Novel Biotherapeutics for the Treatment of Cancer
We’re in an exciting new era of cancer treatment – where biological molecules are allowing us to target tumors and the surrounding host biology in an unprecedented way. We take a look at some emerging new treatment options – from localized tumor vaccines that prevent metastasis, to exploiting viruses that tackle brain tumors.
The rise of immunotherapy
When thinking about the novel cancer treatments coming through the pipeline today, it’s clear that most excitement centres around immunotherapy. Scientists have been looking at ways to harness the innate immune system against cancer for decades. But it was a discovery in the mid-1990s that unlocked the key to the dramatic responses being seen with immunotherapy in the clinic today. Dr James Allison of MD Anderson Cancer Center identified CTLA-4 as an inhibitory checkpoint molecule,1 which restricted activated T-cell responses. Dr Allison proposed that blocking CTLA-4 would boost T-cell responses against cancer, essentially taking the brake off the immune system, which it did.
Since this seminal discovery, there has been a steady stream of drugs in clinical development that block checkpoint molecules such as CTLA-4, PD-1 and PD-L1. In fact, overall, since September 2017, 26 new immunotherapies have been approved, and 17 types of cancer now have at least one approved immunotherapy available as a treatment option.2 As a result, there is renewed optimism about the potential of immunotherapy to provide long-lasting control of even the most advanced cancers. However, these dramatic responses are only seen in a small proportion of patients, so new approaches building on their success are still needed.
There are two main strategies being pursued as immunotherapies: targeting tumor-specific antigens unique to an individual’s cancer or developing ‘off-the-shelf’ approaches that work to enhance the immune system to fight any type of cancer. Professor Ronald Levy of Stanford University is developing the latter – a combination vaccine that has shown dramatic results in mice.3
“I’d heard about a compound called CpG, a ligand for the Toll 9 receptor on dendritic cells, resident within tumors. It was a piece of DNA, which could be injected directly into tumors and accomplish considerable stimulation of the immune response. We’d worked with this compound for a while and done clinical trials with it, but we wanted to augment that effect.”
Levy used an in vivo screening strategy in mice for molecules and antibodies that could synergistically combine with CpG. Levy’s team implanted the same tumor into two different sites in the mouse, and injected CpG into one of the tumors, before also injecting a whole list of candidate immune enhancers.
They found one really effective augmenter – an antibody against a T-cell target called OX40. When injected into the tumor with CpG, the combination triggered a systemic T-cell immune response and eliminated tumors throughout the body. This came as something as a surprise to Levy: “Most of the world is enchanted by a target called PD-1. We thought that PD-1 would be the logical enhancer here, and in fact it turned out to have a weak effect compared to the antibody against OX40. So, we’re a little counter to the mainstream here with our target, which we’re intrigued by.”
They extended the study to a mouse model that gets breast cancers spontaneously driven by an oncogene. “We were able to monitor these animals for the first arising tumors in one of their breast areas, inject these two molecules into the first tumor that appears, and then observe the animals to see what happens.”
Incredibly, immunization in situ in that first tumor prevented the occurrence of subsequent naturally occurring independent tumors in the animal’s other mammary glands. It also prevented metastases from occurring and stopped the mice from dying of the naturally occurring tumors.
“Naturally arising tumors are a very tough target – especially when driven by a strong gene. The innate response we induced this way outraced the strong driving force of the oncogene,” Levy explains. This combination of stimuli given locally in one tumor could be very effective, and a clinical trial in low-grade lymphoma is now being planned to extend the approach to people.
One of the advantages, Levy says, is that the vaccine is off-the-shelf. “We’re not needing to make anything custom for each person. This is ready to go. We do not need to discover the immune targets on a tumor. We are just trying to talk to the immune system to properly activate it, and let it choose its own targets.”
Advances in cell therapy
At the other end of the scale is chimeric antibody receptor (CAR) T-cell therapy, which involves taking immune cells from a patient and genetically engineering them to recognize and respond to their cancer cells. The first CAR T-cell therapy approach has just been approved to treat an often-lethal type of blood and bone marrow cancer affecting children and young adults and is heralded by the FDA as ‘the first gene therapy in the US’.
Professor John Maher, at Kings College London, first developed the signaling portion (the endodomain) of the CAR when working in Professor Michel Sadelain’s lab, about 17 years ago. Now he’s leading an early-phase trial of CAR T-cell therapy for head and neck cancer – one of the first to test the approach in solid tumors.
The CAR being tested is unique in its ability to recognize eight different binding combinations of the ErbB family of receptors. This was inspired, Maher says, by the success of monoclonal antibody cancer drugs.
“It’s a slightly unusual choice because we know that this target is not necessarily a safe target, but I was heavily influenced by the success of monoclonal antibodies targeting that network – drugs like cetuximab, and Herceptin® (trastuzumab) etc – which are all blockbuster drugs in the solid tumor arena. My thinking was that this is a validated target from the point of view of a monoclonal antibody. Let’s make something even more potent in the form of a CAR T-cell and think carefully about how we can deliver the cells to minimize the risk of on-target toxicity.”
In addition to its unique target, an innovative expansion process has been developed to generate the cells quickly. “Our CAR T-cells have been engineered to have heightened responsiveness to the cytokine, interleukin-4 (IL-4),” explains Maher. “This is an advantage because if there is poor efficiency of gene transfer during the engineering step, the IL-4 will enrich for the successfully engineered CAR T-cells during the manufacturing process.” This allows them to start with a very small number of cells and generate several billion CAR T-cells within two-weeks of initially harvesting them from patients.
“In the early days before the success of CAR T-cells in B-cell malignancy, I think people viewed this very much as a boutique activity – that scientists were playing with test tubes in a lab and it would never be a practical treatment for patients. That landscape is changing now I think.”
An alternative to taking the patients’ existing mature immune cells, is to train people’s stem cells before they become part of the immune system. A study by Professor Joseph Wu, of Stanford University School of Medicine, recently showed that induced pluripotent stem cells, a mainstay of regenerative medicine, could be used to train the immune system to attack or even prevent tumors.4
"When we immunized an animal with genetically matching induced pluripotent stem (iPS) cells, the immune system could be primed to reject the development of tumors in the future,” said Wu. The results suggest it may one day be possible to vaccinate an individual with his or her own iPS cells to protect against the development of many types of cancer.
Using viruses to treat cancer
Although immunotherapy may have the monopoly on cancer biotherapeutics, researchers are looking at ways to potentiate its effect – and one of the key contenders is viruses.
Viruses are already being studied as sole agents for treating cancer – for example, Dr Harry Bulstrode at Cambridge University is investigating whether the Zika virus could be used to treat brain tumors. Zika, unlike other viruses, is able to transverse the blood-brain barrier without damaging normal brain tissue and this means it could be used to target the cancer stem cells in the brain that drive glioblastoma.
But two new studies have taken the oncolytic properties of some viruses and tested whether they can prime the immune response ready for the use of checkpoint inhibitors.
In one study, researchers injected the rhabdovirus into tumors in a mouse model of triple-negative breast cancer (TNBC)5 before they were surgically removed. They found that addition of the virus sensitized otherwise refractory TNBC to immune checkpoint blockade, preventing relapse in most of the treated animals.
In an early-phase trial6 involving nine patients with recurrent high-grade gliomas or brain metastases, intravenous infusion of oncolytic human reovirus leads to infection of tumor cells subsequently resected as part of standard clinical care. This proved that the virus can increase the cytotoxic T-cell tumor infiltration relative to patients not treated with virus, and could potentially boost the immune response when combined with checkpoint inhibitors.
Immunotherapies might be stealing the show in cancer biotherapeutics, but it would seem that combining them with other biological agents – DNA or viruses, for example – is the way to seeing dramatic successes in more cancer patients.
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