A plethora of new cancer treatments is under development

IMMUNOTHERAPY offers huge promise, both as an addition to established therapies and as a foundation for future ones. Hundreds of trials are pairing CTLA-4, PD-1 or PD-L1 inhibitors with chemotherapy, radiation and targeted therapies. One hope is that the older treatments will increase the range of antigens that the cancer offers for the immune system to latch on to, both by driving further mutations and by killing cancer cells. Dead cells release more antigens,

Then there is the development of further immunotherapies, which is being pursued both by building on the successes of the first checkpoint inhibitors and by using entirely new technologies, such as genome editing. Dr Wolchok at Memorial Sloan Kettering is working on the next generation of immune-modulators. These include new inhibitory compounds for IDO and TIM-3, another checkpoint. Some researchers are trying to remove further brakes on the system by killing or silencing some of its regulatory cells. Others are looking at molecules which activate the immune system in a similar way to IL-2. Nektar Therapeutics, a biotech firm based in San Francisco, is developing an engineered therapy which does this in a way that should, in principle, encourage tumour-killing T-cells. It is being tested as a combination treatment with an anti-PD-1 drug in five tumour types, including bladder cancer and a hard-to-treat form of breast cancer.

Other approaches seek to make sure that the immune system responds to as many cancer antigens as possible. Viruses genetically engineered to attack cancer cells might be used to this end. Even if such viruses did not kill enough cells to do the cancer much damage, the way in which they kill the cells would release otherwise hard-to-detect antigens that might help the immune system target the tumour better.

Alternatively, the antigens could be provided from outside. Now that immunotherapies have wind in their sails, various old ideas are coming back into vogue. One of them is vaccination. The vaccines with which people are familiar are those against infectious disease. They work by priming the immune system to respond to an antigen associated with a specific pathogen, so that when the system encounters the infection for real it already knows how to fight it. Because some infections can lead to cancer, some of these vaccinations can prevent it. Sometimes, as in vaccination against hepatitis B, which can cause liver cancer, this is an added bonus. Sometimes, as in vaccination against human papilloma virus, which can cause cervical cancer, it is the main point.

But there may be another way to use vaccines against cancer. Equipped with the right antigen, a vaccine might encourage an immune response to a tumour which is already present, but which the immune system has failed to get to grips with. It is an approach that has been frequently tried in the past, and has repeatedly failed. But the availability of checkpoint inhibitors and the ability to pick out the most promising antigens may allow this form of targeting to come into its own.

Neon Therapeutics, Gritstone Oncology, Genocea Biosciences and other biotech firms are all pursuing the creation of personalised vaccines based on the mutations in an individual tumour. The trick is to find which of the novel antigens its genome says the tumour might be churning out are the most likely to provoke a strong response when served up to the immune system in the form of a vaccine. Jill O’Donnell-Tormey at the Cancer Research Institute (CRI), a non-profit in New York that concentrates on immunotherapies, says that everyone has their favourite algorithm to predict which antigens will get the best response. Together with the Parker Institute in San Francisco, CRI is creating a “bake off” where these algorithms will be tested against each other.

If vaccines work in late-stage cancer—which is where most therapies are tried first—there might be scope for bringing them in sooner, at least in some cancers. In decades to come it is possible to imagine an approach where a tailored vaccine might be the first—and, ideally, the only—response to a blood test showing the presence of a cancer.

Reprogramming the genome

Like immunotherapies, vaccines offer a way to hack the immune system by changing the way that its cells fight the cancer and increasing the number of them doing so. A less circuitous way of doing this is now on offer: reprogram the immune system directly. Take some of its cells out of the body, manipulate them so that they do what you want, encourage them to divide and multiply, then put them back and let them get on with the job.

The technology along these lines that has got furthest is called CAR-T, where CAR stands for “Chimeric antigen receptor”. These CARs are produced by splicing together the gene for an antibody that recognises a tumour antigen and the gene for a receptor that sits on the surface of the T-cells; put this new gene into a T-cell and it will be precisely targeted at the tumour. The small clinical trials undertaken to date suggest that this could be extremely effective. A trial of 31 patients with acute lymphoblastic leukaemia brought a complete, and unprecedented, remission in 93% of cases. A CAR-T therapy called Kymriah (tisagenlecleucel), made by the Swiss firm Novartis to treat B-cell acute lymphoblastic leukaemia, was approved for use in America on August 30th.

There are two main limitations to CAR-T. One is that so far the T-cells have been programmed to target a molecule, CD19, which is only common to the surface of a few blood cancers. The other is that CAR-T has been known to trigger immune reactions which can prove fatal. Neither problem is obviously insoluble. Editing genes has been made much easier by a new technology known as CRISPR-Cas9, which has already been used to improve the way that CAR-T cells are engineered in mice. It may well eventually allow the receptors used in such therapies to be personalised to the specifics of the patient’s cancer. And more precision, as well as experience, should lead to immune responses less likely to run away with themselves.

What such advances will not do, though, is make such treatments cheaper. Novartis’s new therapy costs $475,000. Genome-editing treatments seem likely to be the most expensive cancer treatments the world has yet seen. And that is saying quite a lot, since many of the newer cancer treatments are eye-wateringly pricey (see chart).

There are various reasons for this. More sophisticated R&D costs a lot. And antibodies are much more expensive to make than the smaller molecules used in older therapies. Generic versions of them are still few and far between. A company than can make antibodies which pass regulatory muster is much better advised to make ones it can sell for a premium.

Prices are set by what the market will bear

But the overwhelming factor is that in America, the world’s largest market for drugs, prices are set by what the market will bear. When life-saving drugs are available from only one or two providers high prices are a given. This is why pharma companies have piled into oncology over the past decade. They see a market which, by 2025, is forecast to be worth $45bn-100bn a year.

Not all progress is expensive. Effective early diagnostics could save both money and suffering. The knowledge gained from blood biopsies should allow doctors to tailor treatments better, and avoid drugs that will not work on a given patient. And in a different economic setting bespoke vaccines, gene-editing treatments and the like could in times to come short-circuit rising prices. Molecules made inside the body by reprogrammed cells should be cheaper than those made in expensive cultures. Cutting and splicing the genome could be a great deal cheaper than using scalpels and lasers on the body.

But in the world as it is new cancer therapies will continue to be among the most expensive interventions medicine has to offer, creating a challenge for health systems around the world. And some will disappoint. The immune system’s complexity means that it will not always react as doctors hope. Some treatments will prove less effective than at first they seemed. This is a particular problem for cancer drugs, which tend to be approved after comparatively small trials. A recent study of 36 drugs approved between 2008 and 2012 found that 18 did not help patients to live longer. The price of these drugs ranged from $20,000 to almost $170,000 per patient.

The incidence of cancer will continue to be dominated by demographics. In developed countries, new therapies may not reduce the chances of getting cancer for some time, simply because older people get more cancers. But the chances of surviving your first cancer, or your next cancer, will improve—and for those with more amenable cancers, and access to the best treatment, they may do so quite quickly. Ever more people will still be told, “I’m afraid you have cancer.” But the words will become less fateful, the diagnosis ever less feared.

The cost of progress

When Ms Milley was diagnosed with advanced lung cancer, she went on to Google and read the words “death sentence”. It is, alas, fairly typical for patients with terminal cancer to have little idea about their prognosis unless they seek it out. Many might be better served by more openness.

But prognosis is not destiny. Ms Milley started taking Keytruda in December 2015. After two months of treatment her lesions had almost entirely vanished. So far, they have mounted no comeback, and she continues to feel well. She finds the response “amazing”.

On any given drug, in any given trial, most people will not be as fortunate. But one of the strange consolations of the current progress being made against cancer is that modern biomedicine makes it possible to learn more from failure than ever before. Huge amounts of the knowledge now saving lives was gained from dead and dying patients, loved ones and friends who lost their fight for life but left a legacy of data. In any given case, that is scant recompense. Put those contributions together, though, and they make a remarkable memorial.