Patients with a recurrence of the most aggressive brain tumor GBM (GlioBlastoma Multiforme) survive for just an average of 3 to 6 months following diagnosis. In Italy, in 1994, Dr. Riva was the first doctor to administer radioactively labeled IgG antibody against Tenascin C to patients with recurrent glioblastoma. An anti-Tenascin C antibody is a logical choice for this disease because Tenascin is a glycoprotein that is secreted by GBM cells in large amounts into the ‘tumor bed’ or matrix surrounding the tumor cells. In Riva’s study, a third of patients treated with anti-Tenascin antibody had a temporary reduction in tumor size, and some patients survived for longer than a year. This treatment has been repeated at other sites across the world with similar results. The Riva protocol has undergone various modifications but until now none have improved the results.
Cinderella has chosen to use an IgM antibody, which is a much larger molecule than IgG and which has more antigen binding sites, allowing it to bind more efficiently at the tumor site. A further difference is that Cinderella uses Yttrium-90 instead of Iodine-131 as the therapeutic radioisotope. Use of Yttrium-90 improves the concentration of radiation inside the tumor, and has the added advantage that patients need not be admitted to hospital nor isolated due to emission of dangerous radiation to the surrounding environment, as is the case for Iodine-131.
The treatment is given in two steps. In the first step, the antibody is labeled with a diagnostic radioisotope, Indium-111, that can be readily visualized with a gamma camera. This diagnostic radioisotope is administered directly into the recurrent glioma. By fusing the images from the gamma camera with MRI images it is possible to determine how much of the injected antibody has bound at the tumor site. In the second step, the same antibody is labeled with a therapeutic radioisotope, Yttrium-90, and injected into the same site. Using the measurements done in the first step it is possible to calculate how much antibody must be injected in the second step to obtain the desired radiation dose within the tumor. However, this second step is only carried out if the antibody measurements in the first step indicate that the patient has a good chance of the treatment being effective. This new approach has two major advantages: it is possible to determine beforehand which patients are likely to benefit from treatment, and harmful side effects of over-radiation of the brain tissue surrounding the tumor can be avoided.
Twenty cell lines that produce antibodies against Tenascin C have been generated for Cinderella. At the Josefine Nefkens Institute at Erasmus University Medical Center (MC) in Rotterdam, two of these cell lines have been selected for their ability to make an antibody that binds well to gliomas. The antibody also binds to malignant cells in pancreatic cancers, which have also been found to secrete Tenascin C. This means patients with pancreatic cancer can be treated with the same drug.
The relatively small amount of antibody (4 grams) required for treatment of the first 20 patients was going to be produced in the laboratory of a Dutch university. Unfortunately this agreement has been cancelled and so a new manufacturer must be found.
In the meantime, the clinical part of the study was being prepared in collaboration with medical specialists and researchers at Erasmus MC. These clinical studies are expected to take 2 to 3 years.
Unfortunately, at the end of 2012 we discovered that we were unable to obtain assistance from the department of nuclear medicine at Erasmus MC, which is essential for the preparation of the radioactive isotope. As a result, this project can currently not proceed.
Cinderella Therapeutics is willing to share all knowledge obtained with anyone willing to continue the development of this project on a non-commercial basis, and to make the antibody-producing cell lines available to such parties.