A first step has been taken towards revolutionary cancer treatments that use personalised vaccines to target individual genetic defects. In early tests, scientists were able to prime the immune systems of mice to recognise, attack and drive back lung, skin and bowel tumours.
Tumour growth was "profoundly retarded" by the treatment, greatly improving the animals' survival. The ground-breaking technique - now being tested in a clinical trial - may provide a "universally applicable blueprint" for vaccines that are effective against a wide range of human cancers, the scientists believe.
Crucially, it overcomes the problem of cancer presenting an ever-moving target with genetic mutations that vary not only between tumour types but the same cancers in different patients. A patient's own cancer mutations also change as the disease progresses, which can lead to drug resistance. The slippery way that cancer seems able to elude the immune system has frustrated previous attempts to devise effective cancer vaccines.
Commenting on the new findings, published in the journal Nature, Professor Kevin Harrington, from the Institute of Cancer Research, London, said: "This study in mice provides the first evidence that we may be on the threshold of being able to produce individualised vaccines directed against specific mutations present in a patient's tumour. Rapid production of purpose-built vaccines appears to be possible and can now be tested in carefully designed clinical trials. As yet, this approach must be seen as experimental but it potentially represents a new way of harnessing the power of the immune system against cancer."
The scientists, led by Dr Ugur Sahin, from Johannes Gutenberg University in Mainz, Germany, first identified tumour-specific mutations linked to the different cancers and showed that many of them could be recognised by immune system cells called CD4 T-cells. They then created vaccines that used customised sequences of the genetic molecule messenger RNA (mRNA) to encourage an immune system attack on cancer cells containing the target genetic defects.
Messenger RNA normally acts as the vehicle that carries instructions from the genetic code to a cell's protein-making machinery. Two-thirds of the treated mice were still alive after 100 days while all the "control" mice survived no longer than 65 days. When repeated vaccinations were administered, "tumour growth was profoundly retarded", said the authors.The researchers identified a similar abundance of mutations that could be recognised by CD4 T-cells in human cancers. A first-in-concept human trial of the technique involving melanoma skin cancer patients is now the process of recruiting patients.
The scientists wrote: "The tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation .. enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'."
Medical oncologist Professor Peter Johnson, from the Cancer Research UK Centre at Southampton General Hospital, said: "This paper investigating cancer immunotherapy in mice is encouraging because it has demonstrated that it is possible to direct a specific immune response against the mutations that arise in tumours during cancer development. This paper provides the first evidence of a significant anti-tumour effect with such a technique, suggesting that it may be possible to direct the immune system to fight cancer using personalised RNA vaccines."
He added: "If results are similarly encouraging in human trials, this will help to accelerate the development of combination immunotherapy treatments using the antibody therapies already in the clinic, together with vaccines targeting the mutations present in individual cancers."
CD4 T-cells, known as "helper" T-cells, produce immune system signalling molecules called cytokines that marshal immune system defences. In this way, they act as conductors directing the immune system "orchestra". Another kind of "killer" T-cell destroys infected or cancerous cells directly. The study showed that the experimental vaccine induced "killer" T-cells to attack tumours.
