Given its extensive resources in computer simulation-based external beam treatment planning, and the large number of patients participating in radioimmunotherapy/diagnosis trials per year (>100), Memorial Sloan- Kettering Cancer Center offers a unique combination of resources for developing the analytical tools to perform patient-specific treatment planning for radioimmunotherapy. The long-term objective of the proposed work is to develop and validate a set of analytical tools that will facilitate treatment planning for optimation of radiolabeled antibody therapy of cancer. The work will proceed along two parallel pathways: (1) development and validation of mathematical models to simulate and fit the distribution of radiolabeled antibody in patients and (2) development and validation of image analysis and dosimetry tools to provide accurate estimates of the absorbed dose to critical tissues. In particular, the proposed work will examine closely the targeting of hematologic malignancies and pre-vascularized micrometastases. Such tumor cells present fewer impediments to antibody targeting and may offer the greatest promise for treatment success. Using patient kinetic data collected as part of ongoing trials as well as in vitro and ex vivo measurements of antibody internalization and catabolism, we propose to refine and further validate previously developed mathematical models describing the distribution of antibody. These models will then be used to simulate various strategies for improving antibody targeting. The effectiveness of each strategy and the optimum parameters for its implementation will be examined. We also propose to develop a software package that will generate 3-D cumulated activity distributions using SPECT and planar imaging studies with blood, total body, and model-derived distribution data. This information will be used in an already developed 3-D absorbed dose calculation program. The current program will be improved by accounting for tissue heterogeneities as determined from CT or MR images. TLD measurements will be performed to validate the calculations. Mathematical model validation will occur throughout the project period. Model predictions will be compared with patient biopsies, with pharmacokinetics following different mgs of antibody and with 124I PET imaging. No specific human, animal or in vitro experimentation is proposed in this application, data collected as part of currently ongoing trials will be used. The quantitative approach to radioimmunotherapy analysis that will be required in refining and validating these models is likely to lead to a better understanding of the processes involved in radioimmunotherapy and their effect on treatment success. By using these tools to simulate various protocols and thereby select those offering the highest probability of success, the scope of necessary human experimentation may be significantly reduced while improving the effectiveness of radioimmunotherapy.
The aims will be carried out in the context of eventually using the resulting analytical tools to perform patient-specific radioimmunotherapy treatment planning.
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