Top

Published in:

Open Access 01-12-2023 | Glioblastoma | Review

Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators

Authors: Berta Segura-Collar, Sara Hiller-Vallina, Olaya de Dios, Marta Caamaño-Moreno, Lucia Mondejar-Ruescas, Juan M. Sepulveda-Sanchez, Ricardo Gargini

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

Glial-origin brain tumors, including glioblastomas (GBM), have one of the worst prognoses due to their rapid and fatal progression. From an oncological point of view, advances in complete surgical resection fail to eliminate the entire tumor and the remaining cells allow a rapid recurrence, which does not respond to traditional therapeutic treatments. Here, we have reviewed new immunotherapy strategies in association with the knowledge of the immune micro-environment. To understand the best lines for the future, we address the advances in the design of neoantigen vaccines and possible new immune modulators. Recently, the efficacy and availability of vaccine development with different formulations, especially liposome plus mRNA vaccines, has been observed. We believe that the application of new strategies used with mRNA vaccines in combination with personalized medicine (guided by different omic’s strategies) could give good results in glioma therapy. In addition, a large part of the possible advances in new immunotherapy strategies focused on GBM may be key improving current therapies of immune checkpoint inhibitors (ICI), given the fact that this type of tumor has been highly refractory to ICI.

Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, Bignell GR, Bolli N, Borg A, Børresen-Dale AL et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421. https://doi.org/10.1038/nature12477CrossRefPubMedPubMedCentral

Ardon H, Van Gool SW, Verschuere T, Maes W, Fieuws S, Sciot R, Wilms G, Demaerel P, Goffin J, Van Calenbergh F et al (2012) 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 61:2033–2044. https://doi.org/10.1007/s00262-012-1261-1CrossRefPubMed

Arvanitis CD, Ferraro GB, Jain RK (2020) The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat Rev Cancer 20:26–41. https://doi.org/10.1038/s41568-019-0205-xCrossRefPubMed

Bagaev A, Kotlov N, Nomie K, Svekolkin V, Gafurov A, Isaeva O, Osokin N, Kozlov I, Frenkel F, Gancharova O et al (2021) Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 39:845-865.e847. https://doi.org/10.1016/j.ccell.2021.04.014CrossRefPubMed

Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wöhrer A, Dieckmann K, Filipits M, Brandstetter A, Weller M et al (2015) Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol 17:1064–1075. https://doi.org/10.1093/neuonc/nou307CrossRefPubMed

Bloch O, Lim M, Sughrue ME, Komotar RJ, Abrahams JM, O’Rourke DM, D’Ambrosio A, Bruce JN, Parsa AT (2017) Autologous heat shock protein peptide vaccination for newly diagnosed glioblastoma: impact of peripheral PD-L1 expression on response to therapy. Clin Cancer Res 23:3575–3584. https://doi.org/10.1158/1078-0432.CCR-16-1369CrossRefPubMedPubMedCentral

Blum JS, Wearsch PA, Cresswell P (2013) Pathways of antigen processing. Annu Rev Immunol 31:443–473. https://doi.org/10.1146/annurev-immunol-032712-095910CrossRefPubMedPubMedCentral

Boussiotis VA, Charest A (2018) Immunotherapies for malignant glioma. Oncogene 37:1121–1141. https://doi.org/10.1038/s41388-017-0024-zCrossRefPubMed

Bowman RL, Joyce JA (2014) Therapeutic targeting of tumor-associated macrophages and microglia in glioblastoma. Immunotherapy 6:663–666. https://doi.org/10.2217/imt.14.48CrossRefPubMed

10.

Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, Ostberg JR, Blanchard MS, Kilpatrick J, Simpson J et al (2016) Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 375:2561–2569. https://doi.org/10.1056/NEJMoa1610497CrossRefPubMedPubMedCentral

11.

Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, Alansary D, Sonner JK, Green E, Deumelandt K et al (2018) Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med 24:1192–1203. https://doi.org/10.1038/s41591-018-0095-6CrossRefPubMed

12.

Burger MC, Zhang C, Harter PN, Romanski A, Strassheimer F, Senft C, Tonn T, Steinbach JP, Wels WS (2019) CAR-engineered NK cells for the treatment of glioblastoma: turning innate effectors into precision tools for cancer immunotherapy. Front Immunol 10:2683. https://doi.org/10.3389/fimmu.2019.02683CrossRefPubMedPubMedCentral

13.

Castle JC, Kreiter S, Diekmann J, Löwer M, van de Roemer N, de Graaf J, Selmi A, Diken M, Boegel S, Paret C et al (2012) Exploiting the mutanome for tumor vaccination. Cancer Res 72:1081–1091. https://doi.org/10.1158/0008-5472.CAN-11-3722CrossRefPubMed

14.

Castro Dias M, Mapunda JA, Vladymyrov M, Engelhardt B (2019) Structure and junctional complexes of endothelial, epithelial and glial brain barriers. Int J Mol Sci 20:5372. https://doi.org/10.3390/ijms20215372CrossRefPubMedPubMedCentral

15.

Cejalvo T, Gargini R, Segura-Collar B, Mata-Martínez P, Herranz B, Cantero D, Ruano Y, García-Pérez D, Pérez-Núñez Á, Ramos A et al (2020) Immune profiling of gliomas reveals a connection with IDH1/2 mutations tau function and the vascular phenotype. Cancers (Basel). https://doi.org/10.3390/cancers12113230CrossRefPubMed

16.

Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD (2018) TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun 9:4692. https://doi.org/10.1038/s41467-018-06654-8CrossRefPubMedPubMedCentral

17.

Charles N, Holland EC (2010) The perivascular niche microenvironment in brain tumor progression. Cell Cycle 9:3012–3021. https://doi.org/10.4161/cc.9.15.12710CrossRefPubMedPubMedCentral

18.

Chen RQ, Liu F, Qiu XY, Chen XQ (2018) The prognostic and therapeutic value of PD-L1 in glioma. Front Pharmacol 9:1503. https://doi.org/10.3389/fphar.2018.01503CrossRefPubMed

19.

Chryplewicz A, Scotton J, Tichet M, Zomer A, Shchors K, Joyce JA, Homicsko K, Hanahan D (2022) Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity. Cancer Cell 40:1111-1127.e1119. https://doi.org/10.1016/j.ccell.2022.08.014CrossRefPubMedPubMedCentral

20.

Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, Wang AC, Ellingson BM, Rytlewski JA, Sanders CM et al (2019) Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. NatMed 25:477–486

21.

Cobbold M, De La Peña H, Norris A, Polefrone JM, Qian J, English AM, Cummings KL, Penny S, Turner JE, Cottine J et al (2013) MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia. Sci Transl Med 5:203ra125. https://doi.org/10.1126/scitranslmed.3006061CrossRefPubMedPubMedCentral

22.

Coniglio SJ, Segall JE (2013) Review: molecular mechanism of microglia stimulated glioblastoma invasion. Matrix Biol 32:372–380. https://doi.org/10.1016/j.matbio.2013.07.008CrossRefPubMed

23.

Constam DB, Philipp J, Malipiero UV, ten Dijke P, Schachner M, Fontana A (1992) Differential expression of transforming growth factor-beta 1, -beta 2, and -beta 3 by glioblastoma cells, astrocytes, and microglia. J Immunol 148:1404–1410CrossRefPubMed

24.

de Groot J, Penas-Prado M, Alfaro-Munoz K, Hunter K, Pei BL, O’Brien B, Weathers SP, Loghin M, Kamiya Matsouka C, Yung WKA et al (2020) Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages. Neuro Oncol 22:539–549. https://doi.org/10.1093/neuonc/noz185CrossRefPubMed

25.

De Smet C, De Backer O, Faraoni I, Lurquin C, Brasseur F, Boon T (1996) The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc Natl Acad Sci U S A 93:7149–7153. https://doi.org/10.1073/pnas.93.14.7149CrossRefPubMedPubMedCentral

26.

Di Nunno V, Franceschi E, Gatto L, Bartolini S, Brandes AA (2020) Predictive markers of immune response in glioblastoma: hopes and facts. Future Oncol 16:1053–1063. https://doi.org/10.2217/fon-2020-0047CrossRefPubMed

27.

Draaisma K, Wijnenga MM, Weenink B, Gao Y, Smid M, Robe P, van den Bent MJ, French PJ (2015) PI3 kinase mutations and mutational load as poor prognostic markers in diffuse glioma patients. Acta Neuropathol Commun 3:88. https://doi.org/10.1186/s40478-015-0265-4CrossRefPubMedPubMedCentral

28.

Eagles ME, Nassiri F, Badhiwala JH, Suppiah S, Almenawer SA, Zadeh G, Aldape KD (2018) Dendritic cell vaccines for high-grade gliomas. Ther Clin Risk Manag 14:1299–1313. https://doi.org/10.2147/TCRM.S135865CrossRefPubMedPubMedCentral

29.

Emami Nejad A, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, Nedaeinia R, Haghjooy Javanmard S, Taherian M, Ahmadlou M et al (2021) The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int 21:62. https://doi.org/10.1186/s12935-020-01719-5CrossRefPubMedPubMedCentral

30.

Engelhardt B, Vajkoczy P, Weller RO (2017) The movers and shapers in immune privilege of the CNS. Nat Immunol 18:123–131. https://doi.org/10.1038/ni.3666CrossRefPubMed

31.

Filley AC, Henriquez M, Dey M (2017) Recurrent glioma clinical trial, CheckMate-143: the game is not over yet. Oncotarget 8:91779–91794. https://doi.org/10.18632/oncotarget.21586CrossRefPubMedPubMedCentral

32.

Fisk B, Blevins TL, Wharton JT, Ioannides CG (1995) Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J Exp Med 181:2109–2117. https://doi.org/10.1084/jem.181.6.2109CrossRefPubMed

33.

Flores-Toro JA, Luo D, Gopinath A, Sarkisian MR, Campbell JJ, Charo IF, Singh R, Schall TJ, Datta M, Jain RK et al (2020) CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas. Proc Natl Acad Sci USA 117:1129–1138CrossRefPubMed

34.

Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014–1022. https://doi.org/10.1038/ni.2703CrossRefPubMedPubMedCentral

35.

Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G (2015) Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28:690–714. https://doi.org/10.1016/j.ccell.2015.10.012CrossRefPubMed

36.

Galon J, Bruni D (2019) Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 18:197–218. https://doi.org/10.1038/s41573-018-0007-yCrossRefPubMed

37.

Gargini R, Segura-Collar B, Sánchez-Gómez P (2020) Cellular plasticity and tumor microenvironment in gliomas: the struggle to hit a moving target. Cancers (Basel). https://doi.org/10.3390/cancers12061622CrossRefPubMed

38.

Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, Esparza R, Richard C, Ramaswamy V, Remke M et al (2017) Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med 9:eaaf2968. https://doi.org/10.1126/scitranslmed.aaf2968CrossRefPubMed

39.

Goswami S, Walle T, Cornish AE, Basu S, Anandhan S, Fernandez I, Vence L, Blando J, Zhao H, Yadav SS et al (2020) Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma. Nat Med 26:39–46. https://doi.org/10.1038/s41591-019-0694-xCrossRefPubMed

40.

Gromeier M, Brown MC, Zhang G, Lin X, Chen Y, Wei Z, Beaubier N, Yan H, He Y, Desjardins A et al (2021) Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy. Nat Commun 12:352. https://doi.org/10.1038/s41467-020-20469-6CrossRefPubMedPubMedCentral

41.

Grunau C, Sanchez C, Ehrlich M, van der Bruggen P, Hindermann W, Rodriguez C, Krieger S, Dubeau L, Fiala E, De Sario A (2005) Frequent DNA hypomethylation of human juxtacentromeric BAGE loci in cancer. Genes Chromosomes Cancer 43:11–24. https://doi.org/10.1002/gcc.20155CrossRefPubMed

42.

Hambardzumyan D, Bergers G (2015) Glioblastoma: defining tumor niches. Trends Cancer 1:252–265CrossRefPubMedPubMedCentral

43.

Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. NatNeurosci 19:20–27

44.

Han J, Chu J, Keung Chan W, Zhang J, Wang Y, Cohen JB, Victor A, Meisen WH, Kim SH, Grandi P et al (2015) CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci Rep 5:11483. https://doi.org/10.1038/srep11483CrossRefPubMedPubMedCentral

45.

Han J, Hong Y, Lee YS (2017) PD-L1 expression and combined status of PD-L1/PD-1-positive tumor infiltrating mononuclear cell density predict prognosis in glioblastoma patients. J Pathol Transl Med 51:40–48. https://doi.org/10.4132/jptm.2016.08.31CrossRefPubMed

46.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013CrossRefPubMed

47.

Hegde PS, Chen DS (2020) Top 10 challenges in cancer immunotherapy. Immunity 52:17–35. https://doi.org/10.1016/j.immuni.2019.12.011CrossRefPubMed

48.

Hegde PS, Karanikas V, Evers S (2016) The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res 22:1865–1874. https://doi.org/10.1158/1078-0432.CCR-15-1507CrossRefPubMed

49.

Henrik Heiland D, Ravi VM, Behringer SP, Frenking JH, Wurm J, Joseph K, Garrelfs NWC, Strähle J, Heynckes S, Grauvogel J et al (2019) Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma. Nat Commun 10:2541. https://doi.org/10.1038/s41467-019-10493-6CrossRefPubMedPubMedCentral

50.

Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanović S, Gouttefangeas C, Platten M, Tabatabai G, Dutoit V, van der Burg SH et al (2019) Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565:240–245. https://doi.org/10.1038/s41586-018-0810-yCrossRefPubMed

51.

Hodges TR, Ott M, Xiu J, Gatalica Z, Swensen J, Zhou S, Huse JT, de Groot J, Li S, Overwijk WW et al (2017) Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro Oncol 19:1047–1057. https://doi.org/10.1093/neuonc/nox026CrossRefPubMedPubMedCentral

52.

Huettner C, Paulus W, Roggendorf W (1995) Messenger RNA expression of the immunosuppressive cytokine IL-10 in human gliomas. Am J Pathol 146:317–322PubMedPubMedCentral

53.

Hutter G, Theruvath J, Graef CM, Zhang M, Schoen MK, Manz EM, Bennett ML, Olson A, Azad TD, Sinha R et al (2019) Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma. Proc Natl Acad Sci U S A 116:997–1006. https://doi.org/10.1073/pnas.1721434116CrossRefPubMedPubMedCentral

54.

Immisch L, Papafotiou G, Popp O, Mertins P, Blankenstein T, Willimsky G (2022) H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2. J Immunother Cancer 10:e005535. https://doi.org/10.1136/jitc-2022-005535CrossRefPubMedPubMedCentral

55.

Jan CI, Tsai WC, Harn HJ, Shyu WC, Liu MC, Lu HM, Chiu SC, Cho DY (2018) Predictors of response to autologous dendritic cell therapy in glioblastoma multiforme. Front Immunol 9:727. https://doi.org/10.3389/fimmu.2018.00727CrossRefPubMedPubMedCentral

56.

Jardim DL, Goodman A, de Melo GD, Kurzrock R (2021) The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell 39:154–173. https://doi.org/10.1016/j.ccell.2020.10.001CrossRefPubMed

57.

Ji H, Ba Y, Ma S, Hou K, Mi S, Gao X, Jin J, Gong Q, Liu T, Wang F et al (2021) Construction of interferon-gamma-related gene signature to characterize the immune-inflamed phenotype of glioblastoma and predict prognosis, efficacy of immunotherapy and radiotherapy. Front Immunol 12:729359. https://doi.org/10.3389/fimmu.2021.729359CrossRefPubMedPubMedCentral

58.

Jiang N, Xie B, Xiao W, Fan M, Xu S, Duan Y, Hamsafar Y, Evans AC, Huang J, Zhou W et al (2022) Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat Commun 13:1511. https://doi.org/10.1038/s41467-022-29137-3CrossRefPubMedPubMedCentral

59.

Johanns TM, Miller CA, Dorward IG, Tsien C, Chang E, Perry A, Uppaluri R, Ferguson C, Schmidt RE, Dahiya S et al (2016) Immunogenomics of hypermutated glioblastoma: a patient with germline POLE deficiency treated with checkpoint blockade immunotherapy. Cancer Discov 6:1230–1236. https://doi.org/10.1158/2159-8290.CD-16-0575CrossRefPubMedPubMedCentral

60.

Johanns TM, Ward JP, Miller CA, Wilson C, Kobayashi DK, Bender D, Fu Y, Alexandrov A, Mardis ER, Artyomov MN et al (2016) Endogenous neoantigen-specific CD8 T cells identified in two glioblastoma models using a cancer immunogenomics approach. Cancer Immunol Res 4:1007–1015. https://doi.org/10.1158/2326-6066.CIR-16-0156CrossRefPubMedPubMedCentral

61.

Johnson BE, Mazor T, Hong C, Barnes M, Aihara K, McLean CY, Fouse SD, Yamamoto S, Ueda H, Tatsuno K et al (2014) Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343:189–193CrossRefPubMed

62.

Kane JR, Zhao J, Tsujiuchi T, Laffleur B, Arrieta VA, Mahajan A, Rao G, Mela A, Dmello C, Chen L et al (2020) CD8. Clin Cancer Res 26:4390–4401. https://doi.org/10.1158/1078-0432.CCR-19-3104CrossRefPubMedPubMedCentral

63.

Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704. https://doi.org/10.1146/annurev.immunol.26.021607.090331CrossRefPubMed

64.

Kloepper J, Riedemann L, Amoozgar Z, Seano G, Susek K, Yu V, Dalvie N, Amelung RL, Datta M, Song JW et al (2016) Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci USA 113:4476–4481CrossRefPubMedPubMedCentral

65.

Kmiecik J, Poli A, Brons NH, Waha A, Eide GE, Enger P, Zimmer J, Chekenya M (2013) Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. J Neuroimmunol 264:71–83. https://doi.org/10.1016/j.jneuroim.2013.08.013CrossRefPubMed

66.

Knudsen AM, Rudkjøbing SJ, Sørensen MD, Dahlrot RH, Kristensen BW (2021) Expression and prognostic value of the immune checkpoints galectin-9 and PD-L1 in glioblastomas. J Neuropathol Exp Neurol 80:541–551. https://doi.org/10.1093/jnen/nlab041CrossRefPubMed

67.

Landry AP, Balas M, Alli S, Spears J, Zador Z (2020) Distinct regional ontogeny and activation of tumor associated macrophages in human glioblastoma. Sci Rep 10:19542. https://doi.org/10.1038/s41598-020-76657-3CrossRefPubMedPubMedCentral

68.

Lang F, Schrörs B, Löwer M, Türeci Ö, Sahin U (2022) Identification of neoantigens for individualized therapeutic cancer vaccines. Nat Rev Drug Discov 21:261–282. https://doi.org/10.1038/s41573-021-00387-yCrossRefPubMedPubMedCentral

69.

Laumont CM, Vincent K, Hesnard L, Audemard É, Bonneil É, Laverdure JP, Gendron P, Courcelles M, Hardy MP, Côté C et al (2018) Noncoding regions are the main source of targetable tumor-specific antigens. Sci Transl Med 10:eaau5516. https://doi.org/10.1126/scitranslmed.aau5516CrossRefPubMed

70.

Lee KS, Lee K, Yun S, Moon S, Park Y, Han JH, Kim CY, Lee HS, Choe G (2018) Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma. J Neurooncol 136:453–461. https://doi.org/10.1007/s11060-017-2675-6CrossRefPubMed

71.

Li X, Wang B, Gu L, Zhang J, Gao L, Ma C, Liang X (2018) Tim-3 expression predicts the abnormal innate immune status and poor prognosis of glioma patients. Clin Chim Acta 476:178–184. https://doi.org/10.1016/j.cca.2017.11.022CrossRefPubMed

72.

Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, Heth JA, Salacz M, Taylor S, D’Andre SD et al (2018) First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med 16:142. https://doi.org/10.1186/s12967-018-1507-6CrossRefPubMedPubMedCentral

73.

Liu C, Sage JC, Miller MR, Verhaak RG, Hippenmeyer S, Vogel H, Foreman O, Bronson RT, Nishiyama A, Luo L et al (2011) Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146:209–221. https://doi.org/10.1016/j.cell.2011.06.014CrossRefPubMedPubMedCentral

74.

Liu CJ, Schaettler M, Blaha DT, Bowman-Kirigin JA, Kobayashi DK, Livingstone AJ, Bender D, Miller CA, Kranz DM, Johanns TM et al (2020) Treatment of an aggressive orthotopic murine glioblastoma model with combination checkpoint blockade and a multivalent neoantigen vaccine. Neuro Oncol 22:1276–1288. https://doi.org/10.1093/neuonc/noaa050CrossRefPubMedPubMedCentral

75.

Louis DN, Perry A, Reifenberger G, Von DA, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820CrossRefPubMed

76.

Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341. https://doi.org/10.1038/nature14432CrossRefPubMedPubMedCentral

77.

Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, Zha Y, Al-Hallaq HA, Arina A, Khodarev NN, Janisch L et al (2018) Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J Clin Oncol 36:1611–1618. https://doi.org/10.1200/JCO.2017.76.2229CrossRefPubMedPubMedCentral

78.

Lundegaard C, Lamberth K, Harndahl M, Buus S, Lund O, Nielsen M (2008) NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8–11. Nucleic Acids Res 36:W509-512. https://doi.org/10.1093/nar/gkn202CrossRefPubMedPubMedCentral

79.

Lundegaard C, Lund O, Nielsen M (2011) Prediction of epitopes using neural network based methods. J Immunol Methods 374:26–34. https://doi.org/10.1016/j.jim.2010.10.011CrossRefPubMed

80.

Ma Q, Long W, Xing C, Chu J, Luo M, Wang HY, Liu Q, Wang RF (2018) Cancer stem cells and immunosuppressive microenvironment in glioma. Front Immunol 9:2924. https://doi.org/10.3389/fimmu.2018.02924CrossRefPubMedPubMedCentral

81.

Majzner RG, Mackall CL (2019) Clinical lessons learned from the first leg of the CAR T cell journey. Nat Med 25:1341–1355. https://doi.org/10.1038/s41591-019-0564-6CrossRefPubMed

82.

Mantovani A, Allavena P, Marchesi F, Garlanda C (2022) Macrophages as tools and targets in cancer therapy. Nat Rev Drug Discov 21:799–820. https://doi.org/10.1038/s41573-022-00520-5CrossRefPubMedPubMedCentral

83.

Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, Arthur CD, White JM, Chen YS, Shea LK et al (2012) Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482:400–404. https://doi.org/10.1038/nature10755CrossRefPubMedPubMedCentral

84.

Mazzitelli JA, Smyth LCD, Cross KA, Dykstra T, Sun J, Du S, Mamuladze T, Smirnov I, Rustenhoven J, Kipnis J (2022) Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels. Nat Neurosci 25:555–560. https://doi.org/10.1038/s41593-022-01029-1CrossRefPubMedPubMedCentral

85.

Medawar PB (1948) Immunity to homologous grafted skin; the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye. Br J Exp Pathol 29:58–69PubMedPubMedCentral

86.

Melnick K, Dastmalchi F, Mitchell D, Rahman M, Sayour EJ (2022) Contemporary RNA therapeutics for glioblastoma. Neuromolecular Med 24:8–12. https://doi.org/10.1007/s12017-021-08669-9CrossRefPubMed

87.

Merino DM, McShane LM, Fabrizio D, Funari V, Chen SJ, White JR, Wenz P, Baden J, Barrett JC, Chaudhary R et al (2020) Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the friends of cancer research TMB harmonization project. J Immunother Cancer. https://doi.org/10.1136/jitc-2019-000147CrossRefPubMedPubMedCentral

88.

Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, Ling X, Zhou S, Ivan C, Chen JQ et al (2016) PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol 18:195–205. https://doi.org/10.1093/neuonc/nov172CrossRefPubMed

89.

O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, Martinez-Lage M, Brem S, Maloney E, Shen A et al (2017) A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 9:eaaa0984. https://doi.org/10.1126/scitranslmed.aaa0984CrossRefPubMedPubMedCentral

90.

Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, Zhang W, Luoma A, Giobbie-Hurder A, Peter L et al (2017) An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217–221. https://doi.org/10.1038/nature22991CrossRefPubMedPubMedCentral

91.

Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264. https://doi.org/10.1038/nrc3239CrossRefPubMedPubMedCentral

92.

Park JS, Kim IK, Han S, Park I, Kim C, Bae J, Oh SJ, Lee S, Kim JH, Woo DC et al (2016) Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell 30:953–967CrossRefPubMed

93.

Piper K, DePledge L, Karsy M, Cobbs C (2021) Glioma stem cells as immunotherapeutic targets: advancements and challenges. Front Oncol 11:615704. https://doi.org/10.3389/fonc.2021.615704CrossRefPubMedPubMedCentral

94.

Pombo Antunes AR, Scheyltjens I, Duerinck J, Neyns B, Movahedi K, Van Ginderachter JA (2020) Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies. Elife 9:e52176. https://doi.org/10.7554/eLife.52176CrossRefPubMedPubMedCentral

95.

Pratt D, Dominah G, Lobel G, Obungu A, Lynes J, Sanchez V, Adamstein N, Wang X, Edwards NA, Wu T et al (2019) Programmed death ligand 1 is a negative prognostic marker in recurrent isocitrate dehydrogenase-wildtype glioblastoma. Neurosurgery 85:280–289. https://doi.org/10.1093/neuros/nyy268CrossRefPubMed

96.

Pulous FE, Cruz-Hernández JC, Yang C, Kaya Ζ, Paccalet A, Wojtkiewicz G, Capen D, Brown D, Wu JW, Schloss MJ et al (2022) Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis. Nat Neurosci 25:567–576. https://doi.org/10.1038/s41593-022-01060-2CrossRefPubMedPubMedCentral

97.

Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272CrossRefPubMedPubMedCentral

98.

Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT, Holland EC, Sutton JC, Joyce JA (2016) The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science 352:aad3018. https://doi.org/10.1126/science.aad3018CrossRefPubMedPubMedCentral

99.

Quail DF, Joyce JA (2017) The microenvironmental landscape of brain tumors. Cancer Cell 31:326–341CrossRefPubMedPubMedCentral

100.

Raman K (2011) A stochastic differential equation analysis of cerebrospinal fluid dynamics. Fluids Barriers CNS 8:9. https://doi.org/10.1186/2045-8118-8-9CrossRefPubMedPubMedCentral

101.

Rao G, Latha K, Ott M, Sabbagh A, Marisetty A, Ling X, Zamler D, Doucette TA, Yang Y, Kong LY et al (2020) Anti-PD-1 induces M1 polarization in the glioma microenvironment and exerts therapeutic efficacy in the absence of CD8 cytotoxic T cells. Clin Cancer Res 26:4699–4712. https://doi.org/10.1158/1078-0432.CCR-19-4110CrossRefPubMedPubMedCentral

102.

Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, Baehring J, Ahluwalia MS, Roth P, Bähr O et al (2020) Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the checkmate 143 phase 3 randomized clinical trial. JAMA Oncol 6:1003–1010. https://doi.org/10.1001/jamaoncol.2020.1024CrossRefPubMed

103.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128. https://doi.org/10.1126/science.aaa1348CrossRefPubMedPubMedCentral

104.

Sampson JH, Gunn MD, Fecci PE, Ashley DM (2020) Brain immunology and immunotherapy in brain tumours. Nat Rev Cancer 20:12–25CrossRefPubMed

105.

Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, Barron DA, Zehir A, Jordan EJ, Omuro A et al (2019) Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 51:202–206. https://doi.org/10.1038/s41588-018-0312-8CrossRefPubMedPubMedCentral

106.

Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348:69–74. https://doi.org/10.1126/science.aaa4971CrossRefPubMed

107.

Segura-Collar B, Garranzo-Asensio M, Herranz B, Hernández-SanMiguel E, Cejalvo T, Casas BS, Matheu A, Pérez-Núñez Á, Sepúlveda-Sánchez JM, Hernández-Laín A et al (2021) Tumor-derived pericytes driven by EGFR mutations govern the vascular and immune microenvironment of gliomas. Cancer Res. https://doi.org/10.1158/0008-5472.can-20-3558CrossRefPubMed

108.

Segura-Collar B, Mata-Martínez P, Hernández-Laín A, Sánchez-Gómez P, Gargini R (2022) Blood-brain barrier disruption: a common driver of central nervous system diseases. Neuroscientist 28:222–237. https://doi.org/10.1177/1073858420985838CrossRefPubMed

109.

Shinohara H, Yagita H, Ikawa Y, Oyaizu N (2000) Fas drives cell cycle progression in glioma cells via extracellular signal-regulated kinase activation. Cancer Res 60:1766–1772PubMed

110.

Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ (2005) Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5:615–625. https://doi.org/10.1038/nrc1669CrossRefPubMed

111.

Slattery K (2019) NK cell metabolism and TGFβ—implications for immunotherapy. In: Gardiner CM (ed), City

112.

Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16:249–263. https://doi.org/10.1038/nrn3898CrossRefPubMedPubMedCentral

113.

Spranger S, Sivan A, Corrales L, Gajewski TF (2016) Tumor and host factors controlling antitumor immunity and efficacy of cancer immunotherapy. Adv Immunol 130:75–93. https://doi.org/10.1016/bs.ai.2015.12.003CrossRefPubMedPubMedCentral

114.

Stone JD, Harris DT, Kranz DM (2015) TCR affinity for p/MHC formed by tumor antigens that are self-proteins: impact on efficacy and toxicity. Curr Opin Immunol 33:16–22. https://doi.org/10.1016/j.coi.2015.01.003CrossRefPubMedPubMedCentral

115.

Sultan H, Salazar AM, Celis E (2020) Poly-ICLC, a multi-functional immune modulator for treating cancer. Semin Immunol 49:101414. https://doi.org/10.1016/j.smim.2020.101414CrossRefPubMed

116.

Takenaka MC, Gabriely G, Rothhammer V, Mascanfroni ID, Wheeler MA, Chao CC, Gutiérrez-Vázquez C, Kenison J, Tjon EC, Barroso A et al (2019) Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat Neurosci 22:729–740. https://doi.org/10.1038/s41593-019-0370-yCrossRefPubMedPubMedCentral

117.

Takeshima H, Kuratsu J, Takeya M, Yoshimura T, Ushio Y (1994) Expression and localization of messenger RNA and protein for monocyte chemoattractant protein-1 in human malignant glioma. J Neurosurg 80:1056–1062. https://doi.org/10.3171/jns.1994.80.6.1056CrossRefPubMed

118.

Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, Khushalani NI, Lewis K, Lao CD, Postow MA et al (2018) Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med 379:722–730. https://doi.org/10.1056/NEJMoa1805453CrossRefPubMedPubMedCentral

119.

The Cancer Genome Atlas (TCGA) Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068CrossRef

120.

Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA et al (2018) The immune landscape of cancer. Immunity 48:812–830CrossRefPubMedPubMedCentral

121.

Tomaszewski W, Sanchez-Perez L, Gajewski TF, Sampson JH (2019) Brain tumor microenvironment and host state: implications for immunotherapy. Clin Cancer Res 25:4202–4210. https://doi.org/10.1158/1078-0432.CCR-18-1627CrossRefPubMedPubMedCentral

122.

Touat M, Idbaih A, Sanson M, Ligon KL (2017) Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol 28:1457–1472. https://doi.org/10.1093/annonc/mdx106CrossRefPubMedPubMedCentral

123.

Touat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, Cortes-Ciriano I, Birzu C, Geduldig JE, Pelton K et al (2020) Mechanisms and therapeutic implications of hypermutation in gliomas. Nature 580:517–523. https://doi.org/10.1038/s41586-020-2209-9CrossRefPubMedPubMedCentral

124.

Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, Gartner JJ, Zheng Z, Li YF, Ray S et al (2015) Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350:1387–1390. https://doi.org/10.1126/science.aad1253CrossRefPubMedPubMedCentral

125.

Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, Wunderlich JR, Somerville RP, Hogan K, Hinrichs CS et al (2014) Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344:641–645. https://doi.org/10.1126/science.1251102CrossRefPubMedPubMedCentral

126.

Twomey JD, Zhang B (2021) Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. AAPS J 23:39. https://doi.org/10.1208/s12248-021-00574-0CrossRefPubMed

127.

Ugel S, De Sanctis F, Mandruzzato S, Bronte V (2015) Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages. J Clin Invest 125:3365–3376. https://doi.org/10.1172/JCI80006CrossRefPubMedPubMedCentral

128.

Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, Körber C, Kardorff M, Ratliff M, Xie R et al (2019) Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573:532–538. https://doi.org/10.1038/s41586-019-1564-xCrossRefPubMed

129.

Venkatesh HS, Johung TB, Caretti V, Noll A, Tang Y, Nagaraja S, Gibson EM, Mount CW, Polepalli J, Mitra SS et al (2015) Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161:803–816. https://doi.org/10.1016/j.cell.2015.04.012CrossRefPubMedPubMedCentral

130.

Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW (2013) Cancer genome landscapes. Science 339:1546–1558. https://doi.org/10.1126/science.1235122CrossRefPubMedPubMedCentral

131.

von Roemeling CA, Wang Y, Qie Y, Yuan H, Zhao H, Liu X, Yang Z, Yang M, Deng W, Bruno KA et al (2020) Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity. Nat Commun 11:1508. https://doi.org/10.1038/s41467-020-15129-8CrossRef

132.

Wang L, Ge J, Lan Y, Shi Y, Luo Y, Tan Y, Liang M, Deng S, Zhang X, Wang W et al (2020) Tumor mutational burden is associated with poor outcomes in diffuse glioma. BMC Cancer 20:213. https://doi.org/10.1186/s12885-020-6658-1CrossRefPubMedPubMedCentral

133.

Wang Z, Zhang C, Liu X, Sun L, Li G, Liang J, Hu H, Liu Y, Zhang W, Jiang T (2016) Molecular and clinical characterization of PD-L1 expression at transcriptional level via 976 samples of brain glioma. Oncoimmunology 5:e1196310. https://doi.org/10.1080/2162402X.2016.1196310CrossRefPubMedPubMedCentral

134.

Watkins S, Robel S, Kimbrough IF, Robert SM, Ellis-Davies G, Sontheimer H (2014) Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun 5:4196. https://doi.org/10.1038/ncomms5196CrossRefPubMed

135.

Wiendl H, Mitsdoerffer M, Hofmeister V, Wischhusen J, Bornemann A, Meyermann R, Weiss EH, Melms A, Weller M (2002) A functional role of HLA-G expression in human gliomas: an alternative strategy of immune escape. J Immunol 168:4772–4780. https://doi.org/10.4049/jimmunol.168.9.4772CrossRefPubMed

136.

Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P (2009) Brain endothelial cells and the glio-vascular complex. Cell Tissue Res 335:75–96. https://doi.org/10.1007/s00441-008-0658-9CrossRefPubMed

137.

Xie G, Dong H, Liang Y, Ham JD, Rizwan R, Chen J (2020) CAR-NK cells: a promising cellular immunotherapy for cancer. EBioMedicine 59:102975. https://doi.org/10.1016/j.ebiom.2020.102975CrossRefPubMedPubMedCentral

138.

Xue S, Song G, Yu J (2017) The prognostic significance of PD-L1 expression in patients with glioma: a meta-analysis. Sci Rep 7:4231. https://doi.org/10.1038/s41598-017-04023-xCrossRefPubMedPubMedCentral

139.

Yan Y, Zeng S, Gong Z, Xu Z (2020) Clinical implication of cellular vaccine in glioma: current advances and future prospects. J Exp Clin Cancer Res 39:257. https://doi.org/10.1186/s13046-020-01778-6CrossRefPubMedPubMedCentral

140.

Yin J, Kim SS, Choi E, Oh YT, Lin W, Kim TH, Sa JK, Hong JH, Park SH, Kwon HJ et al (2020) ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages. Nat Commun 11:2978. https://doi.org/10.1038/s41467-020-16789-2CrossRefPubMedPubMedCentral

141.

Yin W, Jiang X, Tan J, Xin Z, Zhou Q, Zhan C, Fu X, Wu Z, Guo Y, Jiang Z et al (2020) Development and validation of a tumor mutation burden-related immune prognostic model for lower-grade glioma. Front Oncol 10:1409. https://doi.org/10.3389/fonc.2020.01409CrossRefPubMedPubMedCentral

142.

Zeng J, Zhang XK, Chen HD, Zhong ZH, Wu QL, Lin SX (2016) Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas. Oncotarget 7:8944–8955. https://doi.org/10.18632/oncotarget.6884CrossRefPubMedPubMedCentral

143.

Zhang D, Qiu B, Wang Y, Guan Y, Zhang L, Wu A (2017) Temozolomide increases MHC-I expression via NF-κB signaling in glioma stem cells. Cell Biol Int 41:680–690. https://doi.org/10.1002/cbin.10773CrossRefPubMed

144.

Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, Bordbar D, Shan D, Samanamud J, Mahajan A et al (2019) Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. NatMed 25:462–469

145.

Zhao Q, Laverdure JP, Lanoix J, Durette C, Côté C, Bonneil É, Laumont CM, Gendron P, Vincent K, Courcelles M et al (2020) Proteogenomics uncovers a vast repertoire of shared tumor-specific antigens in ovarian cancer. Cancer Immunol Res 8:544–555. https://doi.org/10.1158/2326-6066.CIR-19-0541CrossRefPubMed

146.

Zhao W, Zhao G, Wang B (2018) Revisiting GM-CSF as an adjuvant for therapeutic vaccines. Cell Mol Immunol 15:187–189. https://doi.org/10.1038/cmi.2017.105CrossRefPubMed

Title: Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators
Authors: Berta Segura-Collar
Sara Hiller-Vallina
Olaya de Dios
Marta Caamaño-Moreno
Lucia Mondejar-Ruescas
Juan M. Sepulveda-Sanchez
Ricardo Gargini
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Glioblastoma
Glioblastoma
Glioblastoma
Glioma
Glioma
Glioma
Checkpoint Inhibitors
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01569-y

At a glance: The STEP trials

Springer Medicine

Advanced immunotherapies for glioblastoma: tumor neoantigen vaccines in combination with immunomodulators

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2023

Traumatic brain injury induces TDP-43 mislocalization and neurodegenerative effects in tissue distal to the primary injury site in a non-transgenic mouse

Late chronic local inflammation, synaptic alterations, vascular remodeling and arteriovenous malformations in the brains of male rats exposed to repetitive low-level blast overpressures

Unsupervised machine learning identifies distinct ALS molecular subtypes in post-mortem motor cortex and blood expression data

Muscle fibrosis as a prognostic biomarker in facioscapulohumeral muscular dystrophy: a retrospective cohort study

Mutational signature of extracranial meningioma metastases and their respective primary tumors

Humanized APOE genotypes influence lifespan independently of tau aggregation in the P301S mouse model of tauopathy