March 2015, Vol. 2, No. 2
Immunotherapy in Glioblastoma, the Most Lethal Form of Brain Cancer
Glioblastoma is one of the major cancer types for which new immune-based cancer treatments are currently in development
The American Cancer Society estimates that approximately 22,850 malignant tumors of the brain and spinal cord (12,900 in men and 9950 in women) will be diagnosed in the United States in 2015, and about 15,320 patients (8940 men and 6380 women) will die of these tumors this year.1 Glioblastoma multiforme, a type of glioma (ie, World Health Organization grade 4 glioma), is the most prevalent and aggressive form of malignant primary brain cancer, accounting for 45.6% of all primary malignant brain tumors.2 In 2015, 10,200 new cases of glioblastoma are predicted to be diagnosed.2 Glioblastoma has been associated with a particularly poor prognosis, with only one-third of patients surviving for 1 year and less than 5% living beyond 5 years.2-4 The median survival time after diagnosis for patients with glioblastoma is 14.6 months.5
Famous people who have had glioblastoma include Senator Edward Kennedy (survived 15 months after diagnosis),6 actress Ethel Merman (survived 10 months),7 Chairman of the Republican National Committee Lee Atwater (survived 12 months),8 and Major League Baseball relief pitcher Frank Edwin “Tug” McGraw Jr (survived 9 months).9
Unmet Need for New Therapies to Treat Glioblastoma
The current standard of care for patients with newly diagnosed glioblastoma is surgical resection followed by fractionated external beam radiotherapy and systemic temozolomide,4 resulting in a median overall survival (OS) of 14.6 months based on data from a randomized phase 3 trial.5 Although this treatment can prolong survival, it is not curative, and the vast majority of patients with glioblastoma experience recurrent disease, with a median time to recurrence of 7 months.10 Currently, there is no standard treatment for patients with recurrent glioblastoma, although additional surgery, radiotherapy, chemotherapy (eg, temozolomide), bevacizumab, and low-intensity electric fields are used4 (Table).
Temozolomide, an alkylating (methylating) agent, is the current standard of care in conjunction with postoperative radiotherapy for patients with newly diagnosed glioblastoma.4 Temozolomide was approved by the Food and Drug Administration (FDA) in 2005 to treat newly diagnosed adult patients with glioblastoma based on results from a randomized phase 3 clinical study (N = 573) in which temozolomide added 2.5 months to the median OS (median survival was 14.6 months for the group receiving temozolomide plus radiotherapy vs 12.1 months for the group receiving radiotherapy alone) and 1.9 months to the median progression-free survival (PFS) time (median PFS was 6.9 months for the group receiving temozolomide plus radiotherapy vs 5.0 months for the group receiving radiotherapy alone).5 However, resistance to temozolomide is modulated by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT).11 MGMT status has been demonstrated to be predictive of response to radiation or chemotherapy. The MGMT gene is responsible for a DNA repair mechanism in cells. Methylation of MGMT impedes the DNA repair mechanism in cancer cells, making them susceptible to radiation or chemotherapy such as temozolomide. The DNA repair mechanism in cancer cells with unmethylated MGMT is intact, enabling them to survive and proliferate. Thus, in a significant subset of glioblastoma tumors, expression of MGMT is silenced by promoter methylation, causing resistance to the drug.11 Over 40% of patients undergoing chemotherapy and 55% of newly diagnosed cases do not benefit at all from the addition of temozolomide to their treatment.12,13
Chemotherapy-Impregnated Implantable Wafers
In 1996, the FDA approved an implantable biodegradable wafer (known as polifeprosan 20 with carmustine implant) as an adjunct to surgery in patients with recurrent glioblastoma based on the results from a double-blind, placebo-controlled, phase 3 study in which the implantation increased survival at 6 months by more than 50% in the subset of patients with glioblastoma (from 36% in the placebo group to 56% in those who received the implantable wafer).18,19 Similar to temozolomide, carmustine is a DNA alkylating agent. The dime-sized wafer is made up of a biocompatible polymer that contains the cancer chemotherapeutic drug carmustine (BCNU). Following removal of the tumor by a neurosurgeon, up to 8 wafers (depending on anatomic limitations) can be implanted in the cavity where the tumor resided. Once implanted, the wafers slowly dissolve, releasing high concentrations of BCNU directly into the tumor site. The specificity of this treatment minimizes drug exposure to other areas of the body.18,20,21 However, the National Comprehensive Cancer Network guidelines warn that BCNU wafers can potentially interact with other agents, resulting in increased toxicity, and implantation of the wafers may preclude future participation in clinical trials of adjuvant therapy.4 In clinical trials, carmustine wafers used in combination with radiation and temozolomide have been shown to modestly prolong survival in subsets of patients. However, because there are complications associated with the use of wafers, including infection, swelling, need for removal, and impairment of wound healing,22-24 they are not used routinely at most centers.25 In addition, BCNU wafers have not been proved to confer a significant advantage in survival for patients with grade 3 tumors when treated with the drug, compared with placebo; there does not appear to be a survival advantage for patients with grade 4 tumors, and no increase in PFS has been shown.14
Antiangiogenic strategies are a promising approach for glioblastomas due to the highly vascular nature of these tumors, and preclinical data have demonstrated that their growth is dependent on angiogenesis.26,27 In 2009, the FDA granted accelerated approval to bevacizumab, a vascular endothelial growth factor A–specific angiogenesis inhibitor, as a single agent for the treatment of patients with recurrent glioblastoma based on results from 2 open-label phase 2 studies.28-30 In the first study, which randomized 167 patients to bevacizumab with or without irinotecan, MRI-defined objective response was achieved in 28% of patients who received bevacizumab alone and in 38% of patients who received both bevacizumab and irinotecan.29 Median survival was approximately 9 months, similar to that found in a previous phase 2 trial.31 In the other pivotal study, 48 heavily pretreated patients with recurrent glioblastoma treated with single-agent bevacizumab had a median OS of 31 weeks, and 6-month OS was 57%.30
In the frontline setting, bevacizumab failed to increase OS or statistically significant PFS for newly diagnosed patients with glioblastoma in the RTOG 0825 study.15 In this randomized, double-blind, placebo-controlled phase 3 study, 637 patients with glioblastoma were treated with radiotherapy and temozolomide. Patients received either bevacizumab or placebo beginning during week 4 of radiotherapy and continued for up to 12 cycles of maintenance chemotherapy. There was no significant difference in the duration of OS between the bevacizumab group and the placebo group (median, 15.7 and 16.1 months, respectively; hazard ratio [HR] for death in the bevacizumab group, 1.13). PFS was longer in the bevacizumab group (10.7 months vs 7.3 months; HR for progression or death, 0.79). Increases in rates of hypertension, thromboembolic events, intestinal perforation, and neutropenia were seen in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life, and a decline in neurocognitive function were more frequent in the bevacizumab group.15
In a similar randomized, double-blind, placebo-controlled phase 3 study (the AVAglio study) of bevacizumab in the frontline setting, 921 patients with glioblastoma treated with radiotherapy and temozolomide received either bevacizumab or placebo (458 patients were assigned to the bevacizumab group and 463 patients to the placebo group).32 In this study, as in the RTOG 0825 study, median PFS was longer in the bevacizumab group than in the placebo group (10.6 months vs 6.2 months; HR for progression or death, 0.64; 95% CI, 0.55-0.74; P <.001), and OS did not differ significantly between groups (HR for death, 0.88; 95% CI, 0.76-1.02; P = .10). The respective OS rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P = .049) and 33.9% and 30.1% at 2 years (P = .24). In contrast to the RTOG 0825 study, baseline quality of life and performance status were maintained longer in the bevacizumab group in the AVAglio study; however, the rate of adverse events was higher with bevacizumab than with placebo. More patients in the bevacizumab group than in the placebo group had grade ?3 adverse events (66.8% vs 51.3%) and grade ?3 adverse events often associated with bevacizumab (32.5% vs 15.8%).32
Overall concerns regarding the use of antiangiogenic therapies such as bevacizumab include that they may promote the emergence of a more aggressive phenotype tumor and aid metastasis, as well as inhibit wound healing and promote infection.16,17
Tumor Treating Fields
In 2011, the FDA approved a portable medical device that generates low-intensity electric fields termed Tumor Treating Fields (TTF) for the treatment of recurrent glioblastoma. Approval was based on results from a clinical trial that randomized 237 patients to TTF or chemotherapy.33 Although TTF therapy was associated with lower toxicity than chemotherapy, as well as improved quality of life, it lacked improved efficacy; similar survival was observed in the 2 groups in the study.33
Emerging Immunotherapeutic Approaches
Because of the limited treatment options for patients with glioblastoma, there is an urgent need for new targeted treatment options. However, the brain has been characterized as one of the “immunologically privileged” sites that are able to tolerate the introduction of an antigen without eliciting an inflammatory immune response.34 Therefore, it might seem that immunotherapy would not be effective in treating brain tumors. However, it is now known that an immune response can be generated against antigens in the brain, making immunotherapeutic approaches for glioblastoma possible.35,36
Many promising immunotherapies for glioblastoma are in development, including passive, active, and adoptive immunotherapeutic approaches. Passive immunotherapy involves administering antibodies or toxins to patients without specifically inducing or expanding a host antitumor response. Active immunotherapy involves immunizing the tumor-bearing host with a “vaccine” to expand an antitumor immune response in vivo. Adoptive immunotherapy, on the other hand, employs the ex vivo expansion of effector cells and return of these cells to the tumor-bearing host. Examples of active immunotherapies include autologous tumor cell vaccines, heat shock protein peptide-based vaccines, and rindopepimut (CDX-110; an epidermal growth factor receptor variant III [EGFRvIII]-specific peptide conjugated to a nonspecific immunomodulator). Adoptive immunotherapy strategies include various dendritic cell vaccines in which autologous dendritic cells are isolated from patients, pulsed with tumor-specific molecules (eg, tumor-specific peptides such as EGFRvIII), expanded ex vivo, and then reintroduced to the patient.
Immunotherapies such as dendritic cell vaccines, heat shock protein vaccines, and EGFRvIII vaccines have shown encouraging results in clinical trials and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase 3 trials. The future of glioblastoma therapeutics will involve focusing on developing strategies and finding the place for these emerging immunotherapies in the multimodal treatment regimen.37
- American Cancer Society. Brain and Spinal Cord Tumors in Adults. What are the key statistics about brain and spinal cord tumors? www.cancer.org/cancer/braincnstu morsinadults/detailedguide/brain-and-spinal-cord-tumors-in-adults-key-statistics. Accessed January 20, 2015.
- Ostrom QT, Gittleman H, Liao P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol. 2014;16(suppl 4):iv1-iv63.
- American Cancer Society. Brain and Spinal Cord Tumors in Adults. Survival rates for selected adult brain and spinal cord tumors. www.cancer.org/cancer/braincns tumorsinadults/detailedguide/brain-and-spinal-cord-tumors-in-adults-survival-rates. Accessed January 20, 2015.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Central Nervous System Cancers. Version 2.2014. www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed January 20, 2015.
- Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.
- Kolata G, Altman LK. Weighing hope and reality in Kennedy’s cancer battle. The New York Times. www.nytimes.com/2009/08/28/health/28brain.html?scp=1&sq=t ed%20kennedy%20gbm&st=cse&_r=1&. August 27, 2009. Accessed January 20, 2015.
- Kenrick J. Ethel Merman biography – part III. Musicals101.com. www.musicals101.com/mermbio3.htm. 2003. Accessed January 20, 2015.
- Brady J. I’m still Lee Atwater. The Washington Post. www.washingtonpost.com/wp-srv/style/longterm/books/bckgrnd/atwater.htm. December 1, 1996. Accessed January 20, 2015.
- ESPN. Former relief pitcher Tug McGraw dead at 59. http://sports.espn.go.com/espn/wire?section=mlb&id=1701250. January 6, 2004. Accessed January 20, 2015.
- Wen PY, DeAngelis LM. Chemotherapy for low-grade gliomas: emerging consensus on its benefits. Neurology. 2007;68:1762-1763.
- Sengupta S, Marrinan J, Frishman C, et al. Impact of temozolomide on immune response during malignant glioma chemotherapy. Clin Dev Immunol. 2012; 2012:831090.
- Mrugala MM, Chamberlain MC. Mechanisms of disease: temozolomide and glioblastoma – look to the future. Nat Clin Pract Oncol. 2008;5:476-486.
- Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006;24:2563-2569.
- Garside R, Pitt M, Anderson R, et al. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation. Health Technol Assess. 2007;11(45):iii-iv, ix-221.
- Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699-708.
- Roukos DH, Tzakos A, Zografos G. Current concerns and challenges regarding tailored anti-angiogenic therapy in cancer. Expert Rev Anticancer Ther. 2009;9:1413-1416.
- Hayden EC. Cutting off cancer’s supply lines. Nature. 2009;458:686-687.
- Gliadel Wafer (carmustine implant) for intracranial use [package insert]. Atlanta, GA: Arbor Pharmaceuticals, LLC; 2013.
- Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet. 1995;345:1008-1012.
- CenterWatch. Gliadel wafer (polifeprosan 20 with carmustine implant). www.centerwatch.com/drug-information/fda-approved-drugs/drug/237/gliadel-wafer-po lifeprosan-20-with-carmustine-implant. Accessed January 20, 2015.
- Reithmeier T, Graf E, Piroth T, et al. BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors. BMC Cancer. 2010;10:30.
- Hart MG, Grant R, Garside R, et al. Chemotherapeutic wafers for high grade glioma. Cochrane Database Syst Rev. 2008;3:CD007294.
- McGirt MJ, Than KD, Weingart JD, et al. Gliadel (BCNU) wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. J Neurosurg. 2009;110:583-588.
- Westphal M, Hilt DC, Bortey E, et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003;5:79-88.
- Wilson TA, Karajannis MA, Harter DH. Glioblastoma multiforme: state of the art and future therapeutics. Surg Neurol Int. 2014;5:64.
- Takahashi JA, Fukumoto M, Igarashi K, et al. Correlation of basic fibroblast growth factor expression levels with the degree of malignancy and vascularity in human gliomas. J Neurosurg. 1992;76:792-798.
- Maxwell M, Naber SP, Wolfe HJ, et al. Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. Cancer Res. 1991;51:1345-1351.
- National Cancer Institute. FDA Approval for Bevacizumab. www.cancer.gov/cancertopics/druginfo/fda-bevacizumab#Anchor-Glioblastoma. Accessed January 23, 2015.
- Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27:4733-4740.
- Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740-745.
- Vredenburgh JJ, Desjardins A, Herndon JE II, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722-4729.
- Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370:709-722.
- Stupp R, Wong ET, Kanner AA, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012;48:2192-2202.
- Hong S, Van Kaer L. Immune privilege: keeping an eye on natural killer T cells. J Exp Med. 1999;190:1197-1200.
- Kanaly CW, Ding D, Heimberger AB, et al. Clinical applications of a peptide-based vaccine for glioblastoma. Neurosurg Clin N Am. 2010;21:95-109.
- Walker PR, Calzascia T, Dietrich PY. All in the head: obstacles for immune rejection of brain tumours. Immunology. 2002;107:28-38.
- Patel MA, Kim JE, Ruzevick J, et al. The future of glioblastoma therapy: synergism of standard of care and immunotherapy. Cancers (Basel). 2014;6:1953-1985.
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