Combination of Immunotherapy and Radiotherapy for Recurrent Malignant Gliomas: Results From a Prospective Study

Haihui Jiang, Kefu Yu, Yong Cui, Xiaohui Ren, Mingxiao Li, Chuanwei Yang, Xuzhe Zhao, Qinghui Zhu, Song Lin, Haihui Jiang, Kefu Yu, Yong Cui, Xiaohui Ren, Mingxiao Li, Chuanwei Yang, Xuzhe Zhao, Qinghui Zhu, Song Lin

Abstract

Background: World Health Organization (WHO) grade IV glioma remains one of the most lethal tumors with a dismal prognosis and inevitable recurrence. We evaluated the safety and efficacy of immunotherapy with radiotherapy in this population of patients.

Methods: This study was a single-arm, open-label, phase I trial based on patients with recurrent WHO grade IV glioma. Patients were treated with intracranial and systemic immunoadjuvants in combination with low-dose reirradiation. The primary endpoint of the present trial was safety. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). This trial is registered at ClinicalTrials.gov, NCT03392545.

Results: Thirty patients were enrolled. The most common adverse events (AEs) were fever (66.7%), vomiting (33.3%), headache (30.0%), and fatigue (23.3%). Only a single patient experienced grade 3 fever, and no grade 4 AEs or deaths related to treatment were observed. Of the 30 patients, 1 (3.3%) had a complete response, 5 (16.7%) had a partial response, 9 (30.0%) had stable disease, and 15 (50.0%) had progressive disease, resulting in an objective response rate of 20.0%. The median PFS of the entire cohort was 88.0 (61.0-254.0) days, and the median OS was 362.0 (197.0-601.0) days. Patients could be divided into responders and non-responders, and these groups exhibited a significant difference in terms of survival time, T lymphocyte subsets, frequency of cell division cycle 27 (CDC27) mutation status, and CD15 and CD68 expression (P<0.05).

Conclusion: The combination of immunotherapy and radiotherapy is well tolerated and may provide clinical benefit for patients with recurrent WHO grade IV glioma. A prospective phase II study is needed to further validate the efficacy of our therapeutic regimen.

Keywords: immuno-oncology; immunoadjuvant; immunotherapy; malignant gliomas; reirradiation.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Jiang, Yu, Cui, Ren, Li, Yang, Zhao, Zhu and Lin.

Figures

Figure 1
Figure 1
Treatment scheme for patients enrolled in the present study.
Figure 2
Figure 2
The clinical efficacy of immunoadjuvant treatment and reirradiation in patients with recurrent WHO grade IV gliomas. (A) Waterfall plot showing the best tumor response in patients treated with immunoadjuvant therapy and reirradiation. (B) Swimmer plot showing disease status and survival time in 30 patients treated with immunoadjuvant therapy and reirradiation. (C) The median progression-free survival and overall survival of patients treated with immunoadjuvant therapy and reirradiation.
Figure 3
Figure 3
(A) Representative MR images of patients with different treatment responses. (B, C) Comparisons of survival rates between responders and non-responders. Responders showed a significantly longer progression-free survival (P < 0.0001) and overall survival (P=0.008) than non-responders.
Figure 4
Figure 4
Comparisons of immunological response between responders and non-responders. (A) In the subgroup of responders, the counts of CD8+ T cells and NK cells were significantly increased after receiving immunoadjuvant infusion (P < 0.05). (B) In the subgroup of non-responders, the counts of CD8+ T cells and NK cells were markedly decreased after receiving immunoadjuvant infusion (P < 0.05). *p < 0.05; ns, not significant.
Figure 5
Figure 5
(A) Oncoplot of significantly different mutations, CNVs and cytobands between the responder and non-responder subgroups. (B) Heatmap showing the z-scored mean marker expression of the panel markers for each PhenoGraph cluster. Clusters and markers are grouped by expression profiles. (C) t-SNE plots of 43071 subsampled single cells from each PhenoGraph cluster identified in the heatmap image. Cells are colored by samples and clusters. (D) Heatmap showing the z-score of the mean percentage of single-cell clusters in each sample. Clusters and patients are grouped by the densities of single-cell clusters. (E) Imaging mass cytometry analysis of the tumor immune microenvironment between responders and non-responders. The non-responders showed higher percentages of CD15+ (green) and CD68+ (red) cells than the responders (P < 0.001). ***p value < 0.001.

References

    1. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. . CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro Oncol (2019) 21:v1–v100. 10.1093/neuonc/noz150
    1. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, 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) 10:459–66. 10.1016/S1470-2045(09)70025-7
    1. Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, et al. . Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. JAMA (2017) 318:2306–16. 10.1001/jama.2017.18718
    1. Jiang H, Zeng W, Ren X, Cui Y, Li M, Yang K, et al. . Super-Early Initiation of Temozolomide Prolongs the Survival of Glioblastoma Patients Without Gross-Total Resection: A Retrospective Cohort Study. J Neurooncol (2019) 144:127–35. 10.1007/s11060-019-03211-1
    1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. . Radiotherapy Plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med (2005) 352:987–96. 10.1056/NEJMoa043330
    1. Tan AC, Ashley DM, Lopez GY, Malinzak M, Friedman HS, Khasraw M. Management of Glioblastoma: State of the Art and Future Directions. CA Cancer J Clin (2020) 70:299–312. 10.3322/caac.21613
    1. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. . Five-Year Survival With Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med (2019) 381:1535–46. 10.1056/NEJMoa1910836
    1. Berner F, Bomze D, Diem S, Ali OH, Fassler M, Ring S, et al. . Association of Checkpoint Inhibitor-Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer. JAMA Oncol (2019) 5:1043–7. 10.1001/jamaoncol.2019.0402
    1. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. . Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med (2020) 382:545–53. 10.1056/NEJMoa1910607
    1. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. . Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med (2018) 379:2108–21. 10.1056/NEJMoa1809615
    1. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. . Structural and Functional Features of Central Nervous System Lymphatic Vessels. Nature (2015) 523:337–41. 10.1038/nature14432
    1. Cloughesy TF, Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. . Neoadjuvant anti-PD-1 Immunotherapy Promotes a Survival Benefit With Intratumoral and Systemic Immune Responses in Recurrent Glioblastoma. Nat Med (2019) 25:477–86. 10.1038/s41591-018-0337-7
    1. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. . Regression of Glioblastoma After Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med (2016) 375:2561–9. 10.1056/NEJMoa1610497
    1. Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanovic S, Gouttefangeas C, et al. . Actively Personalized Vaccination Trial for Newly Diagnosed Glioblastoma. Nature (2019) 565:240–5. 10.1038/s41586-018-0810-y
    1. Desjardins A, Gromeier M, Herndon JE,2, Beaubier N, Bolognesi Dp, Friedman AH, et al. . Recurrent Glioblastoma Treated With Recombinant Poliovirus. N Engl J Med (2018) 379:150–61. 10.1056/NEJMoa1716435
    1. Jackson CM, Choi J, Lim M. Mechanisms of Immunotherapy Resistance: Lessons From Glioblastoma. Nat Immunol (2019) 20:1100–9. 10.1038/s41590-019-0433-y
    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: The CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol (2020) 7:1003–10. 10.1001/jamaoncol.2020.1024
    1. Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, et al. . Combining Radiation and Immunotherapy: A New Systemic Therapy for Solid Tumors? Cancer Immunol Res (2014) 2:831–8. 10.1158/2326-6066.CIR-14-0069
    1. Crittenden M, Kohrt H, Levy R, Jones J, Camphausen K, Dicker A, et al. . Current Clinical Trials Testing Combinations of Immunotherapy and Radiation. Semin Radiat Oncol (2015) 25:54–64. 10.1016/j.semradonc.2014.07.003
    1. Tran TA, Kim YH, Duong TH, Jung S, Kim IY, Moon KS, et al. . Peptide Vaccine Combined Adjuvants Modulate Anti-tumor Effects of Radiation in Glioblastoma Mouse Model. Front Immunol (2020) 11:1165. 10.3389/fimmu.2020.01165
    1. Reznik E, Smith AW, Taube S, Mann J, Yondorf MZ, Parashar B, et al. . Radiation and Immunotherapy in High-grade Gliomas: Where do We Stand? Am J Clin Oncol (2018) 41:197–212. 10.1097/COC.0000000000000406
    1. Grass GD, Krishna N, Kim S. The Immune Mechanisms of Abscopal Effect in Radiation Therapy. Curr Probl Cancer (2016) 40:10–24. 10.1016/j.currproblcancer.2015.10.003
    1. Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D. The Abscopal Effect of Local Radiotherapy: Using Immunotherapy to Make a Rare Event Clinically Relevant. Cancer Treat Rev (2015) 41:503–10. 10.1016/j.ctrv.2015.03.011
    1. Zhu X, Fallert-Junecko BA, Fujita M, Ueda R, Kohanbash G, Kastenhuber ER, et al. . Poly-ICLC Promotes the Infiltration of Effector T Cells Into Intracranial Gliomas Via Induction of CXCL10 in IFN-alpha and IFN-gamma Dependent Manners. Cancer Immunol Immunother (2010) 59:1401–9. 10.1007/s00262-010-0876-3
    1. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. . Metronomic Cyclophosphamide Regimen Selectively Depletes CD4+CD25+ Regulatory T Cells and Restores T and NK Effector Functions in End Stage Cancer Patients. Cancer Immunol Immunother (2007) 56:641–8. 10.1007/s00262-006-0225-8
    1. Berd D, Mastrangelo MJ. Effect of Low Dose Cyclophosphamide on the Immune System of Cancer Patients: Reduction of T-suppressor Function Without Depletion of the CD8+ Subset. Cancer Res (1987) 47:3317–21.
    1. Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W, et al. . Immunotherapy Response Assessment in Neuro-Oncology: A Report of the RANO Working Group. Lancet Oncol (2015) 16:e534–e42. 10.1016/S1470-2045(15)00088-1
    1. Zang YS, Dai C, Xu XM, Cai X, Wang G, Wei JW, et al. . Comprehensive Analysis of Potential Immunotherapy Genomic Biomarkers in 1000 Chinese Patients With Cancer. Cancer Med-Us (2019) 8:4699–708. 10.1002/cam4.2381
    1. McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, et al. . The Ensembl Variant Effect Predictor. Genome Biol (2016) 17:122. 10.1186/s13059-016-0974-4
    1. Medikonda R, Dunn G, Rahman M, Fecci P, Lim M. A review of glioblastoma immunotherapy. J Neurooncol (2021) 151:41–53. 10.1007/s11060-020-03448-1
    1. Kim HR, Kim KH, Kong DS, Seol HJ, Nam DH, Lim DH, et al. . Outcome of Salvage Treatment for Recurrent Glioblastoma. J Clin Neurosci (2015) 22:468–73. 10.1016/j.jocn.2014.09.018
    1. Chen DS, Mellman I. Elements of Cancer Immunity and the Cancer-Immune Set Point. Nature (2017) 541:321–30. 10.1038/nature21349
    1. Cheever MA. Twelve Immunotherapy Drugs That Could Cure Cancers. Immunol Rev (2008) 222:357–68. 10.1111/j.1600-065X.2008.00604.x
    1. Ammi R, De Waele J, Willemen Y, Van Brussel I, Schrijvers DM, Lion E, et al. . Poly(I:C) as Cancer Vaccine Adjuvant: Knocking on the Door of Medical Breakthroughs. Pharmacol Ther (2015) 146:120–31. 10.1016/j.pharmthera.2014.09.010
    1. Glas M, Coch C, Trageser D, Dassler J, Simon M, Koch P, et al. . Targeting the Cytosolic Innate Immune Receptors RIG-I and MDA5 Effectively Counteracts Cancer Cell Heterogeneity in Glioblastoma. Stem Cells (2013) 31:1064–74. 10.1002/stem.1350
    1. Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A, Normolle DP, et al. . Immune Responses and Outcome After Vaccination With Glioma-Associated Antigen Peptides and poly-ICLC in a Pilot Study for Pediatric Recurrent Low-Grade Gliomas. Neuro Oncol (2016) 18:1157–68. 10.1093/neuonc/now026
    1. Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A, Normolle DP, et al. . Antigen-Specific Immunoreactivity and Clinical Outcome Following Vaccination With Glioma-Associated Antigen Peptides in Children With Recurrent High-Grade Gliomas: Results of a Pilot Study. J Neurooncol (2016) 130:517–27. 10.1007/s11060-016-2245-3
    1. Banstola A, Jeong JH, Yook S. Immunoadjuvants for Cancer Immunotherapy: A Review of Recent Developments. Acta Biomater (2020) 114:16–30. 10.1016/j.actbio.2020.07.063
    1. Perez-Giron JV, Belicha-Villanueva A, Hassan E, Gomez-Medina S, Cruz JL, Ludtke A, et al. . Mucosal Polyinosinic-Polycytidylic Acid Improves Protection Elicited by Replicating Influenza Vaccines Via Enhanced Dendritic Cell Function and T Cell Immunity. J Immunol (2014) 193:1324–32. 10.4049/jimmunol.1400222
    1. De Waele J, Marcq E, Van Audenaerde JR, Van Loenhout J, Deben C, Zwaenepoel K, et al. . Poly(I:C) Primes Primary Human Glioblastoma Cells for an Immune Response Invigorated by PD-L1 Blockade. Oncoimmunology (2018) 7:e1407899. 10.1080/2162402X.2017.1407899
    1. Nikolich-Zugich J. The Twilight of Immunity: Emerging Concepts in Aging of the Immune System. Nat Immunol (2018) 19:10–9. 10.1038/s41590-017-0006-x
    1. McElhaney JE, Dutz JP. Better Influenza Vaccines for Older People: What Will it Take? J Infect Dis (2008) 198:632–4. 10.1086/590435
    1. Lieberman NAP, DeGolier K, Kovar HM, Davis A, Hoglund V, Stevens J, et al. . Characterization of the Immune Microenvironment of Diffuse Intrinsic Pontine Glioma: Implications for Development of Immunotherapy. Neuro Oncol (2019) 21:83–94. 10.1093/neuonc/noy145
    1. Pant A, Lim M. Understanding Innate Immune Response in Glioblastoma in Search of a Way Forward. Neuro Oncol (2020) 22:444–5. 10.1093/neuonc/noaa038
    1. Song Y, Song W, Li Z, Song W, Wen Y, Li J, et al. . Cdc27 Promotes Tumor Progression and Affects Pd-L1 Expression in T-Cell Lymphoblastic Lymphoma. Front Oncol (2020) 10:488. 10.3389/fonc.2020.00488
    1. Wang L, Zhang C, Zhang Z, Han B, Shen Z, Li L, et al. . Specific Clinical and Immune Features of CD68 in Glioma Via 1,024 Samples. Cancer Manag Res (2018) 10:6409–19. 10.2147/CMAR.S183293
    1. Dubinski D, Wolfer J, Hasselblatt M, Schneider-Hohendorf T, Bogdahn U, Stummer W, et al. . Cd4+ T Effector Memory Cell Dysfunction is Associated With the Accumulation of Granulocytic Myeloid-Derived Suppressor Cells in Glioblastoma Patients. Neuro Oncol (2016) 18:807–18. 10.1093/neuonc/nov280
    1. Frafjord A, Skarshaug R, Hammarstrom C, Stankovic B, Dorg LT, Aamodt H, et al. . Antibody Combinations for Optimized Staining of Macrophages in Human Lung Tumours. Scand J Immunol (2020) 92:e12889. 10.1111/sji.12889
    1. Nam SJ, Kim YH, Park JE, Ra YS, Khang SK, Cho YH, et al. . Tumor-Infiltrating Immune Cell Subpopulations and Programmed Death Ligand 1 (PD-L1) Expression Associated With Clinicopathological and Prognostic Parameters in Ependymoma. Cancer Immunol Immunother (2019) 68:305–18. 10.1007/s00262-018-2278-x
    1. Hwang I, Kim JW, Ylaya K, Chung EJ, Kitano H, Perry C, et al. . Tumor-Associated Macrophage, Angiogenesis and Lymphangiogenesis Markers Predict Prognosis of non-Small Cell Lung Cancer Patients. J Transl Med (2020) 18:443. 10.1186/s12967-020-02618-z

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