At a symposium organised by the European Commission which took place today in Karlsruhe, Germany, participants heard that the use of Bismuth-213 has rendered targeted alpha-particle therapy feasible. The Bismuth-213 isotope is produced in the Institute for Transuranium Elements (ITU), the Commission's Joint Research Centre in Karlsruhe. First ever tests carried out at Memorial Sloan-Kettering Cancer Center in New York on leukemia patients showed very encouraging results with no significant uptake of the isotope outside the target areas of bone marrow, liver and spleen. The isotope is attached to a monoclonal antibody (HuM195) in order to reach the desired targets. This still ongoing study is the first to show that targeted alpha-particle therapy is feasible and appears safe.
The alpha-immunotherapy is based upon radionuclides which emit alpha particles: (a) alpha particles have high linear energy transfer and are thus 100 to 1000 times more cytotoxic as beta particles; even one or two atoms of targeted Bismuth-213 may be enough to kill a cancer cell; (b) the damage of normal tissue around the target cell is greatly reduced or absent because the path lengths of typical alpha particles are about 60 (m; (c) cells have limited ability to repair the damage to DNA from alpha particle irradiation, which makes alpha particles extremely cytotoxic; (d) alpha particles may kill cells via apoptotic mechanisms.
Bismuth-213 produced by ITU is used in this new form of therapy. An additional production has been developed in collaboration with the Cyclotron Department of the Forschungszentrum Technik und Umwelt in Karlsruhe. The Bismuth-213 decay shows only low energy gamma rays which allows its use without sophisticated shielding or protective equipment in the hospital. Tens of clinical Bismuth-213 generators have currently been delivered by ITU to hospitals in the USA and France. The researchers at ITU have managed to solve the special problems of ensuring stability during transportation and its safe use at the hospital.
At today's symposium, Dr. David Scheinberg, Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center, reported about the phase 1 dose escalation trial to determine the safety, pharmacology, dosimetry and biological activity of Bi-213HuM195. Nine patients with relapsed or refractory acute myelogenous leukemia were treated with up to 2*107Bq/Kg Bi-213HuM195 dose. Each dose was given intravenously over five minutes. No acute toxicities were observed, but myelosuppression was noticed in several patients. No extramedullary toxicity was seen. No significant uptake was observed in any other organ than targeted bone marrow, liver, spleen and blood where estimates of radiation doses delivered were 10,000-40,000 times higher than anywhere else in the body. The absorbed dose ratio by targets was 1000 fold greater than that observed with beta-emitting nuclides in the same system in humans previously. Therefore, the targeted alpha-particle therapy is feasible, and appears safe
Bismuth-213 is being studied for cancers such as leukemia and lymphomas as well as for micrometastatic carcinomas. Alpha particle therapy is being investigated for prostate cancer whose occurrence is considerably higher than acute myelogenous leukemia. First in vitro tests are underway.
The "Institut National de la Sante et de la Recherche Medicale (INSERM)" and the "Laboratoire de physique Subatomique et des Technologies Associees (SUBATECH) de l'Ecole des Mines" of Nantes, France are carrying out an ex-vivo bone-marrow purging feasibility study. In the first preclinical tests at ITU, Bismuth-213 was coupled to the specific antibody B-B4, using benzyl-DTPA as chelating agent. The first results, in addition to demonstrating the technical feasibility of the approach, showed a high dose-dependent tumour cell mortality, with survival dropping rapidly from 28% to around 1‰ for a simple doubling of the dose from 14.8 kBq/105 cells to 29.6 kBq/105 cells. Tumor cell mortality was total at 300 kBq/105 cells.
The University of Heidelberg - Department of Internal Medicine V is looking into the treatment of non-Hodgkin's lymphomas (NHL) with in-vitro tests, using Bismuth-213 conjugated antiCD20 and CD37 antibodies. The therapy would apply to low grade NHL patients who have received high-dose chemotherapy with peripheral blood stem cells support, where persistent minimal residual disease can be expected. The infusion of Bismuth-213 conjugated anti-CD20 and CD37 antibodies to those patients with threatening relapse could be a valid adjuvant treatment.
For further information, please contact:
Mme Gisle Vanwert Tel: +18.104.22.168419 Fax: +22.214.171.124311 E-mail: Gisele.Vanwert@jrc.cec.be
Joint Research Centre Directorate General Rue de la Loi 200, B-1049 Brussels Belgium
Dr. Lothar Koch Tel : +49 7247 951 424 Fax : +49 7247 951 596 E-mail: Koch@ituemail.fzk.de
Dipl. Ing. Willem Janssens Tel : +49 7247 951 211 Fax : +49 7247 951 593 E-mail: Janssens@ituemail.fzk.de
Institute for Transuranium Elements, Joint Research Centre, European Commission Postfach 2340, D-76125 Karlsruhe, Germany