Cancer is a common health issue, with one in two people being diagnosed with some form of cancer every year. One factor that makes the condition so challenging is its ability to evade the immune system, something made easier due to cancer originating from a person’s own cells. This means that cancer cells have ‘self’ antigens, which the immune system recognises to be part of the body, as opposed to ‘foreign’ antigens, which the immune system recognises and attacks to prevent harm. Although the immune system will not attack cancer cells on its own, past research has shown that the immune system can be ‘tricked’ into registering the cells as foreign and attacking them. This is how antibodies came to be used to treat cancer.
Breast cancer is the most common cancer, making up 12.5% of cancer cases worldwide. So, it is no surprise that a wide range of research has been conducted on breast cancer. This research has identified that breast cancer is composed of different subtypes, which are driven by different types of genes and mutations. One subtype of breast cancer, which is very aggressive and rapidly growing, is defined by an amplification of the HER2 gene, classified as HER2 positive (HER2+) breast cancer. This also happens to be one of the only solid tumour cancers treated with tumour-targeting antibodies. At Duke University Medical School, Dr Zachary Hartman is researching how HER2 makes this cancer aggressive, how these HER2-targeting antibodies fight cancer, if these treatments can be improved upon and if there are any other cancer types that this type of treatment could be used for.
How is HER2+ cancer treated currently?
The standard HER2+ cancer treatment starts with chemotherapy and two monoclonal antibody treatments targeting HER2. If the tumour remains contained to the breast tissue, these treatments will be used until the tumour can be removed surgically. The chemotherapy and antibody treatments will be continued after surgery, to ensure there are no cancerous cells left behind. There is a chance that these treatments may not work, the cancer may develop resistance, or the cancer may come back. In these cases, alternative antibody-drug conjugates are used.
What motivates Zachary’s research?
“As tumour-targeting antibodies are barely used for other solid tumours, I want to understand the underlying therapeutic mechanisms for this treatment to see if it could be extended to other cancers and improved upon in breast cancer,” explains Zachary. “And I want to understand why some antibody-drug conjugates work better than others.” Additionally, Zachary aims to explore the potential of a HER2 vaccine, which would stimulate HER2-specific immunity in a similar way to how vaccines are used for viruses (such as COVID-19). This is more difficult, however, as HER2 is also present in healthy cells, and vaccine-generated immunity may not be tumour-specific.
Zachary’s research also aims to fill gaps in our knowledge of tumour immunity. Studies on how HER2 monoclonal antibodies work have been started but are far from complete. These antibodies were originally thought to function by stimulating one type of immune cell (the natural killer cells) or blocking tumour growth signalling, rather than triggering the whole immune system. It has now been found that there are other, more important cells (e.g., macrophages) that can be credited for the response – and researchers are continually learning more about how they stimulate immunity.
What experiments and trials have been done so far?
Zachary’s research has reached the in vivo experiment stage. For this, HER2+ breast cancer cells are injected into mice. Once the cancer has developed, monoclonal antibodies or antibody-drug conjugates are injected to provide insights into how the anti-tumour response is caused. Zachary and his team have also been able to knock out certain genes and proteins and even deplete cell types to study the treatment function and what is needed for the anti-tumour response.
Zachary’s antibody research has not yet reached clinical trials, but he has conducted early-stage HER2 vaccine trials, with under 50 participants, looking at whether HER2-specific antibodies and white blood cell responses are generated from the injection of the recombinant HER2 expressing viruses.
How can the results be used in real life?
So far, Zachary’s research has shown that HER2 vaccines do trigger specific immune responses and can also stop the immune system from tolerating HER2. Whilst this response was not found in all patients, those with the response had better outcomes than those without. Critically, the HER2 vaccines were demonstrated to be very safe and were unable to provoke obvious autoimmunity, thus suggesting their ability to elicit cancer targeting immune responses.
