Clinical Trials Test Treatments for High-Grade Brain Tumors

With a few exceptions, glioblastoma (GBM) remains largely incurable, and the U.S. Food and Drug Administration (FDA) has approved few treatments for the disease. Surgery (when feasible), radiation, and temozolomide are used in most patients. But even if a newly diagnosed tumor can be surgically excised, recurrences are too common.

In this blog post, I simply list some of the new treatments available in clinical trials for GBM and other high-grade brain tumors. Only drugs that have at least some preliminary results of activity are included, and the list is not meant to be fully comprehensive. The interested reader can judge for herself what might be of interest, keeping in mind that no single treatment is suitable or will work for all GBM patients.


Vaccines of different kinds aim to activate the immune system by “presenting” to it specific proteins/peptides that are present in tumors, but aren’t recognized as antigens by the immune system for a variety of reasons. Cell-based vaccines for GBM usually involve isolation of dendritic cells (specialized cells that present antigens to immune cells) from a blood sample. These are “pulsed/primed” with tumor extracts (which implies that freshly excised tumor tissue is needed). The now-“educated” dendritic cells are re-injected into the patient’s blood stream, where they may be able to present these tumor-specific peptides to the immune system and activate it. In theory, at least, when the immune system is newly alerted to the presence of tumor antigens, it can mount an attack against any tumors still present in the brain.

Other vaccines used for GBM are peptide-based. These vaccines consist of synthetic peptides representing proteins found only in tumors, and they act like many vaccines that are commonly used against infectious pathogens. Unfortunately, peptide-based vaccines have so far had no major successes in cancer treatment in general, nor in GBM.

DCVax-L is a personalized dendritic cell vaccine. Clinical trial results reported in 2015 showed that it prolonged overall survival, including for some patients who had a very poor response to their initial treatment (rapid progressors). Historically, the median overall survival (OS) of rapid progressors is about 8 to 10 months, but in the study of DCVax-L, it was increased to 15 months. The OS of patients with intermediate-risk GBM in this small trial was 31 months. An ongoing phase II trial has not yet reached the time point for data analysis. Nonetheless, there is hope that this larger trial will confirm and extend the results of the earlier small trial.

ICT-107, another dendritic cell vaccine, showed some promise in a phase I trial, but a larger trial failed to confirm a meaningful increase in survival for patients who received the vaccine compared to those who received a placebo. ICT-107 is, however, still being tested in trials because the negative results may have been due to poor trial design.

There are many trials testing other personalized dendritic cell-based vaccines and some testing peptide vaccines. Vaccines are sometimes combined with radiation, temozolomide, or immune checkpoint drugs. There are more than 20 trials like that in the U.S.

Immune checkpoint inhibitors

These drugs were designed to modulate immune cells in order to remove inhibitory signals operating within the immune system itself or produced by tumors (which is a common mechanism used by tumors to protect themselves from immune attack). The more established drugs, already FDA-approved for other cancers, are antibodies to the proteins PD-1 or CTLA4 (found on white blood cells called T cells), or to the protein PD-L1 on tumor cells.

Anti-PD-1 drug pembrolizumab (Keytruda) prolonged progression-free survival for GBM patients in the Keynote-028 trial, which enrolled patients with recurrent disease. Historically, only 10% of patients experience no disease progression within 6 months when receiving “salvage” treatments after other treatments have failed. Pembrolizumab has increased the number of patients without cancer progression to 45%. This is comparable to results historically seen with bevacizumab, an FDA-approved drug that inhibits angiogenesis (blood supply) in tumors. However, in the Keynote-028 trial, pembrolizumab produced a higher overall response rate of 28%, as well as more durable responses, with some patients surviving for over 80 weeks on treatment—a large improvement. Pembrolizumab is now being tested in GBM in several trials that combine it with bevacizumab, precision radiation, temozolomide, and other treatments.

Competing anti-PD-1 drug nivolumab (Opdivo) showed a 12-month OS rate of 40% in GBM patients who had experienced their first recurrence, with a median OS time of 10.5 months. Nivolumab is also in trials with ipilimumab (Yervoy; an anti-CTLA4 drug), a combination that may ultimately prove to be more effective than nivolumab alone, as it has, for example, in melanoma. However, combination treatment is associated with significantly more serious side effects.

In another clinical trial, anti-PD-L1 drug durvalumab also produced some long-lasting responses in patients with recurrent GBM, though at a lower rate than pembrolizumab.

CAR T-cell therapy

This new approach is very much in the news, mostly for treatment of lymphomas. Researchers testing it in a clinical trial for GBM recently reported a case of successful treatment using CAR T cells that target the protein IL13Rα2, which is expressed on tumor cells. The patient, who had several brain tumors, received an injection of CAR T cells into the resected tumor cavity and into the ventricular system to deliver them to both resected (surgically removed) and unresected tumors. This worked remarkably well for over 7 months, but new tumors then unfortunately developed. Responses to treatment were also observed in other patients in this trial, which is still ongoing at City of Hope in Duarte, California.

Other trials are testing CAR T-cell therapy in GBM, but the CAR T cells in these trials target EGFRvIII, a particular form of the EGFR protein expressed in about 25% of GBM cancers, and no data are yet available.


PVS-RIPO is a modified, non-pathogenic poliovirus that is injected directly into a tumor, where it kills tumor cells. This treatment has received an FDA breakthrough designation for GBM based on the results of a small trial, which reported a 24-month OS rate of 24% among 24 patients. More trials are ongoing.

DNX-2401 is a modified oncolytic adenovirus that is injected into tumors and is now being tested in trials. OS in one small, completed trial was 13 months, but 12% of treated patients achieved a complete response (they had no more detectable signs of cancer). Two trials testing DNX-2401 are still ongoing but are no longer enrolling new patients. One trial that is still enrolling patients combines this virus with pembrolizumab.

HSV G207 is a modified herpes virus that was moderately successful in a very small trial in which it was combined with radiation. In this trial, which was meant to evaluate the safety of the treatment, 3 of 9 patients had some response. Another ongoing trial is testing HSV G207 in pediatric brain cancer.

TOCA 511 is a retrovirus that does not kill tumor cells directly, unlike the viruses listed above. It was reprogrammed to encode a protein called cytosine deaminase, which converts the inactive compound 5-FC (5-fluorocytosine) into the active chemotherapy drug 5FU. 5-FC is given orally while TOCA 511 is given intravenously. After surgery, the virus is also delivered to the tumor bed—the tissue that surrounds a tumor and helps it grow. In a small trial testing this treatment, patients with high-grade gliomas had a median OS of 13.6 months, versus the typical OS of 8 to 10 months with available salvage treatments.


VAL-083 is a new chemotherapy drug. Its advantage is that it may have activity in GBM patients with unmethylated MGMT. These patients derive little to no benefit from standard treatment with temozolomide and have very few treatment options. VAL-083 is available in a couple of trials specifically for patients with unmethylated MGMT.

Targeted drugs

Mutations in the gene IDH1 are found in about 5% of GBM cases (they are more frequent in lower-grade gliomas). In a small trial, the specific drug AG-120 was able to stabilize the disease in a majority of patients for a median of 8 months. Tumor size reductions were rare (found in only 9% of patients). Other inhibitors of IDH are in trials as well (AG-881, BAY1436032, and more).

If you would like help with identification of relevant clinical trials for brain cancers, please contact Cancer Commons at