Scientists have identified a possible mechanism by which cancer cells become resistance to a novel class of cancer drugs -- immune checkpoint inhibitors. Described in Cancer Discovery on 4 January 2017, the paper reveals that cancer cells discard certain genetic mutations, which otherwise enable the immune system to recognize and attack the cancer cells. The study is carried out by Prof Victor E. Velculescu and colleagues from Johns Hopkins University School of Medicine, and collaborators from Personal Genome Diagnostics. Dr Valsamo Anagnostou is the first author of the paper. Immune checkpoints are molecules in the immune system that turn up or turn down a signal. These molecules prevent the immune system from attacking the normal tissues in the body. But cancer cells cleverly evade immune attack by altering immune checkpoint related proteins. The goal of cancer immunotherapy is to spark the immune system back into action. Immune checkpoint inhibitors amplify T-cell responses against tumors. In recent years, these therapies have shown significant therapeutic responses against many cancers. For example, two checkpoint inhibitor drugs, Yervoy and Keytruda, show promise in treating advanced melanoma. However, a lot of patients become resistant to checkpoint inhibitor drugs, which limits their applications in cancer treatment. Victor E. Velculescu, professor of oncology at Johns Hopkins University School of Medicine, and colleagues investigated five cancer patients who developed resistant to two checkpoint inhibitor drugs, nivolumab and ipilimumab. Four of them had non-small cell lung cancer (NSCLC), and the other one had head and neck cancer. NSCLC accounts for up to 85% of all cases of lung cancer, and most NSCLC patients present with metastatic disease or experience disease recurrence despite treatment. Head and neck cancer is a general term for cancers start in the tissues and organs of the head and neck. Through tumor biopsy and genomic analysis, Velculescu's team found that the tumors had gotten rid of mutations in neoantigen-coding genes, after the patients developed resistance to the drugs. A neoantigen is a new specific antigen that develops in a tumor cell. Cancer is caused by mutations to the DNA within cells. The mutations may lead to the production of altered proteins -- the so-called neoantigens. These neoantigens allow the immune system to distinguish cancer cells from noncancer cells. Accumulating evidence indicate that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. So the loss of mutations in neoantigen-coding genes may make the immune system unable to recognize the cancer cells. Further experiments showed that some of the eliminated neoantigens were able to induce a specific immune cell response in the patients. These data provide clues to how cancer cells evolve during immunotherapy. It may allow scientists to develop better checkpoint inhibitors that less likely to cause resistance. The medicine nivolumab is a human IgG4 anti-PD-1 monoclonal antibody. PD-1 is a checkpoint protein on T cells, and it generally keeps the T cells from attacking other cells. Nivolumab blocks PD-1, thus boosting the immune response against cancer cells. The medicine ipilimumab is a monoclonal antibody that targets a immune checkpoint protein called CTLA-4. Ipilimumab binds to CTLA-4 and therefore promotes T-cell activation and proliferation. PD1 and CTLA-4 are co-inhibitory immune checkpoints as they inhibit immune progress. The effectiveness of immune checkpoint inhibitors has made them a hotpot of cancer research. Cusabio provides PD-1, CTLA-4, and FITC conjugated antibody.
