Glioblastoma multiforme (GBM) is the most common form of brain cancer affecting adults. It is also one of the deadliest and hardest to treat cancers. About half of all people with GBM survive longer than 18 months, but only 15% are still alive five years post diagnosis. Of the approximately two dozen experimental treatments tested in recent years for newly diagnosed patients, none has so far improved patient survival. There is currently no means for the early detection of GBM and no preventive strategies for this cancer.
GBM readily develops drug resistance and is highly adaptive. Although GBM typically expresses many different mutations, only a few of them are addressable by currently available targeted treatments. Clinical trials in GBM are further confounded by the fact that GBM tumors can inhibit immune activity and by the difficulty of drugs to penetrate the brain. Moreover, blocking a single pathway involved in GBM tumor growth often fuels the tumor to upregulate an alternative cancer pathway, leading to disease recurrence.
While this latter point suggests the need for a combination therapy approach to GBM, exploring such a strategy is challenging due to lack of knowledge about which drugs to combine and the high cost of conducting clinical studies to test these combinations. Also adding to the difficulties is the aggressiveness of GBM, which typically leads to many people dying while on a trial.
A recent study now suggests that the timing of immuno-oncology treatment may play a role in its effectiveness against GBM. A small randomized trial published in Nature Medicine showed that treating patients with recurrent, resectable GBM prior to surgery with a PD-1 inhibitor led to a near doubling in median survival time (417 versus 228 days) compared to patients treated with the same drug post-surgery. While most patients still died during the course of the study, the time to progression for those given the drug before surgery was also longer. The researchers were not sure why treatment before surgery was more efficacious. However, they speculated that the drug may help prime the immune system to recognize and attack remaining cancer cells once the tumor-induced immunosuppression was lifted as a result of its surgical removal.
The development of personalized cancer vaccines for GBM has also shown some promise. Northwest Biotherapeutics is currently conducting an international 348 patient, Phase 3 trial with DCVax-L, the company’s autologous cancer vaccine that combines tissue from a patient’s brain tumor with their dendritic cells in an attempt to direct a T-cell response against the tumor. The primary endpoint for this placebo-controlled study, which is expected to be fully enrolled this year, is progression-free survival. In an earlier, smaller trial, the median survival of those treated with the vaccine — not yet reached — is expected to achieve 46-88 months.
A newer GBM vaccine approach targets neoantigens — unique tumor-acquired mutations in proteins that are expressed, processed and presented on the surface of the cancer cell, and subsequently recognized and attacked by T cells. Normal cells do not process neoantigens, making them potential tumor-specific targets for T-cell-directed anticancer approaches.
Neoantigen cancer vaccines are made by sequencing DNA from bits of a tumor, identifying unique mutations, and reproducing those antigens in quantity in the laboratory. The antigen copies are then packaged into a vaccine, along with adjuvant molecules to boost the immune response. Researchers have not yet established which cancer types are most amenable to a neoantigen vaccine approach. GBM is believed to be the most challenging cancer because of its lower somatic mutation rate than many other cancers, leading to fewer possible neoantigen targets. However, two small clinical studies were recently published showing some potential for neoantigen vaccines against GBM.
In the first study, researchers from Dana Farber Cancer Institute found that a patient’s response to the vaccine depended on whether the patient was also treated with the steroid dexamethasone. This drug is frequently given to brain cancer patients to ease brain swelling, headaches and neurological deficits, but it also dampens the immune response, thus limiting the power of the vaccine. In the patients not on the steroid, the researchers identified T cells that were primed to recognize and attack the patient’s GBM neoantigens, and they also found T cells at the site of the tumor; this was not the case in the steroid-treated patients. The Dana Farber researchers are now planning a trial that will combine the neoantigen vaccine with a checkpoint inhibitor, thus preventing PD-1 from hindering T cells in their attack on the tumor.
The second study, conducted in Germany, combined a customized neoantigen vaccine with a cancer vaccine targeting traditional antigens from a number of patients’ GBM cells. Their aim: to boost the number of GBM antigens that the immune system could recognize as a cancer flag. The researchers reported seeing T cells activated against the tumor antigens in several trial participants, showing the potential for this approach. However, most of the patients died or their disease continued to progress during the study.