FIGHTING MELANOMA FROM THE INSIDE
Source: stateofinnovation.thomsonreuters.com, July 2015
IN the summer of 2004, few of the patients enrolling in Study 020 would have been thinking about sunny weather and days on the beach. Looming larger in their minds would have been the fact that within a year, three in every four of them were likely to be dead. All of them, from teenagers to seniors, had late-stage melanoma that chemotherapy could not help, and for which surgery could not be used. This trial was quite literally their last hope.
Instead of the standard drugs that had already failed these people, Study 020 was testing a new kind of cancer medicine. While traditional chemotherapy acts as a poison to kill cancer cells directly, the new drug being tested aimed to use the patient’s own immune system to fight the cancer. Tumors interact with immune cells in such a way to evade being killed by them, and this new drug aimed to put a stop to that. From now on, when the cancer tried to turn off the immune cells by triggering receptors, known as ‘checkpoints’ on their surfaces, it would find that the new drug had blocked it. The tumor could no longer escape the immune system and its cancer-attacking abilities: the body would regain its capacity to fight back.
The new drug in this trial was ipilimumab (Yervoy®), and it was the first of the “immuno-oncology" checkpoint inhibitors. In 2010, the results from Study 020 were reported. In the non-ipilimumab group, only a quarter of the patients were still alive one year after they entered the trial. In contrast, ipilimumab saved an extra two lives in every ten, with almost half of the patients on the drug surviving to their one year point. It was the first drug therapy shown to improve survival in advanced melanoma, and it heralded a revolution in the treatment of not only melanoma, but also many other cancers.
“For the first time, oncologists have a treatment option for patients with unresectable or metastatic melanoma that has been proven in a randomized phase III clinical trial to significantly extend the lives of patients."
Within four years of that groundbreaking data, other checkpoint inhibitors were making similar headlines. In the KEYNOTE-001 trial, the drug pembrolizumab (Keytruda®) gave melanoma patients an estimated one-year survival rate of 74%, thus turning on its head the pre-immuno-oncology-era survival rate of three-in-every-four patients dead at one year, to three-in-every-four patients alive at one year. Multi-drug treatment of melanoma further raised the bar, with a regimen of two agents working on two different checkpoints, ipilimumab and nivolumab (Opdivo®), providing a one-year survival rate of 94%. In non-small-cell lung cancer (NSCLC), nivolumab showed an estimated one year survival rate of 41% in the CheckMate-063 study, up from a historical rate of just 5.5% to 18%.
And the story goes on
Although 94% sounds impressive, it is compared with what had gone before, it is just a one-year survival rate. The median survival in those melanoma patients was 40 months – significantly more than seen previously, but certainly not a cure. It wasn’t even four extra years of life.
There is still a long way to go. However, immuno-oncology is a rapidly evolving field and drug development in this area has not stood still since that first report of these amazing data. Such new immunotherapies target just two of a number of immune checkpoints that we know about so far. Additional drugs are being investigated targeting other checkpoints and other cancers, and immunology research is learning more all the time about the molecules and receptors involved in the workings of these cellular mechanisms. Additionally, checkpoint inhibition is not the only way in which immuno-oncology is targeting cancer; there are now cancer-treating vaccines in development too.
The idea of using vaccines as a tool against cancer has been mainstream since the advent of the Gardasil® and Cervarix® vaccines over the past decade, which prevent cervical cancer by priming the immune system against the viruses that can cause these tumors. However, the new immuno-oncology vaccines are something different. They are being used to fight cancer that has already established itself in the body. In a novel twist of what has gone before, one of the cancer-targeting vaccines, T-Vec, is actually made from a virus, albeit a modified one, that kills tumor cells. In the OPTiM melanoma study, this herpes-virus-based vaccine increased the proportion of patients responding to therapy from 2.1 to 16.3%.
We may normally think of viruses as the enemies of mankind, but it’s their very ability to specifically infect and kill human cells that can make them such promising cancer treatments.
T-Vec works in numerous, clever ways. Upon injection into the tumor, the vaccine infects and kills tumor cells, but not the healthy surrounding cells. It is able to do this because the virus’s genetic makeup has been altered to prevent it from evading the antiviral mechanisms of healthy cells. Tumor cells often lack antiviral mechanisms, so even this altered form of the virus can replicate within them. As the virus replicates inside the cancer cell, not only is it killing it, but also generating more virus particles to kill further tumor cells. T-Vec is effectively forcing the tumor to act as a production plant in the engineering of its own destruction.
As if this were not enough, the vaccine takes things one step further. As the stricken cancer cell explodes, releasing the newly made viruses, it also exposes fragments from inside itself, plus a chemical that the virus has been engineered to produce. The chemical, called GM-CSF, acts as an attractor and a stimulant for cells from the body’s immune system that then use the tumor fragments to learn to recognize and attack such tumor cells. The immune system can then spot cells from the cancer wherever they might hide, enabling the initial vaccination to work its effects even beyond the tumor sites into which it was originally injected.
Innovation is ongoing
The novel therapies ipilimumab, pembrolizumab, nivolumab and T-Vec are not the only ways that scientific and medical professionals are bringing the immune system into the fight against cancer. Other drugs are being developed and other vaccines tried. Research is continuing to look for better ways to tailor the therapy for each patient. Diagnostic tools are being created to measure checkpoint levels to ascertain drug suitability and trial protocols written to enable monitoring of drug effects across new patient subsets.
One such innovation is the Immuno-Oncology Toolkit recently developed by Thomson Reuters for researchers and others in the space to understand the biology, market landscape, participation in and outcomes of clinical trials related to this new therapy area. Such information is vital to those researching such ground breaking treatments for cancer patients and helping to increase the survival rates of those with the disease.
Innovation such as this is constantly adding new data and new products, not just to the immuno-oncology field but to the whole of drug development, and indeed to all spheres of medical and scientific endeavour. The challenge in this era of layer-upon-layer of complex information is in connecting the data dots and seeing how things fit together to suggest new solutions to old problems. In an information age, what becomes crucial is our ability to sift and sort the data, to see the patterns that will enable us to change the world.