Friday August 15 2008
The antibody recruits immune system T-cells which attack the cancer cells
“Drug that uses the body’s cells to blast cancer”, is the headline in the Daily Mail, describing a “‘serial killer’ treatment” that is able to completely eliminate some tumours and make others more susceptible to existing cancer treatments. The drug blinatumomab has been used to treat patients with non-Hodgkin’s lymphoma and may be “on the market in less than five years”, the newspaper says.
The newspaper story is based on results from a small phase I trial that showed that patients with particular types of incurable non-Hodgkin’s lymphoma responded well to the higher doses of blinatumomab, however there were side effects. The positive findings from this study will lead to larger trials and the effect of blinatumomab will be investigated in more people.
Based on this study, there are certainly grounds for optimism, though confirmation of the findings with further research is important. This process will take time and it is difficult to say when, assuming the drug continues to prove to be effective, blinatumomab will be available for patients.
Where did the story come from?
Dr Ralf Bargou and colleagues from the University of Würzburg; the Ludwig-Maximilians-Universität, Munich and other medical and academic centres, as well as the biopharmaceutical company Micromet – who manufacture the drug used in the study – carried out this research. The study was funded by the Interdisciplinary Center of Clinical Research at the University of Würzburg. Some of the researchers note that they are inventors of and hold patents for some of the techniques and drugs used in this study. It was published in the peer-reviewed medical journal: Science.
What kind of scientific study was this?
The study is a phase I trial of a synthetic antibody called blinatumomab. Phase I trials are an early step in the investigation of whether a drug is effective and safe in humans. Usually – as with this study – they enrol only a small number of people to enable researchers to investigate the response to different doses of the study drug. Treatments with encouraging results from phase I studies then go on to further trials - phase II and III studies - where there is a larger sample size and usually a comparison treatment (e.g. another drug or placebo).
In this study, 39 people with incurable, non-responsive (to conventional therapies), non-Hodgkin B-cell lymphoma (a type of cancer affecting the lymph nodes in the body) with measurable disease (at least one tumour bigger than 1.5cm) were included. They received blinatumomab through a portable continuous intravenous infusion device for four to eight weeks. This drug is a synthetic antibody that recruits T-cells, which are helpful in the immune response, and carries them to tumour sites. These T-cells then bind to the surface of tumours and destroy them. Because of this property to engage T-cells, the antibody is known as a BiTE antibody (bispecific T-cell engager).
For the first two weeks, the patients were kept in hospital for monitoring, and then they were allowed home. As the researchers were investigating the response to different doses of the antibody, small groups of patients within the sample received different doses. After four weeks, CT scans were used to assess the effect of the drug on tumours. Patients who had a response after four weeks were offered the chance to continue treatment for another four weeks at which point a second round of CT scans were performed.
The researchers then looked at the size of the tumours and rated whether the patient had a complete response (disappearance of tumours and normalisation of other factors); a partial response (50% reduction in the two longest dimensions of each tumour); a minimal response (25% reduction); no response or whether disease had progressed. The concentration and type of white blood cells (an indicator of immune response) was monitored using regular blood tests.
The researchers recorded the response of the patients to the drugs, as well as any adverse events and events that led to the discontinuation of the study medication.
What were the results of the study?
Overall, the researchers found no response in the 12 patients who were taking the lower three doses of the drug. Of the 19 patients receiving treatment at one of the middle two-dose categories, there was regression of the tumour to some degree in four of them (21%); two of these were complete regression and two were partial regression. Of the seven patients taking the highest dose of blinatumomab, all had some response: two with complete regression and five with partial regression.
What interpretations did the researchers draw from these results?
The researchers say that a response to blinatumomab was observed at a dose of about 0.015 mg/m2 – a considerably lower dose than is required with the alternative monoclonal antibody rituximab. They say this difference in potency may be due to the activity of the T-cells recruited by the antibody to attack the tumours.
A larger (phase II) study is ongoing and this will investigate the activity of blinatumomab in patients who have acute lymphoblastic leukaemia. Overall, the researchers conclude that “T-cell-engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases”.
What does the NHS Knowledge Service make of this study?
This phase I study provides early evidence that people with incurable non-Hodgkin’s lymphoma respond to the new BiTE antibody blinatumomab. There are several points to highlight:
- Given that the study is only in the early stages of testing in humans, it may be some time before the drug comes on the market and is a real option for patients.
- Treatment is not without side effects, including fever, chills and a reduction in circulating white blood cells.
- This study investigated the use of the drug for non-Hodgkin’s lymphoma. Of the group of participants, 39% had mantle cell lymphoma (a rare type of non-Hodgkin’s lymphoma that affects the B-lymphocytes) and 41% had follicular lymphoma (a common non-Hodgkin’s lymphoma also affecting the B-lymphocytes). Though other studies are planned, the findings of this study are limited to these types of cancer.
It remains to be seen what the ideal regimen for delivering this drug might be and if the results will be confirmed in trials with longer follow-up.
Sir Muir Gray adds...
Cancer cells are different from the patient’s normal cells, so they should be able to be attacked just as bacteria are attacked, but this approach has been difficult to develop; it will be good to see more results.