This project will be responsible for conducting clinical trials based on the translational research from the preclinicalstudies included in this P01. The clinical trials will be carried out in collaboration with Roswell Park Cancer Instituteand Fox Chase Cancer Center. Preliminary results already have provided a rationale for the development of a Phase I/IItrial to determine if a combination of Rituxan (chimeric anti-CD20 IgG) with 90Y-labeled humanized anti-CD22 IgG(hLL2 IgG) will be an effective treatment for aggressive-types of NHL. Clinical and preclinical data have shown thatRituxan clears B-cells from the blood and may even be able to reduce the number of malignant cells prior to ^Y-anti-CD22 treatment. There is also an indication that Rituxan can make cells more susceptible to chemotherapy andradiation, and there is early preclinical evidence that suggests Rituxan may actually up-regulate CD22 expression,thereby amplifying the number of receptors for anti-CD22 binding. Quantitative imaging and pharmacokinetics will beused to study the biodistribution and tumor targeting of'' 'ln-hLL2 prior to the start of Rituxan and then after 2 fullcycles of Rituxan have been administered. 90Y-hLL2 would be given one day after the 4th Rituxan injection. Comparisonof the pre- and post-Rituxan ni!n-hLL2 imaging study will examine Rituxan's influence on hLL2 targeting, while antitumorresponse will examine the therapeutic impact. A second trial to be initiated in Year 03 will examine pretargetingusing a 90Y-labeled peptide in combination with a recombinant humanized anti-CD20 x anti-peptide bsMAb. This trialwould first examine how to optimize the pretargeting procedure, and then determine the MTD for a single administrationof the 90Y-peptide following the bsMAb. In addition to these 2 planned clinical trials, it is expected that data from thepreclinical studies in Projects 1-4 will lead to the development of additional clinical trials that will contribute to thetreatment of NHL, multiple myeloma, CLL, and other B-cell malignancies.
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