Novel immunotherapy approach targets cancers

Designer antibodies can alert the immune system to cancerous proteins, slowing tumour growth in mice – three independent studies demonstrate.

Researchers at the John Hopkins University School of Medicine, Maryland, investigated the notorious cancer proteins, p53 and RAS. Mutations in p53 and RAS are common among cancers, however, drug therapies have been largely unsuccessful. Therefore, researchers aimed to develop specific antibodies, like those of our immune system, to target these proteins instead. Antibodies detect precise protein fragments, called peptides.

'These peptides can be presented on the cell surface when complexed with the human leukocyte antigen (HLA) proteins,' said Dr Katharine Wright, lead author of one of the studies. HLA proteins present peptides to immune cells called T cells. 'These mutant peptide-HLA complexes serve as antigens and mark cancer cells as foreign to the immune system.'

The researchers designed specific antibodies to recognise a one amino acid difference between mutant and normal p53 and RAS proteins. The mutant proteins are expressed at very low levels, meaning that the antibodies had to be extremely potent – a feat that took the researchers more than five years to overcome. Additionally, the antibodies had to recognise T cells to alert the immune system to the cancer.

In vitro cultures of cancer cell and T cell lines, the bispecific antibodies recognised the mutant p53 or RAS antigens and activated the T cells to kill the cancer cells. In preclinical studies in mice, the immunotherapy also moderately reduced the tumour size.

'This therapeutic strategy is dependent on a cancer containing at least one p53 or RAS alteration and the patient having an HLA type that will bind to the mutant peptide to present it on the cell surface,' said Professor Shibin Zhou, one of the study leaders.

The immunotherapy could target cancers that often evade the immune system, but are caused by RAS or p53 mutations, such as pancreatic cancer. It could also be adapted to target other cancerous genes or proteins.

Dr Alexander Pearlman, co-author of the three studies, said 'We intend to develop a large number of bispecific antibodies that would target such genes.'  

The studies were published in the journals Science, Science Immunology and Science Translational Medicine.