier L. M., D’Amico R., Mandigo C. E., Fontana E. J., Waziri A., Assanah M. C., Canoll P., Anderson R. C., Anderson D. E., Bruce J. N. Dynamics of central and peripheral immunomodulation in a murine glioma model. BMC Immunology 2009; 10: article 11.

66. Prins R. M., Shu C. J., Radu C. G., Vo D. D., Khan-Farooqi H., Soto H., Yang M. Y., Lin M. S., Shelly S., Witte O. N., Ribas A., Liau L. M. Anti-tumor activity and trafficking of self, tumor-specific T cells against tumors located in the brain. Cancer Immunol. Immunother. 2008; 57 (9): 1279–89.

67. Chung D. S., Shin H. J., Hong Y. K. A new hope in immunotherapy for malignant gliomas: adoptive T cell transfer therapy. J. Immunol. Res. 2014; 2014:326545.

68. Bullain S. S., Sahin A., Szentirmai O., Sanchez C., Lin N., Baratta E., Waterman P., Weissleder R., Mulligan R. C., Carter B. S. Genetically engineered T cells to target EGFRvIII expressing glioblastoma. J. Neurooncol. 2009; 94 (3): 373–82.

69. Ahmed N., Salsman V. S., Kew Y., Shaffer D., Powell S., Zhang Y. J., Grossman R. G., Heslop H. E., Gottschalk S. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin. Cancer Res. 2010; 16 (2): 474–85.

70. Kong S., Sengupta S., Tyler B., Bais A. J., Ma Q., Doucette S., Zhou J., Sahin A., Carter B. S.,

71. Brem H., Junghans R. P., Sampath P. Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells. Clin. Cancer Res. 2012; 18 (21): 5949–60.

72. Crough T., Beagley L., Smith C., Jones L., Walker D. G., Khanna R. Ex vivo functional analysis, expansion and adoptive transfer of cytomegalovirus-specific T-cells in patients with glioblastoma multiforme. Immunol. Cell Biol. 2012; 90 (9): 872–80.

73. Cao J. X., Zhang X. Y., Liu J. L., Li D., Li J. L., Liu Y. S., Wang M., Xu B. L., Wang H. B., Wang Z. X. Clinical efficacy of tumor antigen-pulsed DC treatment for high-grade glioma patients: evidence from a meta-analysis. PLoS One. 2014; 9 (9): e107173.


Дополнительные файлы

Для цитирования: Борисов К.Е., Сакаева Д.Д. Иммунотерапия злокачественных глиом: современное состояние проблемы и перспективные направления. Злокачественные опухоли. 2015;(2):22-39. https://doi.org/10.18027/2224-5057-2015-2-22-39

For citation: Borisov K.E., SAKAEVA D. Immunotherapy for malignant gliomas: current status and perspective. Malignant tumours. 2015;(2):22-39. (In Russ.) https://doi.org/10.18027/2224-5057-2015-2-22-39

Просмотров: 731

Обратные ссылки

  • Обратные ссылки не определены.


Creative Commons License
Контент доступен под лицензией Creative Commons Attribution 4.0 License.


ISSN 2224-5057 (Print)
ISSN 2587-6813 (Online)