March 2015, Vol. 2, No. 2
Exploring Immune Checkpoint Blockade for Glioblastoma
The blockade of immune checkpoints is among the most promising approaches to activating therapeutic antitumor immunity
Immune “checkpoints” refer to the numerous negative immunologic regulators (inhibitory pathways) that are crucial for maintaining self-tolerance (ie, the prevention of autoimmunity) and modulating the immune responses in peripheral tissues.1
Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) receptor are 2 important cellular targets that play nonredundant roles in regulating adaptive immunity.2 Whereas CTLA-4 attenuates the early activation of naive and memory T cells, the major role of PD-1 is to limit the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity.1,3,4 The approvals by the Food and Drug Administration (FDA) of the CTLA-4–blocking antibody, ipilimumab (in 2011), and the PD-1–blocking antibody, pembrolizumab (in 2014), for the treatment of patients with advanced melanoma demonstrate that checkpoint-blocking antibodies have a promising role in immunotherapy.
Nivolumab is a fully human monoclonal immunoglobulin (Ig) G4 immune checkpoint inhibitor antibody that binds to the PD-1 receptor and selectively prevents its interaction with its ligands PD-L1 and PD-L2, thereby blocking the ability of PD-1 to suppress T-cell antitumor function.5,6 PD-1 pathway blocking agents, such as nivolumab, are therefore capable of reversing T-cell suppression and ultimately inducing antitumor responses.7 Results from a phase 1/2 study indicate that nivolumab is active in multiple tumor types, and nivolumab monotherapy is currently being studied in phase 3 clinical trials in advanced melanoma, renal cell carcinoma, and non–small cell lung carcinoma.7
Ipilimumab is a fully humanized IgG1 monoclonal antibody that binds to CTLA-4 and prevents CTLA-4–mediated negative regulation of T cells, thus promoting antitumor immunity.1 Ipilimumab is FDA approved as a treatment for metastatic melanoma and has demonstrated clinical activity against brain metastases in patients with advanced melanoma.8
Dual Blockade of CTLA-4 and PD-1 with Nivolumab and Ipilimumab
Although single-agent CTLA-4 or PD-1 pathway blockade has demonstrated clear antitumor activity across multiple tumor types, combined blockade of PD-1 and CTLA-4 appears to achieve more pronounced antitumor activity than blockade of either pathway alone.2,9
Preclinical data suggest that combining CTLA-4 and PD-1 blockade may improve antitumor activity achieved over blocking either receptor alone.10,11
The first clinical study of combined checkpoint blockade was a phase 1 dose-escalation study (NCT01024231) in 53 patients with advanced melanoma.12,13 In this study, a dose of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg every 3 weeks was established for the treatment of advanced melanoma. At these doses, 53% of patients had an objective response, all with tumor reduction of ?80%. This regimen is currently being investigated in a phase 3 study (NCT01844505) in advanced melanoma.
Nivolumab and Ipilimumab in Glioblastoma
Preclinical data in murine glioblastoma models strongly support the evaluation of immune checkpoint inhibitors among patients with glioblastoma.14
The first clinical study (NCT02017717) to examine the safety and efficacy of nivolumab (alone or in combination with ipilimumab) versus bevacizumab in an estimated 260 patients with recurrent glioblastoma is under way at 64 sites in 13 countries.15 It is an open-label, randomized, phase 2b study in patients with grade 4 malignant gliomas (glioblastomas or gliosarcomas) and documented first recurrence of glioblastoma after treatment with radiation and temozolomide. After a safety lead-in phase, patients will be randomized to receive either nivolumab alone or nivolumab plus ipilimumab or bevacizumab alone. The estimated study completion date is January 2018.
- Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264.
- Callahan MK, Postow MA, Wolchok JD. CTLA-4 and PD-1 pathway blockade: combinations in the clinic. Front Oncol. 2015;4:385.
- Kyi C, Postow MA. Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett. 2014;588:368-376.
- Momtaz P, Postow MA. Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. Pharmgenomics Pers Med. 2014;7:357-365.
- Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.
- Wang C, Thudium KB, Han M, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014;2:846-856.
- Gunturi A, McDermott DF. Nivolumab for the treatment of cancer. Expert Opin Investig Drugs. 2015;24:253-260.
- Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459-465.
- Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy [published online January 20, 2015]. J Clin Oncol.
- Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275-4280.
- Duraiswamy J, Kaluza KM, Freeman GJ, et al. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013;73:3591-3603.
- Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.
- Sznol M, Kluger HM, Callahan MK, et al. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). J Clin Oncol. 2014;32(suppl). Abstract LBA9003.
- Reardon DA, Gokhale PC, Hodi FS, et al. Immune checkpoint blockade for glioblastoma: preclinical activity of single agent and combinatorial therapy. J Clin Oncol. 2014;32(suppl). Abstract 2084.
- Sampson JH, Vlahovic G, Desjardins A, et al. Randomized phase IIb study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) alone or in combination with ipilimumab versus bevacizumab in patients (pts) with recurrent glioblastoma (GBM). J Clin Oncol. 2014;32(suppl). Abstract TPS2101.
A mutation of the epidermal growth factor receptor (EGFR), known as EGFR variant III (EGFRvIII), is expressed in a significant proportion of glioblastoma tumors and is linked to poor long-term survival. Unlike unmutated EGFR, EGFRvIII has not been detected at a significant level in normal tissues; therefore, targeting of this [ Read More ]
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, [ Read More ]