DEVELOPMENT OF IMMUNOCONJUGATE THERAPY FOR BREAST CANCER

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The goal of this project is to develop effective therapy for breast cancer using biologically active radioimmunoconjugates combined with other strategies. About half of patients with breast cancer die of their disease despite improved detection and standard therapy. Breast cancer provides an excellent model for the use of radioimmunotherapy in solid tumors because it is relatively radiosensitive and often occurs in superficial locations that facilitate accurate evaluation by examination, imaging and biopsy. During the last grant period, measurable tumor responses greater than 50% were observed in breast cancer patients that were treated with 131I-Chimeric L6 (ChL6). Although these results are remarkable for a Phase I therapy trial in patients with advanced breast cancer using a single agent, further therapeutic enhancement is needed for radioimmunotherapy to achieve enduring and complete responses. A number of strategies were examined to improve the therapeutic index: various radionuclides and antibodies, conjugation radiochemistries, radiation and cytokines to increase delivery to the tumor, immunoabsorption to decrease radiation to n normal tissues, colony stimulating factors to decrease marrow toxicity and autologous peripheral blood stem cells to increase marrow reserve. During the next grant period we have chosen to focus on two biologically active chimeric antibodies, Chl6 and H170, because their biologic and immunologic characteristics are most relevant to our stated objectives. When the current trial of 131I ChL6 therapy is completed, future trials of therapy with ChL6 or H170 will incorporate 90Y and novel macrocyclic chelates developed in Project 4 because these radiolabeled antibody constructs dramatically improve the therapeutic index due to retention of 90Y in cancer tissue in association with minimum 90Y in liver, bone and other normal tissues. Autologous peripheral blood stem cells for marrow reconstitution and Cyclosporin A repression of immunogenic response will be used to extend the MTD and increase the number of does that can be given. Methods to be used include 1) quantitative imaging for pharmacokinetics and dosimetry; 2) classic MTD protocol design; and 3) in vitro serologic and cellular assays of in vivo biologic activation of effector mechanisms. Strengths of this project include a cohesive investigative team that has a commitment to breast cancer therapy and a track record in radioimmunotherapy. This project benefits from the studies in Project 4 where new constructs and radiochemistry are generated and from Project 1 which allows opportunities to compare variations of radiochemistry and mechanisms for enhanced delivery as well as differences in the biology and radiobiology of lymphoma and breast cancer.