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Journal of Neuro-Oncology
Published in: Journal of Neuro-Oncology 1/2021

01-01-2021 | Glioblastoma | Topic Review

Glucocorticoids and immune checkpoint inhibitors in glioblastoma

Authors: William J. Kelly, Mark R. Gilbert

Published in: Journal of Neuro-Oncology | Issue 1/2021

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Abstract

Purpose

Immunotherapy, activation of the immune system to target tumor cells, represents a paradigm shift in the treatment of cancer. Immune checkpoint therapies, which target immunomodulatory molecules expressed on T-lymphocytes, have demonstrated improved survival in a variety of malignancies. However, benefit in glioblastoma, the most common and devastating malignant brain tumor, remains to be seen. With several recent clinical trials failing to show efficacy of immunotherapy, concerns have been raised regarding the impact of glucocorticoid use in this patient population that may impair the ability for immune checkpoint inhibitors to affect a response.

Methods

For this article we examined the mechanism by which immune checkpoint inhibitors activate, and glucocorticoids impair, T-lymphocyte function.

Results

In this context, we review the clinical data of immune checkpoint inhibitors in glioblastoma as well as the impact glucocorticoids have on immune checkpoint inhibitor efficacy. Finally, we highlight key questions that remain in the field, and the potential benefit of further research for central nervous system tumors.

Conclusion

More information on the extent, character and duration of glucocorticoids on patients treated with PD-(L)1 will better inform both clinical management and novel therapeutic development of immunotherapy in patients with CNS malignancies.
Literature
1.
Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092PubMed
2.
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D et al (2019) Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380(12):1116–1127PubMed
3.
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34PubMedPubMedCentral
4.
Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H et al (2018) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379(22):2108–2121PubMed
5.
Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL et al (2018) Nivolumab for relapsed/refractory classic hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial. J Clin Oncol 36(14):1428–1439PubMedPubMedCentral
6.
Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192(7):1027–1034PubMedPubMedCentral
7.
Jacobs JF, Idema AJ, Bol KF, Nierkens S, Grauer OM, Wesseling P et al (2009) Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors. Neuro Oncol 11(4):394–402PubMedPubMedCentral
8.
Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182(2):459–465PubMed
9.
Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z et al (2008) CTLA-4 control over Foxp3 + regulatory T cell function. Science 322(5899):271–275PubMed
10.
Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP (1992) CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356(6370):607–609PubMed
11.
Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T et al (2018) Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol 20(5):674–686PubMed
12.
Reardon DAOA, Brandes AA et al (2017) OS10.3 randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143. Neuro-Oncology 1(19(3):iii21
13.
14.
15.
Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB et al (2019) Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 25(3):477–486PubMedPubMedCentral
16.
Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, Lopez-Janeiro A, Porciuncula A, Idoate MA et al (2019) Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat Med 25(3):470–476PubMed
17.
Zhao J, Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T et al (2019) Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med 25(3):462–469PubMedPubMedCentral
18.
Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M et al (2016) MAP Kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44(3):609–621PubMed
19.
Hapgood JP, Avenant C, Moliki JM (2016) Glucocorticoid-independent modulation of GR activity: implications for immunotherapy. Pharmacol Ther 165:93–113PubMedPubMedCentral
20.
De Bosscher K, Schmitz ML, Vanden Berghe W, Plaisance S, Fiers W, Haegeman G (1997) Glucocorticoid-mediated repression of nuclear factor-kappaB-dependent transcription involves direct interference with transactivation. Proc Natl Acad Sci USA 94(25):13504–13509PubMedPubMedCentral
21.
Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36(17):1714–1768PubMed
22.
23.
Galicich JH, French LA, Melby JC (1961) Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet 81:46–53PubMed
24.
Czock D, Keller F, Rasche FM, Haussler U (2005) Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet 44(1):61–98PubMed
25.
Loew D, Schuster O, Graul EH (1986) Dose-dependent pharmacokinetics of dexamethasone. Eur J Clin Pharmacol 30(2):225–230PubMed
26.
Spoorenberg SM, Deneer VH, Grutters JC, Pulles AE, Voorn GP, Rijkers GT et al (2014) Pharmacokinetics of oral vs. intravenous dexamethasone in patients hospitalized with community-acquired pneumonia. Br J Clin Pharmacol 78(1):78–83PubMed
27.
Weissman DE, Janjan NA, Erickson B, Wilson FJ, Greenberg M, Ritch PS et al (1991) Twice-daily tapering dexamethasone treatment during cranial radiation for newly diagnosed brain metastases. J Neurooncol 11(3):235–239PubMed
28.
Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S et al (2016) Corticosteroids compromise survival in glioblastoma. Brain 139(Pt 5):1458–1471PubMedPubMedCentral
29.
Wong ET, Lok E, Gautam S, Swanson KD (2015) Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. Br J Cancer 113(2):232–241PubMedPubMedCentral
30.
Hughes MA, Parisi M, Grossman S, Kleinberg L (2005) Primary brain tumors treated with steroids and radiotherapy: low CD4 counts and risk of infection. Int J Radiat Oncol Biol Phys 62(5):1423–1426PubMed
31.
Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A et al (2015) Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro-Oncology 17(8):1064–1075PubMed
32.
Berghoff AS, Fuchs E, Ricken G, Mlecnik B, Bindea G, Spanberger T et al (2016) Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases. Oncoimmunology 5(1):e1057388PubMed
33.
Giles AJ, Hutchinson MND, Sonnemann HM, Jung J, Fecci PE, Ratnam NM et al (2018) Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer 6(1):51PubMedPubMedCentral
34.
Fuca G, Galli G, Poggi M, Lo Russo G, Proto C, Imbimbo M et al (2019) Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open 4(1):e000457PubMedPubMedCentral
35.
Cohen JJ (1972) Thymus-derived lymphocytes sequestered in the bone marrow of hydrocortisone-treated mice. J Immunol 108(3):841–844PubMed
36.
Bloemena E, Weinreich S, Schellekens PT (1990) The influence of prednisolone on the recirculation of peripheral blood lymphocytes in vivo. Clin Exp Immunol 80(3):460–466PubMedPubMedCentral
37.
Van Laethem F, Baus E, Smyth LA, Andris F, Bex F, Urbain J et al (2001) Glucocorticoids attenuate T cell receptor signaling. J Exp Med 193(7):803–814PubMedPubMedCentral
38.
Lowenberg M, Tuynman J, Bilderbeek J, Gaber T, Buttgereit F, van Deventer S et al (2005) Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn. Blood 106(5):1703–1710PubMed
39.
Marchetti MC, Di Marco B, Cifone G, Migliorati G, Riccardi C (2003) Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation. Blood 101(2):585–593PubMed
40.
Northrop JP, Crabtree GR, Mattila PS (1992) Negative regulation of interleukin 2 transcription by the glucocorticoid receptor. J Exp Med 175(5):1235–1245PubMed
41.
Paliogianni F, Raptis A, Ahuja SS, Najjar SM, Boumpas DT (1993) Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT. J Clin Invest 91(4):1481–1489PubMedPubMedCentral
42.
Nijhuis EW, Hinloopen B, van Lier RA, Nagelkerken L (1995) Differential sensitivity of human naive and memory CD4 + T cells for dexamethasone. Int Immunol 7(4):591–595PubMed
43.
Lanza L, Scudeletti M, Puppo F, Bosco O, Peirano L, Filaci G et al (1996) Prednisone increases apoptosis in in vitro activated human peripheral blood T lymphocytes. Clin Exp Immunol 103(3):482–490PubMedPubMedCentral
44.
Olnes MJ, Kotliarov Y, Biancotto A, Cheung F, Chen J, Shi R et al (2016) Effects of systemically administered hydrocortisone on the human immunome. Sci Rep 6:23002PubMedPubMedCentral
45.
Xia M, Gasser J, Feige U (1999) Dexamethasone enhances CTLA-4 expression during T cell activation. Cell Mol Life Sci 55(12):1649–1656PubMed
46.
Xing K, Gu B, Zhang P, Wu X (2015) Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy. BMC Immunol 16:39PubMedPubMedCentral
47.
Harmankaya K, Erasim C, Koelblinger C, Ibrahim R, Hoos A, Pehamberger H et al (2011) Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy. Med Oncol 28(4):1140–1144PubMed
48.
Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK et al (2015) Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 33(28):3193–3198PubMedPubMedCentral
49.
Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC et al (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23(25):6043–6053PubMed
50.
Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE et al (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13(22 Pt 1):6681–6688PubMedPubMedCentral
51.
Garant A, Guilbault C, Ekmekjian T, Greenwald Z, Murgoi P, Vuong T (2017) Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with hematologic or solid neoplasms: a systematic review. Crit Rev Oncol Hematol 120:86–92PubMed
52.
Parakh S, Park JJ, Mendis S, Rai R, Xu W, Lo S et al (2017) Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases. Br J Cancer 116(12):1558–1563PubMedPubMedCentral
53.
Queirolo P, Spagnolo F, Ascierto PA, Simeone E, Marchetti P, Scoppola A et al (2014) Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neurooncol 118(1):109–116PubMedPubMedCentral
54.
Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I et al (2012) Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 13(5):459–465PubMed
55.
Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A et al (2018) Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 36(28):2872–2878PubMed
56.
Della Corte CM, Morgillo F (2019) Early use of steroids affects immune cells and impairs immunotherapy efficacy. ESMO Open 4(1):e000477PubMedPubMedCentral
57.
Banna GL, Passiglia F, Colonese F, Canova S, Menis J, Addeo A et al (2018) Immune-checkpoint inhibitors in non-small cell lung cancer: a tool to improve patients’ selection. Crit Rev Oncol Hematol 129:27–39PubMed
Metadata
Title
Glucocorticoids and immune checkpoint inhibitors in glioblastoma
Authors
William J. Kelly
Mark R. Gilbert
Publication date
01-01-2021
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 1/2021
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-020-03439-2

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