Lana Kandalaft is Director of the Centre for Experimental Therapies at Lausanne University Hospital. One of her main projects is the development of a new generation of vaccines against cancer that will be generated by the sole identification of immunogenic tumor antigens specific to each patient.
Éric Raymond is Director of the Department of medical oncology at Lausanne University Hospital. Medical oncologist, specializing in cancers of the digestive system and expert in molecular pharmacology, Éric Raymond is one of the leading figures in the development of oncology drugs.
Immunotherapy, which aims to mobilise the immune system in the fight against cancer cells, has for some years been the focus of rapid advances. The current development of a Swiss Cancer Centre will provide Lausanne with all the skills and infrastructure required to become a centre of excellence in this field.
Immunology is booming. And the reason why is clear: this technique, which involves mobilising a patient’s immune system to arm him more effectively in the fight against a tumour, has already chalked up some impressive successes, notably in the case of difficult-to-treat cancers such as metastasising melanomas and ovarian cancer. “Immunotherapy is currently one of the most dynamic areas of oncology in terms of scientific knowledge and therapeutic developments”, observes Eric Raymond, director of the department of medical oncology at Lausanne University Hospital. “It’s the future,” adds an enthusiastic Lana Kandalaft, director of the hospital’s Centre for Experimental Therapies. Combined with other treatments, these new therapies are expected to rewrite the strategy for fighting cancer, a fight that will become increasingly personalised.
Policing the body
Effectively acting as the body’s army, the immune system defends us against foreign pathogenic agents – viruses, bacteria and parasites – that invade our bodies. But it also has a policing role to play: it must rid us of home-grown attackers and, foremost among these, of cancerous cells which threaten our health. This policing role is, however, more complex than that of defence. This is firstly because an individual’s cancerous cells are not very different from healthy ones, and secondly because the appropriately named malignant cells develop a range of strategies to repel the forces of law and order. Immunotherapy is therefore aimed at mobilising and re-arming the police to enable them to accomplish their task more effectively.
Freeing up the immune system
According to Eric Raymond, researchers realised that the key thing was to “free up” the mechanism that was holding back the functioning of the immune system and to help it “recognise tumour cells”, attack them more effectively and destroy them. Several approaches are used in pursuit of this strategy: monoclonal antibodies, vaccination, cell therapy and interventions in healthy cells that surround the tumour and help it develop.
Monoclonal antibodies prevent immune cells switching sides
“The tumour is ready and waiting for the police,” as the head of medical oncology points out. “There are in fact numerous immune cells to be found in the tumour, notably T cells. But most of the time they are deactivated and sometimes even mutate and become the tumour’s formidable ally.” The immune cells therefore switch to the enemy side and help the tumour produce factors which it cannot manufacture itself. Antibodies are used to prevent these cells from behaving in this way. Acting as natural defenders, antibodies spot intruders or abnormal cells and are produced in their thousands from one single, cloned cell; hence their name, monoclonal antibodies.
“It is in this field that we are currently observing the greatest progress, as the monoclonal antibodies display remarkable antitumour activity,” continues Eric Raymond. Some of them, destined to be used against metastasising melanoma, have already received marketing authorisation. Others, targeted at lung cancer, could shortly come on the market.
Therapeutic vaccine: still at a very experimental stage
The fight against cancer also involves perfecting therapeutic vaccines designed to treat the disease. The task, however, is not simple. As the oncologist explains, the immune system has difficulty recognising tumour cells which display only “a few anomalies” that distinguish them from healthy cells. We therefore have to “identify and isolate their immunogenic parts – that is those parts likely to be recognised by the immune system – and use them to produce vaccines. This approach is still at a very experimental stage even though we are making progress.
Producing several billion T cells
Another avenue involves exploiting T lymphocytes extracted from the tumour. These T cells “circulate round the body and their presence in a tumour indicates that they are capable of recognising cancerous cells,” explains Lana Kandalaft. The method consists of extracting T cells from the patient’s tumour then, in the laboratory, stimulating and multiplying them to obtain several billion which are then re-injected into the patient. But this requires a cell-production platform close to the patient’s bedside, a facility which will be available in Lausanne.
Combining cell therapy and vaccination
This cell therapy, combined with vaccination, has already produced some promising results. While they were working at the University of Pennsylvania in the United States, George Coukos, current director of the department of oncology at Lausanne University Hospital, and Lana Kandalaft devised a two-phase strategy to combat ovarian cancer, one of the deadliest forms of the disease.
They firstly took a sample of dendritic cells from the tumours of patients. “These cells act as spies,” explains Lana Kandalaft. “They patrol our bodies and when they spot tumour cells they head for the lymph nodes to recruit T cells. They train these soldiers and convey the order to them to go to the front and kill the tumour.” In the laboratory, the dendritic cells are exposed to the tumour’s antigens and are then re-injected into the patient’s lymph nodes in combination with a drug used in chemotherapy.
Remission in ovarian cancer
This well-tolerated vaccine triggers a reaction in the T cells which are then mobilised to fight the tumour. “In this way we have gained a large number of soldiers,” explains Lana Kandalaft, and these soldiers have been equipped with new weapons by researchers to make them more effective. The researchers extracted these T cells from patients, then stimulated and multiplied them to re-inject them in vast quantities – “up to 30 billion” – into their hosts.
Among the 31 women who took part in a clinical trial, the vaccine alone stopped or at least slowed progression of the disease in 65% of them. In the case of the 11 patients who benefited from the second phase of the treatment, 73% saw their tumour reduced or stabilised. Lana Kandalaft also cites the case of one woman “who was operated on twice and whose ovarian cancer had recurred each time.” As her case seemed hopeless, immunotherapy was tried. “Today, five years later, her cancer appears resorbed.”
Transforming T cells into serial killers
Once the T cells have been extracted from the tumours, they can be genetically modified to create genuine “serial killers”, according to the cell-therapy specialist. The experiment was tried in the United States on adults and children some of whom – notably a 9-year-old girl who made the front page of the New York Times – are in full remission. However, this shock therapy “entails numerous side effects and demands caution. We will only offer it to our patients when we are able to carry out clinical trials in the safest possible conditions.”
Attacking the tumour’s ecosystem
A further tactic to complement the above approaches involves intervening in the “stroma, that is to say the ecosystem in which the tumour proliferates,” explains Eric Raymond. The tumour is in effect surrounded by tissue cells and vessels without which it would be unable to live and grow.
Anti-angiogenic drugs have already been created to destroy the blood vessels that the tumour hijacks for its benefit to feed itself. They are “now part of clinical routine”. Numerous teams, and notably that of Eric Raymond, are currently seeking to disrupt communications between the tumour and its micro-environment. “The stroma secretes signals such as transforming growth factor-ß, which increases the tumour’s aggressiveness towards the immune system.” By using drugs to help block these signals, it is hoped to destroy the tumour cells.
Multiple approaches are therefore available. Certain immunotherapy techniques are already producing good results in initial clinical trials, but the objective, as Lana Kandalaft emphasises, is to “make them available to a large number of patients.” No single one represents the miracle cure. However, when combined together or with forms of chemotherapy, it is anticipated that they will enable every patient to be treated according to the nature of their tumour. The anticancer strategy is in effect being rewritten.