James P Allison of the US and Tasuku Honjo of Japan have been awarded the Nobel Prize in Physiology or Medicine for developing a paradigm-breaking cancer therapy by “inhibition of negative immune regulation”, which has bettered the chances of full recovery in certain kinds of cancer by over three times.
Instead of relying on external attacks on tumours with radiation and chemicals, which is the traditional method, immune checkpoint inhibitor therapy unleashes the body’s own defence system against the enemy within. While the technique remains under research and the chemical pathways producing side-effects are not completely understood, six checkpoint inhibitor drugs have been approved for clinical use since 2011.
Traditionally, cancers have been dealt with by a war of attrition — a war of numbers. Surgery may be first used to drastically reduce the population of malignant cells to a manageable count. What remains is then attacked by chemotherapy and radiation therapy, until the point when the malignant tissue stops growing, or disappears altogether. Metastasis is usually the watershed at which this strategy falters, but in the lab, the immune method has shown promising success against metastatic cancers.
Releasing the brake
The immune system tells between the self and the other — an invading organism or cells of the self that have gone rogue — by a form of ‘friend or foe identification’, the technology that prevents military weapon systems from attacking their own side. But like all other living systems, it is contained by feedback mechanisms which take cues from the body and the environment, to curb an action before it can go too far.
Parallels would explain the mechanisms better. In the gross world, when the brain activates your muscles to reach for a pencil on your desk, for instance, it also inhibits the action when your hand reaches the pencil, triggered by cues from the senses of vision, touch and proprioception, the sense by which the mind is aware of the orientation of the body in space. In the absence of this brake in the feedback loop, your hand would carry on reaching forward until it smashed through the tabletop, and caused you an injury.
Autoimmune disorders are aberrations of the brake at the molecular level. The action of the immune system is capable of damaging whole organisms or tissues if it runs amok, as in lupus and rheumatoid arthritis. These are cases of the immune system misidentifying the self as the other. Some cancers subvert feedback in the opposite manner, keeping the brake on tight so that the immune system does not attack them. They use the apparatus of the immunoglobulin cytotoxic T-lymphocyte antigen 4 (CTLA-4) and the programmed cell death protein-1 (PD-1) to commit the lethal fraud. Working independently in the 1990s, Allison and Honjo showed that these proteins inhibit the immune system’s response to cancer, and that inhibiting them would, in turn, give patients a fighting chance.
PD-1, a receptor on the cell surface, is an ‘immune checkpoint’ which damps down the immune response and promotes self-tolerance, normally preventing auto-immune diseases. CTLA-4 performs a similar function on T-cells (so named because they mature in the thymus and the tonsils), which play an important role in immunity at the molecular level. Cancer cells take advantage of these checkpoints to tone down the body’s immune response to themselves. But if these brakes are taken off by, say, a PD-1 inhibitor, the immune system is free to attack, exactly as they address a common infection like a cold in the head.
Ipilimumab, the pioneering immune checkpoint drug which releases the CTLS-4 brake, was approved for clinical use in 2011. Five more drugs directed at the PD-1 protein and its associated ligands have been released until last year. Hundreds of trials are in progress to broaden the immune checkpoint method to attack a variety of cancers. Currently, it is used in conjunction with traditional methods, but it has the promise to emerge as a standalone strategy. In fact, in the future, it is likely to be an element of personalised medicine.
At present, a study of the treatment of second stage breast cancer has shown that while the disease was completely eliminated by chemotherapy in one out of five patients, a combination of chemotherapy and immune checkpoint inhibitors increased the strike rate to two out of three. Fine-tuning of the method to specific cancers and the organ systems that they affect would increase the rate further, and in the foreseeable feature, it could unseat the emperor of all maladies.
Against the current
The award to Allison and Honjo goes against the trend of the decade. In 2010 and after, the majority of Nobels in medicine have rewarded work which primarily explains the human organism, rather than work which directly advances clinical methods. Of the nine awards made in that span of time, only four have a direct bearing on the practice of medicine. Robert Edwards won in 2010 for developing in vitro fertilisation, John Gurdon and Shinya Yamanaka won two years later for discovering that mature cells can be reprogrammed to function as stem cells, and in 2015, work on malaria and parasitical roundworms was recognised. And now, Allison and Honjo have been awarded for spearheading the development of a method which is already in clinical use.
Two-thirds of the awards have recognised work that explains fundamental physiological processes — science actuated by curiosity, rather than the goal of possible uses. Last year, it was the molecular basis of the circadian rhythm. The year before, Yoshinori Ohsumi was celebrated for explaining autophagy, a fundamental process by which cells break down and reuse their own contents. Other research has included neurotransmission, immunity and a region of the brain.
Allison and Honjo were among the favourites for the prize this year. But there was more excitement about the CRISPR/Cas9 gene editing system, which has revolutionised molecular biology and brought unprecedented accuracy to its interventions. Of course, it is equally a candidate for the Nobel Prize in Chemistry, which will be announced on Wednesday.