): 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA078346-02
Application #
2896549
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
1998-07-10
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195