Monte Carlo modeling of Targeted Alpha Therapy from single cell to tumor

Purpose: Targeted Alpha Therapy for cancer applications relate to hematologic malignancies and now extend to solid tumors. Because the short range and high Linear Energy Transfer of alpha particles and the heterogeneous uptake of alpha-immunoconjugates, conventional macroscopic dosimetry is not applicable to Targeted Alpha Therapy. This thesis is concerned with the development of microdosimetric techniques to investigate therapeutic efficacy and the limitations of alpha and beta radioimmunotherapy at different stages of cancer development.Methods: Specific Monte Carlo microdosimetric models were developed for each cancer stage as follows:1. Isolated cancer cells in transit in the lymphatic and vascular circulation,2. Pre-vascular cancer cell clusters, and3. Solid tumors with vasculature.Specific energy distributions in the target were calculated using the Geant4 Monte Carlo technique. Hit probability, cell survival fraction and tumor control probability were calculated with different geometries size, different source distribution and different isotopes. Lymphocyte and capillary endothelial cell models were constructed to calculate the therapeutic toxicity.In laboratory studies, two vascular disruption agents were tested in vitro or in vivo for the potential synergy of Targeted Alpha Therapy with 213Bi by enhancing the delivery of alpha-immunoconjugates in solid tumor.Results: The efficacy of alpha particles to regress isolated cancer cells, small cell clusters and small solid tumors was determined but was found to be limited in larger cell clusters and solid tumors because of the short range and shallow penetration. Compared to beta particles, alpha particles could deposit three logs more dose in the tumor. The therapeutic gain of 180 was found for 213Bi in the metastatic melanoma clinical trial and validated the hypothesis of Tumor Anti-vascular Alpha Therapy.A vascular disrupting agent was demonstrated to disrupt capillaries formed in vitro by human vascular endothelial cells. However, in vivo studies were inconclusive.Conclusion: The results of this study provide a comprehensive understanding of the damage effects of the Targeted Alpha Therapy for cancer. The success of Targeted Alpha Therapy for solid tumor relies on the extravascular diffusion of the alpha-immunoconjugates, which could be enhanced by vascular disruption agents