Highly mutated cancer cells could be used to create a vaccine to boost the effectiveness of immunotherapy, according to a major new report.
The international study – carried out by scientists at The Institute of Cancer Research, London, England, the Mayo Clinic in Rochester, USA, and the University of Leeds, England – is the first to show that the role of the molecule APOBEC3B in driving cancer evolution can be used in a vaccine to improve the immune response.
Writing in the latest edition of Nature Communications, they describe using the mutated cancer cells to cure mice with a variety of otherwise treatment-resistant tumours.
The rapid genetic changes in human cancer cells occurred when high levels of APOBEC3B, which can edit the DNA code of cells, resulted in genetic changes that can be seen as signatures.
Genetic analysis revealed more than a million extra mutations in the cells expressing APOBEC3B, compared with control cells. Of these, about 68,000 contained the classical APOBEC signature, which make cancer cells vulnerable to treatment with immune checkpoint blockade.
The researchers used the genetic signature APOBEC3B left behind to create cancer vaccines, each of which was tailored to the particular genetic profile of a specific tumour.
They gave mice the highly mutated cancer cell vaccines, which led to an immune attack against their tumours, and by combining them with checkpoint inhibitor immunotherapy, the mice were cured of melanoma and brain tumours.
Study author Alan Melcher, Professor of Translational Immunotherapy at The Institute of Cancer Research, London, said: “Our new study rather paradoxically takes advantage of a mechanism used by cancers to rapidly evolve and become resistant to chemotherapy, and instead makes them much more vulnerable to the effects of immunotherapy.
“Our new approach has the potential to be effective against cancers that do not currently respond to treatment, and we’re keen to take it into clinical trials as soon as possible.”
Co-author Dr Adel Samson, from the University of Leeds’ School of Medicine, added: “Adult cancers are caused by an accumulation of genetic mutations, which can provide resistance to conventional chemotherapy drugs. However, the same mutations make it possible for the immune system to detect and kill the cancer.
“This study demonstrates how we might apply this concept to future therapeutic cancer vaccines, by artificially mutating patient-derived cancerous cells in the laboratory, then injecting the mutated cell proteins back into the same patient.”
They now want to use this new technique to create personalised vaccines into the clinic, beginning with a trial in children with brain tumours.
APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy. Nature Communications 10 February 2020
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