Why investors cannot resist immunotherapy
Research into ways of tweaking the body’s cellular defences has huge clinical potential
The pandemic has brought unprecedented public attention to the human immune system. Anyone interested in Covid-19 has learnt how antibodies, B-cells and T-cells play a vital role in determining the course of disease and in developing drugs to treat it and vaccines to prevent it.
Yet Covid-19 is just the latest and most vivid example of the growing role that immunology is playing in medicine. Immunity-based therapies are transforming oncology and the treatment of diseases in which the immune system damages a patient’s own body, as well as the more traditional field of infections.
Martin Murphy, chief executive of the UK life sciences group Syncona, has a wide perspective on the field because his company is building a portfolio of cell and gene therapy start-up investments focusing on immunotherapies, particularly for cancer, which exemplify the possibilities. “We are deeply engaged in modulating the immune system,” he says. “The advent of cell and gene therapies around 2013 or 14 really made this possible, achieving remarkable outcomes in patients who were poorly served by existing technologies.”
Syncona’s Autolus is one of many innovative companies developing Car-T therapies, which seek to overcome the natural reluctance of the immune system — designed to handle external threats — to attack tumours. The technology involves extracting T-cells from the patient, genetically engineering them in the lab to recognise the cancer cells, and then infusing them back into the bloodstream.
Another Syncona company, Achilles Therapeutics, is developing a personalised therapy based on “clonal neoantigen” molecules that are unique to each patient’s tumour. These proteins are present on all cancer cells but not on any healthy cells. As with Car-T, this technology involves manufacturing personalised T-cells in the lab and putting them into the patient. An important difference is that Achilles does not genetically engineer immune cells but finds and multiplies natural ones that have arisen early in the evolution of the cancer — and are likely to be present in all its cells.
A third Syncona venture, Quell Therapeutics, uses T-cells in a quite different way — not in oncology but to treat autoimmune and inflammatory diseases, as well as preventing rejection in organ transplantation. It focuses on a category called T regulatory cells or Tregs, which can dampen an excessive immune response.
Unlike its sister companies Autolus and Achilles, Quell’s cell therapies are not yet in the clinic. The first application will be in liver transplants, where the company hopes its Tregs will reduce the toxic cocktail of immunosuppressant drugs that patients have to take today to prevent rejection.
A new Syncona cell therapy company will be set up shortly, Mr Murphy says, building on research at the University of Edinburgh into macrophages. These are another type of white blood cell which play a bigger role in the innate immune system than in adaptive immunity where T-cells operate. The start-up (to be called Resolution Therapeutics) will begin by using macrophages to treat liver disease such as cirrhosis.
“Macrophages are cells that eat dead material in the body and help fight infections, but recently researchers have found that they are able to break down scar tissue and . . . stimulate regeneration in tissue such as the liver — and help co-ordinate the regenerative response in those organs,” says Stuart Forbes, director of Edinburgh’s Centre for Regenerative Medicine.
While therapies based on white blood cells are a fast-growing novelty, the other key component of the immune system — antibodies — has expanded over the past 30 years into one of the largest and most profitable sectors of the pharmaceutical industry, with sales of about $150bn last year.
In the body, B-cells make antibodies to target specific proteins — antigens — on pathogens. In the lab and now in biological production facilities, identical copies of “monoclonal antibodies” can be made in large quantities to treat cancers, autoimmune, metabolic and infectious diseases.
The best-selling drug in history, at least in revenue terms, is AbbVie’s Humira, with global sales of $19bn a year, for treating a range of autoimmune diseases from arthritis and psoriasis to Crohn’s disease and ulcerative colitis. It targets tumour necrosis factor, a protein produced by the immune system. When the body produces too much TNF, inflammation results. Humira works by binding to TNF molecules and blocking them — helping to reduce the inflammation that can lead to symptoms of Crohn’s disease or ulcerative colitis.
But most of the other successful antibody therapies treat cancer. An important feature of the immune system is its use of “checkpoints” to distinguish between the body’s own healthy cells, which it leaves alone, and foreign intruders, which it attacks.
Checkpoints are molecules on certain immune cells that need to be activated or inactivated to start an immune response. Cancer cells evolve ways to use checkpoints to hide from the immune system; checkpoint inhibitors strip away this camouflage.
A favourite target is PD-1, a checkpoint protein on T-cells that normally acts as a type of “off switch” to stop them attacking other cells in the body, by attaching to another protein called PD-L1. This binding is a signal for the T-cell not to attack. Monoclonal antibodies that target PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells.
PD-1 inhibitors include Keytruda (Merck of the US) and Opdivo (Bristol-Myers Squibb), while PD-L1 inhibitors include Tecentriq (Roche) and Imfinzi (AstraZeneca). A different protein on T-cells that keeps the immune system at bay is CTLA-4; Bristol-Myers Squibb’s Yervoy, an antibody that attaches to CTLA-4 and stops it from working, is one of the fastest-growing cancer treatments.
The world’s attention is rightly focused this year on antibodies and other immunotherapies for Covid-19 but the big financial action and most extensive research remain elsewhere — particularly in treating cancer and autoimmune disease.