Projects

Radioimmunotherapy with alpha-particle emitting radionuclides

Radioimmunoconjugates (RICs) are radionuclides conjugated to monoclonal antibodies. The administration of RICs to patiens is aimed at improving upon the clinical response rates attained with unconjugated antibodies. The goal of radioimmunotherapy is to target radiation to tumor tissue while limiting the toxicity to normal cells. Our goal is to test the feasibility of the alpha-particle emitting radionuclide thorium-227 for radioimmunotherapy. It is estimated that 3-6 alpha-particle traversals thorough the nucleus are required to induce cell death, which corresponds to only a few RICs per cell. The range of alpha-particles is less than 0.1 mm. Thus, the alpha emitting RICs will be suitable for treatment of small tumors, disseminated tumors and micrometastatic disease. The short penetration of alpha-particles also has the potential of limiting toxicity to adjacent normal tissue as compared with other types of immunotherapy. The low dose rate of the treatment suggests that the bystander effect may be an important contributor to the therapeutic outcome. Curently, we are working on the following subjects:

• ²²⁷Thorium-rituximab against CD20 positive lymphoma
• ²²⁷Thorium-trazstuzumab against HER2 positive cancer mammae and ovarian cancer
• Cell studies of antibody binding and cell death induced by low dose rate radioimmunconjugates.
• Studies in mice of biodistribution, tumor uptake, stability of RIC, toxicity and therapy of mice with tumor xenografts.
• Microdosimetry of alpha radioimmunotherapy.

Bystander effects of ionizing radiation

Bystander effects are effects mediated by irradiated cells on non-irradiated cells. We investigate bystander effects by the medium transfer method: Cells that are not irradiated, get medium from irradiated cells. The medium contains unknown signalling molecules that give bystander effects on the non-irradiated cells. To investigate bystander effects, we use an alpha-irradiator based on a Plutonium-238 source.

The group members involved in the bystander project is Erta Kalanxhi (PhD-student) and Jostein Dahle.

The bystander effect project is a contribution to the integrated project Non-Targeted Effects of Ionizing Radiation (NOTE), a Euratom specific programme for research and training on nuclear energy, 6th FP of the EC. (https://ssl.note-ip.org/index.asp)

Radioimmunotherapy with beta-particle emitting 177-Lutetium HH1
Patients selected for CD20-directed radioimmunotherapy have often been pretreated with several cycles of cold rituximab. Prolonged rituximab treatment could result in antigenic drift causing reduced expression of CD20. Long residence time of rituximab in the blood can cause blocking of subsequent treatments with CD20-directed radioimmunotherapy. Thus, a different approach to lymphoma treatment might be to target other antigens than CD20 after some cycles of rituximab treatment. A monoclonal antibody (HH1) against the CD37 B-cell antigen has been developed at the Norwegian Radium Hospital. We have started Nordic Nanovector AS in order to develop 177Lu-HH1 towards clinical use.