Combining drugs could help immune system fight cancer
Southampton researchers have identified a combination of two immunotherapy drugs that could help the body fight a form of blood cancer.
Results from the UK clinical trial provide clues that could help more patients when the cancer has become resistant to treatment.
The multi-centre RiVa trial is being run by the Cancer Research UK Southampton Clinical Trials Unit. It is looking at whether combining rituximab and varlilumab could improve outcomes for people with B cell lymphoma.
Dr Sean Lim has presented preliminary results at this month’s American Society of Hematology (ASH) annual meeting.
Resistance to treatment
Lymphoma is a blood cancer that develops in the body’s infection-fighting white blood cells, called lymphocytes or B cells.
Rituximab works by sticking to the surface of cancerous lymphoma cells and marking them out for destruction by the immune system. It has been shown to be very effective for people with lymphoma. But over time, some people’s cancer will become resistant to the treatment.
Previous laboratory research, carried out by Dr Lim and her team at Southampton’s Centre for Cancer Immunology, showed that combining rituximab with varlilumab may be able to counter this resistance.
Varlilumab acts to increase the number of cancer-fighting immune cells in the patient’s body.
Dr Lim, Associate Professor in haematological cancers at the University of Southampton, said: “In this small trial, some people responded to the combination treatment and some did not, as one would expect from any study. But what is really interesting is that we have found clues as to what the varlilumab is doing in the tumours, helping us to better understand why there is a response in some patients and not in others.”
Destroying cancerous B cells
Varlilumab is a CD27 agonist. This means it binds to the CD27 receptor on T cells and stimulates a pathway that leads to more T cells being produced. The process releases chemicals that activate another type of immune cell called macrophages. These macrophages are able to destroy the cancerous B cells that have been marked by the rituximab.
“With RiVa, we took needle biopsies of the tumours from patients who only had rituximab versus those who had the combination of rituximab and varlilumab,” Dr Lim said.
“What we saw in those who also had varlilumab was an increase in activated T cells and evidence of activated macrophages. This data gives us confidence that varlilumab is stimulating the immune system.”
Benefits of a ‘hotter’ immune environment
The Southampton team is continuing to analyse all the data from the trial to further understanding of the stimulatory pathways work. This will lead to vital research in future clinical trials.
Dr Lim said: “When we looked at the patients who responded to the combination treatment, versus those who did not, we found that the responders had a greater increase in the number of T cells, and a ‘hotter’ immune environment, so more expression of the genes that lead to an immune response.
“This suggests that the patients who are going to respond to T cell stimulation are probably the ones with a more active immune environment. We don’t have a means to pick these people out yet, but we are another step along the way.”
The research team will next look for a more effective agonist.
“We see that varlilumab is stimulating the immune pathways, but it’s a weak agonist,” Dr Lim explained. “My lab is now looking at how we can engineer antibodies to optimally bind to CD27. We are also looking at other immune-stimulatory antibodies, beyond CD27.”
Image: Dr Sean Lim is an Associate Professor and Honorary Consultant in Haematological Oncology at University Hospital Southampton