): The candidate is a physician scientist dedicated to translational research in the field of oncology. Emerging from a doctoral degree in biomedical engineering, she is motivated by the challenge of therapeutic design and implementation in biomedical research. She has forged a career at the intersection of adult and pediatric oncology through her clinical training and ongoing research in hematopoietic malignancies. Her long-term career goals a r e to develop innovative strategies for the application of radioimniunotherapy in non-Hodgkin's lymphomas and rapidly translate promising preclinical studies into human protocols. The proposed studies will examine strategies for improving the therapeutic ratio of targeted radiation in B cell lymphomas. Specifically, her research i n vestigates """"""""pretargeting"""""""" strategies and alternative antibody-isotope c o m b i nations. Pretargeting studies will compare and contrast the pharmacokinetics, tumor localization, and tumor-to-normal organ ratios of absorbed radiation in a mouse xenograft model utilizing streptavidin-biotin """"""""pretargeted"""""""" anti-CD20 antibody and the applicants' current """"""""one step"""""""" 131I-anti-CD20 antibody. Following system optimization, further studies will test the hypothesis that the anticipated improved tumor-to-normal organ ratios of absorbed radiation in the pretargeting model will translate into greater therapeutic efficacy and diminished toxicity. Alternative antibody-isotope combinations will be investigated in tandem studies which assess the differences in biodistribution of internalizing ( a n ti-CD19) and non-internalizing (anti-CD20) antibodies labeled with radioiodine (131I) and radiometals (90Y and 111In). A murine xenograft system will initially be utilized and results used to stratify the radioimmunoconjugates for testing in a subsequent human trial. In the human trial, subjects with relapsed non-Hodgkin's lymphoma will undergo sequential weekly trace labeled test infusions, serial gamma camera imaging, and tissue sampling to permit critical pharmacokinetic and biodistribution assessment for comparison of an optimized radiometal-conjugated internalizing antibody (projected to be 90Y anti-CD19) with the applicants' standard radioimmuno-conjugate, 131I anti-CD20. Studies will be conducted at the University of Washington and the Fred Hutchinson Cancer Research Center. Together these institutions afford a unique environment for the conduct of these experiments because of their i n t ense research focus on hematologic malignancies and expertise in radiolabeled antibody therapy of malignancies. If the proposed experiments identify a new radioimmunoconjugate or pretargeting strategy with improved radionuclide localization and retention at tumor sites but limited non-specific normal organ radiation, the applicants are poised to rapidly incorporate these advances into the next generation of therapeutic human trials.
| Press, O W; Corcoran, M; Subbiah, K et al. (2001) A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts. Blood 98:2535-43 |
