The newly emerging class of immune checkpoint blockade drugs has produced impressive benefits for patients in several solid tumor types and there are reasons to suggest this strategy may be successful against central nervous system tumors as well, including glioblastoma, said Michael Lim, MD, in a presentation at the 2015 Society for Neuro-Oncology Annual Meeting.

“Although it’s relatively new, this approach is changing the paradigm of cancer therapy,” said Lim, director of Brain Tumor Immunotherapy and associate professor of Neurosurgery at Johns Hopkins University School of Medicine in Baltimore.

The success of monoclonal antibodies targeting immune checkpoints in melanoma and non—small cell lung cancer (NSCLC) has attracted the interest of researchers seeking new therapies against glioblastoma, Lim indicated. The rationale for employing this strategy in glial tumors also has been established in preclinical studies.

Ipilimumab (Yervoy), which inhibits CTLA-4, launched the checkpoint field in 2011 when the FDA approved the drug for patients with unresectable or metastatic melanoma. Since September 2014, the FDA has approved the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) in melanoma and NSCLC, and additional agents that target the PD-1 ligand, PD-L1, are advancing in clinical development. Nivolumab also is approved in combination with ipilimumab for patients with 

In an article submitted as part of the conference, Lim and colleague William T. Curry, MD, a neurosurgeon at Massachusetts General Hospital, noted three clinical studies currently under way that are evaluating checkpoint inhibitors in patients with glioblastoma

		Nivolumab—The CheckMate 143 study is comparing nivolumab alone (3 mg/kg) versus bevacizumab alone (10 mg/kg) in patients with recurrent glioblastoma.

 Preliminary results from one cohort presented at the 2015 ASCO Annual Meeting demonstrated that nivolumab monotherapy was well tolerated without treatment-related grade 3/4 adverse events.

The trial also was designed to test the safety of nivolumab alone versus the combination of nivolumab and ipilimumab, but 4 of 10 patients discontinued the combination because of toxicities.

The trial is now proceeding to phase III as a comparison of nivolumab monotherapy with bevacizumab.

The estimated completion date for collecting data on the primary outcome measures of safety and overall survival is June 2017.

 An estimated 440 patients are expected to enroil.

		Pembrolizumab—Researchers at Dana-Farber Cancer Institute have launched a single-center phase II study randomizing participants to pembrolizumab alone or in combination with bevacizumab. The study, which seeks to enroll about 80 participants with grade 4 malignant glioma at first or second relapse, has a primary endpoint of 6-month progression-free survival and a primary completion date of February 2017.

		Durvalumab—The PD-L1 inhibitor, formerly known as MEDI4736, is being evaluated in a 3-cohort, phase II trial. The cohorts consist of patients who will receive durvalumab with these regimens: (a)  in combination with standard radiotherapy in patients with newly diagnosed unmethylated MGMT glioblastoma; (b) as monotherapy in bevacizumab-naïve patients with recurrent disease; (c) in combination with continued bevacizumab in bevacizumab-refractory patients with recurrent glioblastoma.

The trial, which aims to enroll approximately 100 participants, has a primary completion date of April 2017.

A variety of strategies are being employed as researchers explore the concept of immune checkpoint modulation in glioblastoma, Lim indicated.

In addition to the PD-1 and CTLA-4 checkpoints, preclinical murine studies against gliomas have delved into agents that target the co-inhibitory Tim3 checkpoint and the co-stimulatory CD137 checkpoint.  In each study, the antitumor effect was mediated by T-cell populations: either CD4-positive T cells, CD8-positive T cells, or both. In both studies, the improved survival was again seen when the mice were challenged anew with the same tumor.

Because of the marked increase in overall survival seen with combined checkpoint inhibitors in some tumor types, combinating such agents is becoming one of the exciting new directions in which the field is moving, Lim noted. Another strategy being explored is the combination of immune checkpoint inhibitors with other immunotherapies, such as other agents that stimulate immune responses, IDO pathway inhibitors, and viruses.  

Also of major interest is combining checkpoint inhibition with nonimmunotherapy approaches, Lim noted. Results of radiation therapy combined with checkpoint inhibitors in preclinical and clinical studies suggest the combination may produce a synergistic effect.

In glioblastoma, data from one study showed that radiation therapy increased MHC expression, an additional benefit when enhancing immune system function is the goal.

 The same study also showed radiation increased antigen-specific tumor-infiltrating immune cells.

When combining chemotherapy with checkpoint inhibitors, preclinical research has shown more benefit when the chemotherapy is delivered directly to the tumor, Lim noted, with an increase both in tumor-infiltrating lymphocytes and peripheral blood lymphocytes compared with systemic delivery. 

“Combining modalities may help get better response rates, and that is important since currently, response rate averages range from 20% to 30%,” said Lim. 

Toxicities from checkpoint inhibitors can include colitis, hypophysitis, pancreatitis, nephritis, dermatitis, and pneumonitis, with most toxicities time dependent, and liver toxicity and hypophysitis most likely to be of longest duration.   

Improved biomarkers and reduced toxicity are needed to spur continued progress with checkpoint inhibitors and monitor efficacy during treatment, said Lim. Quantification of checkpoint molecules is one approach toward that goal, but may not work as well with this immunotherapy as with other designs.

Other methods might include gauging immune cell populations and/or activation, assaying cells for genetic mutations for known drivers or overall mutation burden, and quantifying circulating tumor cell DNA or T-cell repertoires. 

“Immune checkpoint blockade therapies have been approved in other solid tumors because they have shown substantial benefits to patients with those cancers,” Lim said. “There are good reasons to suggest we may see this new approach provide meaningful benefits for patients with CNS tumors, as well.

			Curry WT, Lim M. Immunomodulation: checkpoint blockade etc. 

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02017717.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02337491.

			NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02336165.

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