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Iorgulescu JB, Gokhale PC, Speranza MC, et al. Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma. Clin Cancer Res. 2020;27(1):276-287doi: 10.1158/1078-0432.CCR-20-2291.
Iorgulescu, J. B., Gokhale, P. C., Speranza, M. C., Eschle, B. K., Poitras, M. J., Wilkens, M. K., Soroko, K. M., Chhoeu, C., Knott, A., Gao, Y., Lim-Fat, M. J., Baker, G. J., Bonal, D. M., Nguyen, Q. D., Grant, G. R. L., Ligon, K. L., Sorger, P. K., Chiocca, E. A., Anderson, A. C., Kirschmeier, P. T., Sharpe, A. H., Freeman, G. J., & Reardon, D. A. (2021). Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research, 27(1), 276-287. https://doi.org/10.1158/1078-0432.CCR-20-2291
Iorgulescu, J Bryan, et al. "Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma." Clinical cancer research : an official journal of the American Association for Cancer Research vol. 27,1 (2021): 276-287. doi: https://doi.org/10.1158/1078-0432.CCR-20-2291
Iorgulescu JB, Gokhale PC, Speranza MC, Eschle BK, Poitras MJ, Wilkens MK, Soroko KM, Chhoeu C, Knott A, Gao Y, Lim-Fat MJ, Baker GJ, Bonal DM, Nguyen QD, Grant GRL, Ligon KL, Sorger PK, Chiocca EA, Anderson AC, Kirschmeier PT, Sharpe AH, Freeman GJ, Reardon DA. Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma. Clin Cancer Res. 2021 Jan 01;27(1):276-287. doi: 10.1158/1078-0432.CCR-20-2291. Epub 2020 Nov 25. PMID: 33239433; PMCID: PMC8034990.
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Clin Cancer Res. 2021 Jan 01;27(1):276-287. doi: 10.1158/1078-0432.CCR-20-2291. Epub 2020 Nov 25.

Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma.

Clinical cancer research : an official journal of the American Association for Cancer Research

J Bryan Iorgulescu, Prafulla C Gokhale, Maria C Speranza, Benjamin K Eschle, Michael J Poitras, Margaret K Wilkens, Kara M Soroko, Chhayheng Chhoeu, Aine Knott, Yan Gao, Mary Jane Lim-Fat, Gregory J Baker, Dennis M Bonal, Quang-Dé Nguyen, Gareth R L Grant, Keith L Ligon, Peter K Sorger, E Antonio Chiocca, Ana C Anderson, Paul T Kirschmeier, Arlene H Sharpe, Gordon J Freeman, David A Reardon

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  2. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
  3. Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  4. Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  5. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.
  6. Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
  7. University of Glasgow Medical School, Glasgow, Scotland, United Kingdom.
  8. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  9. Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
  10. Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts.
  11. Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts.
  12. Department of Immunology, Blavatnik Institute, Harvard Medical School and Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, Massachusetts.
  13. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. [email protected].

PMID: 33239433 PMCID: PMC8034990 DOI: 10.1158/1078-0432.CCR-20-2291

Abstract

PURPOSE: Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy.

EXPERIMENTAL DESIGN: We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors.

RESULTS: Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; <2 mg HR, 2.16; 95% confidence interval (CI), 1.30-3.68;

CONCLUSIONS: Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.

©2020 American Association for Cancer Research.

References

  1. Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma. JAMA Oncol. 2020;6:1–8. - PubMed
  2. Nduom EK, Weller M, Heimberger AB. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 2015;17:vii9–14. - PubMed
  3. Perng P, Lim M. Immunosuppressive mechanisms of malignant gliomas: parallels at non-CNS sites. Front Oncol. 2015;5:153. - PubMed
  4. Ladomersky E, Zhai L, Lauing K, Bell A, Xu J, Kocherginsky M, et al. Advanced age increases immunosuppression in the brain and decreases immunotherapeutic efficacy in subjects with glioblastoma. Clin Cancer Res. 2020;26:5232–45. - PubMed
  5. Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. 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. 2018;36:2872–8. - PubMed
  6. Ricciuti B, Dahlberg SE, Adeni A, Sholl LM, Nishino M, Awad MM. Immune checkpoint inhibitor outcomes for patients with non–small-cell lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications. J Clin Oncol. 2019;37:1927–34. - PubMed
  7. Tokunaga A, Sugiyama D, Maeda Y, Warner AB, Panageas KS, Ito S, et al. Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids. J Exp Med. 2019;216:2701–13. - PubMed
  8. Chiocca EA, Yu JS, Lukas RV, Solomon IH, Ligon KL, Nakashima H, et al. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial. Sci Transl Med. 2019;11:eaaw5680. - PubMed
  9. Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2019;565:234–9. - PubMed
  10. Kostaras X, Cusano F, Kline GA, Roa W, Easaw J. Use of dexamethasone in patients with high-grade glioma: a clinical practice guideline. Curr Oncol Tor Ont. 2014;21:e493–503. - PubMed
  11. Roth P, Happold C, Weller M. Corticosteroid use in neuro-oncology: an update. Neuro-Oncol Pract. 2015;2:6–12. - PubMed
  12. Dietrich J, Rao K, Pastorino S, Kesari S. Corticosteroids in brain cancer patients: benefits and pitfalls. Expert Rev Clin Pharmacol. 2011;4:233–42. - PubMed
  13. Reardon DA, Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol Res. 2016;4:124–35. - PubMed
  14. Maes W, Van Gool SW. Experimental immunotherapy for malignant glioma: lessons from two decades of research in the GL261 model. Cancer Immunol Immunother. 2011;60:153–60. - PubMed
  15. Nakashima H, Alayo QA, Penaloza-MacMaster P, Freeman GJ, Kuchroo VK, Reardon DA, et al. Modeling tumor immunity of mouse glioblastoma by exhausted CD8+ T cells. Sci Rep. 2018;8:208. - PubMed
  16. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22:886–94. - PubMed
  17. Faje AT, Lawrence D, Flaherty K, Freedman C, Fadden R, Rubin K, et al. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. Cancer. 2018;124:3706–14. - PubMed
  18. Pitter KL, Tamagno I, Alikhanyan K, Hosni-Ahmed A, Pattwell SS, Donnola S, et al. Corticosteroids compromise survival in glioblastoma. Brain. 2016;139:1458–71. - PubMed
  19. Shields LBE, Shelton BJ, Shearer AJ, Chen L, Sun DA, Parsons S, et al. Dexamethasone administration during definitive radiation and temozolomide renders a poor prognosis in a retrospective analysis of newly diagnosed glioblastoma patients. Radiat Oncol. 2015;10:222. - PubMed
  20. Gustafson MP, Lin Y, New KC, Bulur PA, O'Neill BP, Gastineau DA, et al. Systemic immune suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and dexamethasone. Neuro Oncol. 2010;12:631–44. - PubMed
  21. Chitadze G, Flüh C, Quabius ES, Freitag-Wolf S, Peters C, Lettau M, et al. In-depth immunophenotyping of patients with glioblastoma multiforme: impact of steroid treatment. Oncoimmunology. 2017;6:e1358839. - PubMed
  22. Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86:343–9. - PubMed
  23. Johanns TM, Ward JP, Miller CA, Wilson C, Kobayashi DK, Bender D, et al. Endogenous neoantigen-specific CD8 T cells identified in two glioblastoma models using a cancer immunogenomics approach. Cancer Immunol Res. 2016;4:1007–15. - PubMed
  24. Touat M, Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature. 2020;580:517–23. - PubMed
  25. Rutledge WC, Kong J, Gao J, Gutman DA, Cooper LAD, Appin C, et al. Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Clin Cancer Res. 2013;19:4951–60. - PubMed
  26. Maxwell R, Luksik AS, Garzon-Muvdi T, Hung AL, Kim ES, Wu A, et al. Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system. Oncoimmunology. 2018;7:e1500108. - PubMed
  27. Giles AJ, Hutchinson M-KND, Sonnemann HM, Jung J, Fecci PE, Ratnam NM, et al. Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy. J Immunother Cancer. 2018;6:51. - PubMed
  28. Kumar D, Sehrawat S. Divergent effects of a transient corticosteroid therapy on virus-specific quiescent and effector CD8+ T cells. Front Immunol. 2019;10:1521. - PubMed
  29. Aston WJ, Hope DE, Cook AM, Boon L, Dick I, Nowak AK, et al. Dexamethasone differentially depletes tumour and peripheral blood lymphocytes and can impact the efficacy of chemotherapy/checkpoint blockade combination treatment. Oncoimmunology. 2019;8:e1641390. - PubMed
  30. Bianchi M, Meng C, Ivashkiv LB. Inhibition of IL-2-induced Jak-STAT signaling by glucocorticoids. Proc Natl Acad Sci U S A. 2000;97:9573–9578. - PubMed
  31. Franchimont D, Galon J, Vacchio MS, Fan S, Visconti R, Frucht DM, et al. Positive effects of glucocorticoids on T cell function by up-regulation of IL-7 receptor alpha. J Immunol. 2002;168:2212–8. - PubMed
  32. Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in immune privilege of the CNS. Nat Immunol. 2017;18:123–131. - PubMed
  33. Medikonda R, Dunn G, Rahman M, Fecci P, Lim M. A review of glioblastoma immunotherapy. J Neurooncol. 2020. - PubMed
  34. Parakh S, Park JJ, Mendis S, Rai R, Xu W, Lo S, et al. Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases. Br J Cancer. 2017;116:1558–1563. - PubMed
  35. Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459–465. - PubMed
  36. Candolfi M, Curtin JF, Nichols WS, Muhammad AG, King GD, Pluhar GE, et al. Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression. J Neurooncol. 2007;85:133–48. - PubMed
  37. Kleijn A, Kloezeman J, Treffers-Westerlaken E, Fulci G, Leenstra S, Dirven C, et al. The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity. PLoS One. 2014;9:e97495. - PubMed

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