A study in Nature describes a new type of cancer vaccine that works by obstructing a tactic used by tumours to escape the immune system. The vaccine was effective in mouse models of aggressive cancer, was safe in non-human primates and is set to be tested in clinical trials.
The vaccine targets a conserved domain on two proteins produced by many types of cancer cells in response to DNA damage – MICA and MICB stress proteins. These proteins would normally act as a signal to invoke T cells and natural killer cells of the immune system. To prevent recognition by the immune system, cancer cells shed MICA/MICB proteins.
The vaccine increases the density of MICA/MICB proteins on the surface of tumour cells by inhibiting proteolytic shedding. Through this mechanism, the vaccine enhances the presentation of tumour antigens by dendritic cells to T cells and augments the cytotoxic function of natural killer cells. In this way, the tumour is attacked by both T cells and natural killer cells.
Cancer recurrence caused by micrometastases is a challenging problem in oncology. So the researchers tested the vaccine in two models of spontaneous metastasis. The vaccine greatly reduced the number of lung metastases in models of melanoma and triple-negative breast cancer more than 1 month after the removal of the primary tumour.
The vaccine was also tested in immunotherapy-resistant tumours caused by inactivating mutations. Here, the vaccine was efficacious against tumours with mutations resulting in loss of MHC-I, MHC-II or the interferon-γ receptor. At a molecular level, the researchers showed that efficacy was mediated by T helper cells recruiting natural killer cells to the resistant tumours.
The approach described in this study might be better than other cancer vaccine strategies because it overcomes the need to personalise cancer vaccines that target peptide antigens. And having a vaccine elicits a broad immune response reduces the risk of immune escape.
The authors note that a first-in-human clinical trial is planned, in which serum levels of shed MICA/MICB and tumour-cell expression of MICA/MICB will be used as a biomarker to select patients. The authors also note that the vaccine could be combined with local radiation therapy because DNA damage enhances MICA/MICB expression on cancer cells.
Written by Charlotte Harrison, Science Writer
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