Evaluation of B7H3 as a novel target for immunotherapy in childhood cancer

24 May 2016

Dr Kathleen Birley, UCL Institute of Child Health

Kathleen Birley was awarded a Clinical Studentship in December 2015 - our first such studentship - to support her research into a new immunotherapy approach for childhood cancers.

She is focusing on a protein called B7H3 which is present on cancers including neuroblastoma and the brain tumour DIPG; it is hoped that this may represent a new target for the treatment of these cancers.

Background – the need for new treatments

Kathleen BirleyOne of the difficulties in developing new treatments for childhood cancers is finding ways to attack the cancer cells without damaging healthy cells. This is an important consideration since the effects of cancer treatment can have a serious impact on children’s health and development.

Immunotherapy is becoming an increasingly important tool in the treatment of cancer, and some early success has been achieved in certain childhood cancers. It potentially offers increased effectiveness with fewer side effects.

Normally, immune cells (called T-cells) recognise abnormal cancer cells and destroy them. But sometimes, cancer cells escape detection and are able to grow and multiply – forming a tumour.

In this work, Kathleen is focusing on a protein known as B7H3 which is found on cancer cells but rarely on healthy cells. Research has shown that when cancer cells have lots of B7H3 they are more resistant to T-cell attack. B7H3 is thought to inhibit or “switch off” T-cells.

Research has also shown that B7H3 helps the cancer cells to grow and multiply, and to evade the chemotherapy drugs used to treat cancer.

So not only does B7H3 help the cancer to develop in the first place, by avoiding immune surveillance, but it also reduces the effectiveness of chemotherapy. When researchers have prevented cancer cells producing B7H3 in the lab, the cancer cells don’t grow or spread as well and are more sensitive to chemotherapy.

Attacking the cancer without damaging healthy cells

In the course of this project, Kathleen is aiming to make antibodies - proteins usually made by immune cells – that recognise and specifically attach to B7H3. Antibodies act as a flag, attracting immune cells, which then attack the cells to which the antibodies are attached. Because B7H3 is present on cancer cells, but not healthy cells, the antibodies should selectively attach to cancer cells, causing them to be destroyed without affecting normal cells.

Kathleen will generate and test a new antibody using ‘chains’ of antibodies against B7H3 produced by a mouse. The antibody will be tested against cancer cells grown in the lab to evaluate its effect; it will also be tested in combination with other immune cells such as ‘natural killer’ (NK) cells and other proteins found in blood known as ‘complement’.

B7H3 is thought to inhibit or “switch off” immune cells like T-cells. Antibodies will attach to B7H3 and the team will see if this can keep T-cells activated or “switched on”, improving the body’s own natural defence against cancer.

B7H3 is also known to help the cancer cells invade, grow and resist treatment. The effects of antibody attachment to B7H3 will be evaluated to see if it reduces cancer cell growth and resistance.

About Kathleen

Kathleen graduated with a medical degree from University College London in 2010 and has been working as a paediatrician for a number of years. She is particularly interested in paediatric oncology and in the development of new treatments for young patients. This studentship will allow her to take time out of her training program to learn new research skills and study for a PhD.

The UCL Institute of Child Health, where her research is based, works in partnership with Great Ormond Street Hospital, forming part of the largest concentration of children’s health research in Europe.

Kathleen will work in the lab of Professor John Anderson and Dr Karin Straathof, two of the UK’s leading experts in the development of new immunotherapy techniques for childhood cancer. This provides an excellent environment for Kathleen’s research, with access to all of the necessary equipment and resources. The Anderson-Straathof team has a track record of translation of preclinical data; taking the therapies developed through laboratory research and using them to treat children. This means the project can provide experience both in lab-based research and in clinical trial development.

What difference will this project make?

DIPG is a type of brain tumour which is almost universally fatal. The average child with DIPG lives around nine months and no treatment has been shown to be effective. DIPG cells express large amounts of B7H3 on their surface and antibodies against B7H3 could provide a much-needed new treatment for this devastating tumour.

B7H3 is also found on other types of cancer such as neuroblastoma. Neuroblastoma can be divided into low, intermediate and high risk categories. Roughly half of new cases are high risk and have a five-year survival of 30 to 40 per cent. Because B7H3 is expressed on the surfaces of neuroblastoma cells as well as DIPG, similar treatments could be used to treat both.

B7H3 is also found in lots of other rare childhood cancer types, meaning that this work potentially has broader application.

If Kathleen’s work is successful, the infrastructure at UCL ICH means that the therapy can be rapidly taken forward from the lab towards the point where it can be tested in young patients.

Another key aim of this grant, and our studentship scheme generally, is the development of Kathleen’s research expertise. Through this grant and the research she is carrying out she will obtain first a Masters and then a PhD; this will enable her to develop a dual career combining research and clinical practice so that she can continue to address the need for new treatments for her young patients.

Read more: About childhood brain tumours | About neuroblastomaCurrent research projects

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