Immunotherapy against cardiovascular disease
Obstruction of the blood flow in the heart causes myocardial infarction (MI) with deleterious consequences on heart function. Most treatments involve restoration of blood flow alongside agents that protect the heart muscle. However, existing therapies for CVD reduce cardiovascular events only by 30 % and several new therapies failed to prevent the deterioration of heart function after MI. There is a pressing need for new therapies to limit the burden of CVD. The EU-funded RITA-MI project worked from the hypothesis that B lymphocytes play an instrumental role in the inflammation that follows an ischaemic myocardial injury. Accumulating evidence indicates that these B lymphocytes secrete the CCL7 chemokine and attract inflammatory monocytes to the infarction site, thereby orchestrating the inflammatory response that causes further deterioration of heart function. Heart attack patients with high blood levels of substances produced by or that activate B cells after a heart attack are at increased risk of death and recurrent MI. “Our objective was to develop a new therapy for patients with acute myocardial infarction (MI) based on selective targeting of the B cell immune response,″ explains project coordinator Prof. Ziad Mallat. Depleting B lymphocytes Monoclonal antibodies against the CD20 antigen of B lymphocytes already exist, making it easy to test in a proof-of-concept clinical trial. Rituximab has been used for more than 15 years in immune-mediated diseases like rheumatoid arthritis and in cancer patients, and leads to the depletion of CD20-expressing mature B lymphocytes. Data from over 10 million treated patients demonstrate good tolerance and pharmacokinetics. Although the drug has yet to be tested against heart disease, recent evidence shows that it may be useful in treating inflammation and preventing heart failure after a heart attack. Previous work by the consortium showed that a single dose of anti-CD20 antibody in a pre-clinical mouse model of MI improved heart function and decreased infarct size and inflammation. The administered anti-CD20 antibody functioned in an equivalent manner to rituximab by temporarily depleting the circulating levels of immune B cells. Clinical evidence for immunotherapy after MI RITA-MI was designed as a phase I safety study to assess the safety of rituximab in acute MI patients. Researchers monitored patients’ response to the drug in a controlled environment and on extended follow up. In addition, they assessed the effect of rituximab on circulating B cells immediately after administration and on follow up. Preliminary data indicates that a single infusion of rituximab during the first 24 hours of an acute MI is safe and substantially depletes the level of circulating mature B cells. “The next step now is to assess the impact of rituximab on the recovery of heart function after MI in a phase II clinical trial. Our pre-clinical data suggest that B cell depletion will improve the recovery of heart function after MI,″ states Prof. Mallat. Immunotherapy should be administered during the acute phase of MI to minimise tissue necrosis and inflammation and improve the recovery of heart function. Prof. Mallat encourages the participation of pharmaceutical companies in this second trial and emphasises the need for training health workers to handle and dispense the drug, as well as to recognise and treat all potential adverse events.
Keywords
RITA-MI, myocardial infarction (MI), cardiovascular disease (CVD), B lymphocytes, rituximab, immunotherapy, CD20 antibody, phase I safety study
