Zika, polio and adenovirus are hardly the first trio that comes to mind when considering the ‘next big thing’ in cancer therapy. Polio alone killed over 3,000 Americans per year in the 1950s before vaccination programs and continues to ravage the developing world, while babies with severe brain deformities due to Zika are still being born in South America.
Despite this, these killer viruses may well be a surprising source of hope for those with currently incurable cancers.
The idea to use viruses as cancer therapy is not new, having been proposed in a hard-to-pinpoint time in the early 20th century, with traceable work beginning in earnest in the 1960s. My earliest experience of a cancer research lab was fifteen years ago in London, UK when I was still in high school, with a scientist studying viral therapies for pancreatic cancer. As I progressed through my education, finally becoming a cancer research scientist, I would sporadically check in on viral treatments, wondering whether much progress had been made and if anything had been approved.
For several years, nothing stood out, but in 2015, I discovered that Amgen’s Imlygic (also known as T-VEC), a herpesvirus-based therapy for melanoma, was the first viral therapy to be FDA-approved. One of the more surprising results from initial trials and data gained with more widespread use since then, has been that infection of tumor cells with the virus itself, is not the only way in which the therapy affects the cancer.
Phil Daschner, Program Director of the NCI’s Cancer Immunology, Hematology and Etiology department, said: ‘Imlygic not only treated the primary tumor, but It triggered the immune system to go after the metastases too.’
This was somewhat a surprise to the researchers conducting the trial. Imlygic had not only shown efficacy in treating the tumor which it was targeted to, but had also somehow triggered the destruction of far-away metastatic tumors, despite not directly entering those cells.
‘Imlygic showed us that the effect of these therapies was not just virus going into the cells until the tumor cell breaks open and lyses. The immune system gets involved, increasing the response,’ said Daschner.
Imlygic remains the only viral therapy fully FDA approved to this date, but more are edging their way through the trial system. Pleasingly, a couple of them are designed to tackle a devastating type of brain cancer called glioblastoma, which Senator John McCain was recently diagnosed with, which only around 10% of patients survive for 3 years or more post diagnosis and most die within a year.
Zika would seem to be an odd solution to this problem, producing devastating effects in infected babies, resulting in abnormally small and deformed brains. But it is just this propensity to affect developing brain cells that may make it a suitable treatment for glioblastoma, which originates from similar pools of developing brain cells. Duke University scientists also won FDA breakthrough therapy status for their poliovirus-based brain tumor therapy in 2016, so unusually brain cancer has found itself at the forefront of developing these breakthrough therapies.
Another researcher leading the development of viruses against hard-to-treat brain cancer is Juan Fueyo, M.D. at the MD Anderson Cancer Centre, Department of Neuro-Oncology. He recently led a trial of a new adenovirus-based therapy for glioma called tasadenoturev, which binds selectively to tumor cells, with very promising results. Similar to the early results for Imlygic, the immune system played a huge role in the anti-tumor effect of the adenovirus therapy.
‘When we designed oncolytic viruses, we didn’t originally think it was immunotherapy. It’s the immune system that is actually orchestrating the destruction of the tumor and our current hypothesis is that this (not the virus itself) is the main mechanism of treatment,’ said Fueyo.
In Fueyo’s most recent study, 37 patients with recurrent brain cancer, including 28 with glioblastoma were treated with tasadenoturev. Five patients survived more than 3 years after the treatment, with one patient surviving 4.5 years and still alive at the time of publication of the paper in February of this year.
These may seem like fairly sobering survival statistics when compared to more treatable cancers, but for this type of aggressive brain tumor, this is notable progress. In Fueyo’s trial, those who did respond to the therapy achieved survival times in excess of the expected and a superior quality of life on treatment, however, almost all of the patients finally succumbed to their disease.
‘In this fight between the cancer and the immune system, the cancer won, eventually,’ said Fueyo.
The current hypothesis as to why this happens seems to be similar to that for many cancer relapses; that there is a tiny proportion of cancer cells already existing in the tumor which are resistant to the therapy. Most of the tumor cells are killed by the therapy, scans no longer pick up the tumor and patients seem to be in remission, but months or years later, this small population of cells multiplies into a fully fledged, therapy-resistant tumor. Researchers aren’t yet sure how this resistance against viral therapies works and Fueyo stresses that further clinical trials will try to address this.
Conventional therapies for brain tumors such as invasive surgeries, radiotherapy and chemotherapies such as temozolomide, often come with a host of side effects, which can greatly impact quality of life, perhaps an even more important consideration for those who are unlikely to achieve cure and where the goal is not just more time, but more quality time. One of the most interesting revelations of the study was that patients experienced minimal side-effects from the treatment.
‘Patients on our trial had an excellent quality of life. They were able to return to their lives, to work. None of our patients had toxicity,’ said Fueyo.
The variety of viruses that researchers are modifying to target different types of cancers is extensive. Polio and Zika for brain tumors, adenoviruses for multiple tumor types, including pancreatic and even measles virus for ovarian cancer and leukemia, but should a line be drawn where we conclude that some viruses, for example, Ebola – are just too dangerous to try to make cancer therapies from?
‘All of this hype saying all viruses can be modified – I don’t believe that, I think we will end up using three or four types of virus, ultimately. In some clinical trials with viruses, patients have died, we need to study this carefully and figure out which are toxic,’ said Fueyo.
As Fueyo eludes to, not all patients in trials with viral cancer therapies have experienced minimal to no side effects like his patients.
‘Viruses are dangerous, they are dirty bombs which of course we try to control but they can behave in an unregulated way, we must be careful’ said Fueyo.
So after decades of research, why have viral therapies just now started to make it through approvals and into human clinical trials?
‘The molecular engineering of safety components has become easier with the greater knowledge of viral genomes and techniques like CRISPR, for example,’ said Daschner.
‘In the 90s, no pharma company would invest in oncolytic viruses, it was just too risky,’ said Fueyo.
Today, multiple pharma companies are running oncolytic viral therapy discovery programs including Pfizer, Celgene and Bristol-Myers Squibb. After Imlygic’s successful FDA-approval and promising early clinical trial results for glioblastoma viral therapies, can we expect viral therapies to flood the market now?
‘Imlygic set an important regulatory precedent, I don’t see it as a floodgate opener, more that Imlygic expanded the pipeline for the development of these viral therapies. Much like immunotherapy and CAR-T-cells, it’s going to take time for approval of these therapies,’ said Daschner
Both Fueyo and Daschner are enthusiastic about the potential for viruses in cancer therapy, particularly in combination with immunotherapy agents that are designed to unleash the immune system on cancers.
‘The potential for viral vectors and immunotherapy agents is huge,’ said Daschner.
Soon after Imylgic’s first promising trials on melanoma, researchers published data showing that combining Imlygic with the PD-1 blocking immunotherapy agent pembrolizumab was more effective than using either alone.
Several additional combination therapies are indeed snaking their way through the clinical trial system with trials for liver, colorectal and lung cancers ongoing in the U.S. and treatment of brain cancers continues to lead the way with a large U.S. based 13 center clinical trial combining the adenovirus and Merck’s PD-1 targeting immunotherapy agent, pembrolizumab with the hope that the combination will further strengthen the immune system to attack the tumor.
Viruses are undoubtedly still in the early stages of development, but people with rarer tumors with low survival rates currently will be relieved that their cancers are at the forefront of drug development for a change, often being overlooked for more common cancers.