Bad Year for Brain Tumors, but Still Reasons for Hope



Checkpoint inhibitors and targeted therapies are reshaping the landscape of cancer care across multiple tumor sites, but treatments for brain tumors remain decidedly unchanged. The standard of care for high-grade gliomas in the front-line setting—a combination of surgery and chemoradiation—is the same in 2016 as it was 20 years ago, with nearly the same outcome.


We believe that [the ORIEN] network will enable better evaluation and selection of patients for clinical trials—especially patients with glioblastoma—based on their molecular profile and clinical characteristics.
— Olivier Rixe, MD, PhD

That news, combined with negative results for targeted therapies in several phase II and III trials, could make for a dismal year in review, but, according to Olivier Rixe, MD, PhD, neuro-oncologists still have reasons for hope.

At the Cedars-Sinai annual symposium on New Therapeutics in Oncology: The Road to Personalized Medicine, Dr. Rixe, Professor of Internal Medicine and Director of Experimental Therapeutics at the University of New Mexico Comprehensive Cancer Center in Albuquerque, shared the promise of an information exchange network that uses genetic profiling to better evaluate patients and outlined several ongoing immunotherapy trials in ­glioblastoma.1

Oncology Research Information Exchange Network

Initially funded by Moffitt Cancer Center and The Ohio State University, the Oncology Research Information Exchange Network (ORIEN) has expanded to include 16 centers across the country, with the goal of gathering data from 50,000 patients per year. With the help of next-generation sequencing technology, clinicians hope to obtain a genetic profile for all participating patients to complement monthly clinical annotation.

“Using the Total Cancer Care Protocol, we can identify patients with both genotypic data as well as phenotypic information and assign them to an ‘in silico’ community of other patients like them,” said Dr. Rixe, who noted that the network’s goal is to provide a system of continuous learning that will ultimately anticipate the needs of patients.

According to Dr. Rixe, the database will provide collaborative working groups and principal investigators robust information about patient characteristics and volume in real time. Also important, he said, is the longitudinal evaluation of these patients as they progress, develop resistance, and are rebiopsied.

“We believe that this network will enable better evaluation and selection of patients for clinical trials—especially patients with glioblastoma—based on their molecular profile and clinical characteristics,” he said.

Immunotherapeutics in Development

As Dr. Rixe reported, clinical trials in the United States are also trying to reproduce the success of immunotherapy in melanoma by randomizing patients with newly diagnosed glioblastoma to chemoradiation therapy (including temozolomide plus ipilimumab [Yervoy] or nivolumab [Opdivo]. In addition, the combination of the anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blocker tremelimumab and the programmed cell death ligand 1 (PD-L1) inhibitor durvalumab is being tested in patients with recurrent glioblastoma.

While acknowledging that these trials are “neither super-exciting nor innovative in their design, they open a new avenue for the treatment of high-grade gliomas,” said Dr. Rixe. He indicated that researchers have managed to acquire very interesting data concerning PD-L1 expression.

“When patients have a recurrence, the PD-L1 status in recurrent tissue is usually similar to the initial biopsy,” he explained. “There is also a huge heterogeneity of PD-L1 expression in gliomas for the same patient and a huge variation among patients. Finally, we’ve learned that PD-L1 might not be predictive of outcome for patients with glioblastoma, as it is in melanoma, but it should be addressed prospectively.”

Moreover, research is not limited to PD-L1 and CTLA-4 therapy. Investigators are also studying immune-checkpoint inhibitors that target the tumor necrosis factor (TNF) receptor, including GITR (glucocorticoid-induced TNF receptor–related protein), CD137, and OX40, as well as other immune therapeutics that include ­vaccines.

“With its strong activation of T cells, GITR is quite fascinating as a single agent,” said Dr. Rixe, “but it’s even more important as a combination therapy.”

Despite the promise of these molecules, however, testing immunotherapeutics in glioblastoma remains a challenge because the majority of patients are on high-dose steroids or experience rapid disease progression after front-line therapies and are therefore excluded from early-phase clinical trials, he observed.

Indoleamine 2,3-Dioxygenase

First identified in the placenta, indoleamine 2,3-dioxygenase (IDO) is critical for maternofetal tolerance, but the enzyme has also been found to play a role in the tumor microenvironment.2,3

“When IDO is overexpressed in the placenta,” said Dr. Rixe, “it creates an immune tolerance between the embryo and the mother. Without IDO, a fetus would not be able to survive. But this enzyme is also overexpressed in the tumor microenvironment to create exactly the same immunosuppressive milieu as initially demonstrated by [David H. Munn, MD].”

In addition, research has shown that IDO promotes regulatory T-cell (Treg) activation and prevents vaccine-induced reprogramming of Tregs into T-helper cells.

IDO inhibition has thus become a promising area of research in glioblastoma. In murine models, IDO blockade synergizes with chemoradiation therapy.4 It also appears to drive vascular activation after chemotherapy and tumor necrosis following chemoradiation therapy.

“We speculate that this represents a fundamental pathway by which the tumor regulates intratumoral vascular activation and protects itself from immune-mediated tumor destruction,” said Dr. Rixe, who added that early results of a phase I combination study in patients with relapsed glioblastoma have been promising. (Dr. Rixe is the principal investigator for this ongoing phase I/II clinical trial.)

“The IDO world is expanding a lot,” he concluded. “We know that as single agents, IDO inhibitors do not have much activity, but in combination with other immune-checkpoint inhibitors, they are extremely synergistic.” ■

Disclosure: Dr. Rixe reported no potential conflicts of interest.

References

1. Rixe O: Redlich Lecture: New developments for the treatment of brain tumors. 2016 New Therapeutics in Oncology Conference. Presented November 5, 2016.

2. Hönig A, Rieger L, Kapp M, et al: Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance. J Reprod Immunol 61:79-86, 2004.

3. Munn DH, Mellor AL: IDO in the tumor microenvironment: Inflammation, counter-regulation, and tolerance. Trends Immunol 37:193-207, 2016.

4. Li M, Bolduc AR, Hoda MN, et al: The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer 2:21, 2014.


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