Immunotoxin therapy for CNS tumor: Establishing a clinically relevant intracranial tumor model and assessing the efficacy and toxicity of various diphtheria-based fusion proteins.

摘要

The use of targeted toxin therapy is a relatively new form of adjuvant treatment in clinical cancer research. The theory behind immunotoxins is that they will act as a "smart bomb" homing in on the cancer cells and avoiding normal cells thus reducing the systemic or regional toxicity that is associated with chemotherapy or radiation therapy respectively. Furthermore, the possibility of achieving the paradigm of successful cancer treatment which necessitates that chemotherapy achieves a high drug concentration within the tumor bed while essentially avoiding non-cancer cells is what makes immunotoxin therapy so attractive. Various cancer cell membrane surface-antigens have been targeted using modified toxins. Early immunotoxins were designed using monoclonal antibodies against specific cell membrane receptors found on cancer cells. Modified plant or bacterial toxins or radioactive isotopes were bound to these antibodies. However, the large molecular weight of these molecules made uniform tumor penetration unachievable. Furthermore, the use of non-human antibodies as the source for these immunotoxins resulted in a host immunological response known as HAMA (human anti-mouse antibodies) in clinical trials. To overcome these restrictions, great advances in genetic engineering and tumor biology have been made resulting in recombinant technology that allows for the production of smaller, more specific immunotoxins consisting of specific cancer-associated receptor-ligands linked to modified toxins.; Malignant brain tumors provide a special challenge to neurosurgeons and neuro-oncologist. First, the brain is immunologically-privileged due its blood-brain-barrier making effective drug delivery unfeasible. Therefore the advancement of immunotoxin therapy provides an alternative treatment modality where surgical intervention, radiation therapy, and chemotherapy have failed. Several immunotoxin clinical trials for the brain tumors have been done; however, all have had limited success. One reason for this is due to the limited translational work that has been done with immunotoxins before embarking on clinical trials.; The basis for my research was to create a clinically-relevant murine tumor model to study the efficacy of three diphtheria-based immunotoxins DTAT, DTIL13, and DTAT13. Furthermore, very little information exists on the pharmacokinetic properties of immunotoxins specifically those designed to treat brain tumors. Thus a second goal was to compare and contrast the efficacy, toxicity, biodistribution and receptor-binding properties of these three immunotoxins to further understand the potentials and limitations of immunotoxin therapy in brain tumor models. Finally, a third goal was to assess the effectiveness and reliability of magnetic resonance imaging as a non-invasive tool to assess tumor growth, tumor response, and associated drug toxicity.