Posted on May 16th, 2016
by Jeffrey Bacha
Yesterday evening, the CBS News program 60 Minutes ran an update on its spring 2015 story on Duke University’s experimental brain cancer treatment, which was recently granted “breakthrough therapy status” by the US FDA.
Duke’s therapy involves using the polio vaccine to switch on an inflammatory response which, in turn, sets off alarm bells to awaken the immune system against cancer. Both the spring 2015 story and last night’s update illustrate the promise and challenges of harnessing the immune system against cancer.
These ideas are not new. Indeed, Duke’s molecular biologist has been working on using viruses to treat cancer for more than 25 years. And, 60 Minutes’ own Morley Safer presented a report on the progress of immunotherapy and the search for a cancer cure entitled “Can Cancer Be Cured” way back in 1973 … 43 YEARS AGO!
Today, there are a number of programs seeking to leverage a virus to illicit an immune response against a tumor. In addition to polio: HIV, the virus that causes AIDS; measles virus; and even the common cold virus is being studied in this way. Last fall, researchers at the University of Texas MD Anderson Cancer Center presented data using the common cold virus that, like Duke University’s polio virus, saw glioblastoma tumors vanish in some patients.
Last night’s 60 Minutes story described results in 38 patients that have been treated so far with this experimental therapy. Details of Duke’s clinical trial using a modified polio virus can be found on the clinicaltrials.gov website (clinicaltrials.gov identifier: NCT01491893).
Patients in the trial had a glioblastoma that recurred following surgery and front-line therapy consisting of radiation and chemotherapy. Generally, as the story noted, patients with recurrent glioblastoma have a poor prognosis with median survival of approximately 10 months.
In the Duke trial, median survival was improved by five months, and like the MD Anderson cold virus study, they observed remarkable responses in a few cases where the tumor disappeared entirely over time.
The improvement in median survival demonstrated in the Duke trial is meaningful, but must be considered in the context of very careful patient selection and the extraordinary care delivered at leading cancer centers. Larger randomized clinical trials will be required to validate the results.
The next step will be to expand the Duke trial to multiple centers in a Phase II clinical trial where hundreds of patients will be treated over the next few years. If the results continue to be promising, and the safety profile acceptable, the FDA could grant approval without requiring additional studies.
It is also important to note that the inflammatory response driven by the virus can be very dangerous, even deadly, in some patients. And, of course, the therapy is not a cure all – the cases of tumor disappearance are rare, and recurrence is likely. Still, adding months of good quality life is extremely meaningful in any case.
One important aspect of the 60 Minutes story was the confirmation that the combination of their immunotherapy with chemotherapy yielded dramatic results, even when the patient didn’t seem to respond to the virus at first.
As I’ve said before, a key component of an immunotherapy regimen is an active chemotherapy – they go hand in glove. It is really ‘chemo-immunooncology’ that we’re talking about as the multi-modal approach that could truly change the landscape of cancer in the future. This is because, immunotherapies are, in general, pro-inflammatory, and may render tumors more susceptible to traditional chemotherapies. This is exactly what was observed in the Duke trial.
This also highlights one of the biggest challenges in the treatment of glioblastoma. Approximately 2/3 of the patient’s tumors exhibit features that make them resistant to the chemotherapies that are available to treat glioblastoma, so the promise of chemo-immunooncology is limited in glioblastoma patients.
The main culprit in this resistance to current chemotherapy in the treatment of glioblastoma is an enzyme called O6-methylguanine methyltransferase, or MGMT. MGMT is a DNA repair enzyme that counteracts the effects of the chemotherapies, such as temozolomide or nitrosoureas, currently used to treat glioblastoma.
That’s where DelMar’s research comes into play. We are developing our lead compound, VAL-083, as a new chemotherapy for the treatment of cancer. Prior clinical trials sponsored by the US National Cancer Institute demonstrated that VAL-083 was active against a range of tumor types, including glioblastoma.
We have demonstrated that VAL-083’s unique anticancer mechanism can overcome MGMT-mediated resistance. We first presented these data at the American Association of Cancer Research meeting in 2012. The fact that VAL-083 works where current chemotherapies fail supports potential of VAL-083 as a real paradigm shift in the treatment of glioblastoma – especially in combination with other treatments such as immunotherapy, that that may become available in the future.
Our Phase I/II clinical trials to date have focused on glioblastoma patients that have failed not only front line radiation and chemotherapy, but also second line therapy with Avastin. These patients have a particularly poor prognosis with median survival of less than 5 months. To date, we have presented data supporting median survival between eight and nine months following Avastin failure.
We are also planning to launch additional clinical trials with VAL-083, specifically in glioblastoma patients that have a high expression of MGMT. The first of these will be initiated in collaboration with MD Anderson Cancer Center for patients with high expression of MGMT that have failed radiation and chemotherapy and the second will involve newly diagnosed glioblastoma patients where we will study VAL-083 in combination with radiation as an alternative to temozolomide in patients with high expression of MGMT.
Glioblastoma is among the most deadly of cancer diagnoses and has been left behind in the huge leaps and bounds that have been made in the treatment of many cancers. New immunotherapies being studied offer hope that physicians may soon have new weapons in the armamentarium against this horrible cancer.
We look forward to continuing to watch the progress of promising immunotherapies such as Duke’s polio virus vaccine, and to continuing our work to develop VAL-083 as a unique chemotherapy and as a key component of future chemo-immunotherapy regimens in the treatment of glioblastoma and other cancers.
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