Challenges in Immunotherapy Presented by the Glioblastoma Multiforme Microenvironment

Overview

Journal Clin Dev Immunol

Specialty Allergy & Immunology

Date 2011 Dec 23

PMID 22190972

Citations 89

Authors

Christopher Jackson

Jacob Ruzevick

Jillian Phallen

Zineb Belcaid

Michael Lim

Affiliations

Soon will be listed here.

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite intensive treatment, the prognosis for patients with GBM remains grim with a median survival of only 14.6 months. Immunotherapy has emerged as a promising approach for treating many cancers and affords the advantages of cellular-level specificity and the potential to generate durable immune surveillance. The complexity of the tumor microenvironment poses a significant challenge to the development of immunotherapy for GBM, as multiple signaling pathways, cytokines, and cell types are intricately coordinated to generate an immunosuppressive milieu. The development of new immunotherapy approaches frequently uncovers new mechanisms of tumor-mediated immunosuppression. In this review, we discuss many of the current approaches to immunotherapy and focus on the challenges presented by the tumor microenvironment.

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References

Annes J, Munger J, Rifkin D . Making sense of latent TGFbeta activation. J Cell Sci. 2002; 116(Pt 2):217-24. DOI: 10.1242/jcs.00229. View

Hussain S, Heimberger A . Immunotherapy for human glioma: innovative approaches and recent results. Expert Rev Anticancer Ther. 2005; 5(5):777-90. DOI: 10.1586/14737140.5.5.777. View

Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B . Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia. 2009; 57(13):1458-67. DOI: 10.1002/glia.20863. View

McCord A, Jamal M, Williams E, Camphausen K, Tofilon P . CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin Cancer Res. 2009; 15(16):5145-53. PMC: 6290462. DOI: 10.1158/1078-0432.CCR-09-0263. View

Jobling M, Mott J, Finnegan M, Jurukovski V, Erickson A, Walian P . Isoform-specific activation of latent transforming growth factor beta (LTGF-beta) by reactive oxygen species. Radiat Res. 2006; 166(6):839-48. DOI: 10.1667/RR0695.1. View

Pachter J, de Vries H, Fabry Z . The blood-brain barrier and its role in immune privilege in the central nervous system. J Neuropathol Exp Neurol. 2003; 62(6):593-604. DOI: 10.1093/jnen/62.6.593. View

de Vleeschouwer S, Van Calenbergh F, Demaerel P, Flamen P, Rutkowski S, Kaempgen E . Transient local response and persistent tumor control in a child with recurrent malignant glioma: treatment with combination therapy including dendritic cell therapy. Case report. J Neurosurg. 2004; 100(5 Suppl Pediatrics):492-7. DOI: 10.3171/ped.2004.100.5.0492. View

Kawakami K, Kioi M, Liu Q, Kawakami M, Puri R . Evidence that IL-13R alpha2 chain in human glioma cells is responsible for the antitumor activity mediated by receptor-directed cytotoxin therapy. J Immunother. 2005; 28(3):193-202. DOI: 10.1097/01.cji.0000161393.04207.e1. View

Barba D, Saris S, Holder C, Rosenberg S, Oldfield E . Intratumoral LAK cell and interleukin-2 therapy of human gliomas. J Neurosurg. 1989; 70(2):175-82. DOI: 10.3171/jns.1989.70.2.0175. View

10.

Harris J, Markl J . Keyhole limpet hemocyanin (KLH): a biomedical review. Micron. 1999; 30(6):597-623. DOI: 10.1016/s0968-4328(99)00036-0. View

11.

Kaplan D, Shankaran V, Dighe A, STOCKERT E, Aguet M, Old L . Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A. 1998; 95(13):7556-61. PMC: 22681. DOI: 10.1073/pnas.95.13.7556. View

12.

Lampson L, Wen P, Roman V, Morris J, Sarid J . Disseminating tumor cells and their interactions with leukocytes visualized in the brain. Cancer Res. 1992; 52(4):1018-25. View

13.

Allen J, Packer R, Bleyer A, Zeltzer P, Prados M, Nirenberg A . Recombinant interferon beta: a phase I-II trial in children with recurrent brain tumors. J Clin Oncol. 1991; 9(5):783-8. DOI: 10.1200/JCO.1991.9.5.783. View

14.

Tabatabai G, Frank B, Mohle R, Weller M, Wick W . Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-beta-dependent HIF-1alpha-mediated induction of CXCL12. Brain. 2006; 129(Pt 9):2426-35. DOI: 10.1093/brain/awl173. View

15.

Hayes R, Koslow M, Hiesiger E, Hymes K, Hochster H, Moore E . Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma. Cancer. 1995; 76(5):840-52. DOI: 10.1002/1097-0142(19950901)76:5<840::aid-cncr2820760519>3.0.co;2-r. View

16.

Algarra I, Cabrera T, Garrido F . The HLA crossroad in tumor immunology. Hum Immunol. 2000; 61(1):65-73. DOI: 10.1016/s0198-8859(99)00156-1. View

17.

Tjoa B, Simmons S, Elgamal A, Rogers M, RAGDE H, Kenny G . Follow-up evaluation of a phase II prostate cancer vaccine trial. Prostate. 1999; 40(2):125-9. DOI: 10.1002/(sici)1097-0045(19990701)40:2<125::aid-pros8>3.0.co;2-y. View

18.

Libermann T, Nusbaum H, Razon N, Kris R, Lax I, Soreq H . Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985; 313(5998):144-7. DOI: 10.1038/313144a0. View

19.

Wen Z, Zhong Z, Darnell Jr J . Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995; 82(2):241-50. DOI: 10.1016/0092-8674(95)90311-9. View

20.

Langowski J, Zhang X, Wu L, Mattson J, Chen T, Smith K . IL-23 promotes tumour incidence and growth. Nature. 2006; 442(7101):461-5. DOI: 10.1038/nature04808. View