In September 2012, Adrian Webb's wife spotted that a mole on his back had changed colour. It was a melanoma and it had spread to his lymph nodes. Despite a number of surgeries and an intensive course of radiation therapy, the cancer continued to spread to his lungs, bowel, liver and spine. "I was given 12 months to live," says the 51-year-old.
With few other treatment options on offer, Webb's oncologist suggested he could enrol in clinical trials for two types of immunotherapy, an emerging field that focuses on manipulating the body's own immune system so it can better recognise and kill cancer cells. With cycles of these experimental treatments, his tumours progressively shrank until July 2016, when his oncologist told him he was clear of cancer. Speaking over the phone from his home in the West Midlands two months later, he says: "I'm in a very happy place."
The dramatic results seen in patients such as Webb have opened up a field of cancer research that had been broadly unsuccessful for decades. Immunotherapy is a term that encompasses a range of treatments designed to reprogram elements of a patient's immune response so that it can more effectively target cancer cells or viruses such as HIV, just as it targets other pathogens.
"You are trying to wake the immune system up and tell it, 'There's cancer growing in the system, you need to seek and destroy it,'" explains oncologist Michael Postow, assistant attending physician with the Melanoma-Sarcoma Oncology Service at the Memorial Sloan Kettering Cancer Center in New York.
The idea that the immune system can recognise cancer has been around for more than a century, explains Peter Johnson, Cancer Research UK's chief clinician. In the 1890s, a US doctor called William Coley deliberately injected cancer patients with bacteria to trigger their immune systems to fight their tumours. It was a crude technique, but established the idea that with a little manipulation, the immune system could detect and destroy abnormal cells.
However, as Johnson and colleagues discovered a century later, the immune system is difficult to manipulate. They tried many approaches, injecting patients with "all sorts of molecules". With the exception of using antibodies to target lymphoma, they had limited success.
"The immune system is very complex and deliberately very balanced: any perturbation you make to it is often balanced out," Johnson says.
Cancer also has several strategies for evading detection by suppressing the immune system. Immunotherapies attempt to readdress this by pulling on a range of levers. "We can either improve the ability of the immune system to recognise and kill the cancer, or we can block the cancer's ability to inhibit the immune system," says Wendell Lim, a professor of cellular and molecular pharmacology at the University of California, San Francisco.
The two most successful ways that have been found to pull on the immune system's levers so far are checkpoint inhibitors and engineered T cells. Checkpoint inhibitors are drugs that target the body's own immune cells, rather than cancer cells, to suppress the body's immune response. Leading the way is ipilimumab1, one of the two drugs Webb was given. This drug first piqued the oncology community's interest when it delivered dramatic improvements in some melanoma patients during clinical trials in the late aughts.
It works by targeting a molecular "switch" found on the surface of the body's cancer-fighting T cells. The switch, a protein called CTLA-4, suppresses the body's immune response. By blocking the effect of CTLA-4 with ipilimumab, the T cells can attack the tumour. "We saw very striking results," said Johnson. "For a long period, cancer immunology was regarded as being interesting but futile, so this galvanised research in the field."
Although checkpoint inhibitors have worked for some patients with melanoma and lung cancer, this approach doesn't always yield positive results. "Individuals have a lot of variation," says Lim. Some people's immune systems have an intrinsic ability to recognise certain types of cancers while failing to recognise others. It's all very well releasing T cells into the body, but if the cancer is using a clever defence strategy they might travel straight past it.
Engineered T cells offer a possible solution. A patient's T cells are genetically modified in the lab to better recognise specific cancers cells. The new cells, known as chimeric antigen receptor (CAR) T cells, are then injected back into the patient.
"Because it's a patient's own cells there won't be a rejection, but you've given them a boost and created a super T cell," explains Áine McCarthy, a PhD researcher specialising in blood cancer who also works as Cancer Research UK's science information officer. Theoretically, engineered T cells give doctors better control over the attack mechanism than checkpoint inhibitors do. However, they are more complex and very expensive to produce.
A third option being explored is the development of a type of vaccine - not administered to prevent a disease, but after a patient has been diagnosed with cancer. These vaccines2 are made from pieces of genetic material, ribonucleic acid (RNA), extracted from the patient's own cancer cells, cultivated in the lab and then injected back into the patient to train the immune system to recognise the cancer's distinctive signature.
Any treatment that manipulates the immune system is likely to attack some healthy tissue, leading to side effects. "It's like having a temporary autoimmune disease," says Postow. These side effects can include rashes and itching, inflammation of the lining of the lungs and bowel and, in some cases, attacks on the thyroid and pituitary glands.
Webb found that, as the ipilimumab shrunk his tumours, he developed "uncontrollable headaches" behind his left eye. "After an MRI scan they found that my pituitary gland was trying to burst out of the back of my head," he says. He then switched to a different checkpoint inhibitor, pembrolizumab, but had to deal with temporary rheumatoid arthritis.
The body's inflammatory response to immunotherapies can be fatal. Seattle-based pharmaceutical company Juno Therapeutics has halted the development of an engineered T cell treatment called JCAR015 after three patients, all under 25, died during clinical trials.
Checkpoint inhibitors: These drugs target protein receptors called checkpoints and stop the immune system from going into overdrive. They lack precision targeting but have effectively treated certain cancers.
Cytokines: One of the earliest immune therapies involved injecting patients with molecules called cytokines - small proteins produced by white blood cells. They boost the patient's own white blood cells and cancer-killing capabilities.
Treatment cancer vaccines: These are given once the patient is already sick. The first one to be approved was for metastatic prostate cancer with a substance called a protein fusion, which makes the cancer cells vulnerable.
Engineered T cells: This involves extracting blood and T cells and genetically modifying them for precision targeting of a specific cancer. Early signs look promising for treating blood cancers such as B-cell leukaemia.
In its current state, immunotherapy remains a rather blunt instrument, and researchers don't fully understand why some cancers and people respond whereas others don't. It appears that cancers with the most genetic mutations, such as melanoma, lung and bladder cancer, are more responsive to immunotherapies.
Gaining precise control requires shifting to a more personalised approach – in line with the broader oncological trends – and targeting the many subtypes of cancers as well as a patient's tissue type and intrinsic immune cells.
"Ideally we would sequence all genomic abnormalities in a cancer, find out which ones are a danger signal to the immune system and find a vaccine for those," explains Johnson. "We'd combine the individual cancer vaccine with checkpoint antibodies to set off a population of T cells to attack the cancer through a specific signal. And if the cancer doesn't show any kind of signal itself, we'd find a way to flag the cancer cell to the immune system."
With a large enough database of cancer genomes, researchers can use machine learning to identify common molecular signatures of the disease and engineer personalised treatments. Lim has launched Cell Design Labs to do this. "Think of face-recognition algorithms," he says. "We need to develop the same capabilities with these immune cells."
The ultimate aim is for doctors to be able to sequence and analyse their patients' tumours, then compare them to a database of the molecular signatures of the cancer to inform which type of T-cell is required and which off-the-shelf module can be inserted to make it more lethal to cancer.
"What we are seeing are the caveman or Model T versions of what immunotherapies could look like. We really are just at the beginning," enthuses Lim.
For Webb and others like him, immunotherapy is already a lifesaver. "I've been lucky," he says. "I know there are risks and that it is still in its infancy, but do the risks outweigh the quality of life after? I believe they do."
- Leach, D, Krummel, M and Allison, J. (1996). Enhancement of Antitumor Immunity by CTLA-4 Blockade. Science, 1734-1736.
- Guo, C; Manjili, MH; Subjeck, JR; Sarkar, D; Fisher, PB; Wang, XY. Therapeutic Cancer Vaccines: Past, Present and Future. Elsevier, 130, 191-249.
- Lee, S and Margolin, K. (2011). Cytokines in Cancer Immunotherapy. Cancers (Basel). 3(4): 1734-1736.
- Andrew, F; Carl, J; Bruce, L. (2016). Engineered T cells: the promise and challenges of cancer immunotherapy. (16): 566-581. Nature.
This article was originally published by WIRED UK
