Our goal is to develop clinical treatments that eradicate all neoplastic cells. We believe host antitumor mechanisms will facilitate this process. Preclinical data support the hypotheses that immune-mediated tumor destruction will be most effective: a. in the minimal residual disease setting; b. using effector cells that selectively recognize tumor; c. with augmented numbers, activation and specificity of effector cells; d. by combining physiologically distinct antitumor destruction mechanisms. In order to begin testing these hypotheses clinically, we propose four years of integrated clinical and laboratory research to be performed through the CATBRM mechanism. Specifically, we will: 1. Perform sequential clinical trials of combined-modality treatment resulting in in vivo antibody-directed cellular cytotoxicity. These integrate laboratory monitoring and preclinical testing of patient specimens; 2. Test the biologic effects of combined antitumor monoclonal antibodies against GD2 and GD3 in combination) and proceed to clinical testing utilizing molecularly modified derivatives of these reagents. These include fusion proteins and """"""""artificial receptors,"""""""" which use gene fusion techniques to link tumor recognition to effector-cell triggering. 3. Utilize recombinant human effector cell activators in vivo, including IL-2 and GM-CSF to mediate augmented antibody directed tumor destruction; 4. Measure the clinical tolerance, toxicity, and antitumor effects of thee approaches utilizing detailed clinical assessments performed through our UW-GCRC; 5. Analyze the biologic effects at the cellular and molecular level by performing sequential laboratory analyses on patient specimens in our UWCCC immunology/biologic therapy monitoring laboratory; 6. Evaluate potential protocol modifications and additional biologic agents being considered for incorporation into subsequent clinical protocols by performing in vitro tests with specimens from these patients at sequential times during their treatment; 7. Utilize the specimens from patients treated as participants in these clinical trials for separately funded preclinical investigations characterizing the biologic mechanisms of immune activation and antitumor activity relevant to future protocol and reagent development.
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