Our Long Range Objective is to carry out preclinical investigation evaluating monoclonal antibodies against growth factor receptors for their efficacy as therapeutic agents in the treatment of human cancer. Our studies in cell culture and with nude mouse xenografts have demonstrated the feasibility of this approach to cancer therapy, using anti-EGF receptor monoclonal antibodies (MAb). We have produced antibodies which bind to the EGF receptor, block EGF binding, prevent EGF-induced activation of receptor tyrosine kinase, and inhibit EGF-mediated proliferation of human tumor cells. Our preclinical observations, supported by this NCDDG, have led to a phase I trial with 111In-225 IgG1 anti-EGF receptor MAb in patients with squamous cell lung cancer, a malignancy that expresses high levels of EGF receptors. Our most recent preclinical experiments in the laboratory have demonstrated that combination therapy with anti-EGF receptor MAb plus a chemotherapeutic agent (doxorubicin, cisplatinum, or Taxol) can eradicate well established xenografts of human squamous carcinoma and adenocarcinoma xenografts in nude mice. When either treatment was given alone to these established tumors, only partial responses were observed. In this Program of the NCDDG we are pursuing four Specific Aims: 1) to determine the effectiveness of chemotherapy plus MAb-mediated blockade of EGF receptors against a panel of different types of human epithelial tumor cell lines, both in culture and in nude mouse xenografts. Chemotherapeutic agents to be studied include cisplatinum, doxorubicin, taxol, melphalan, and 5-fluorouracil. 2) to establish the optimal schedule, dose and sequence for administering antireceptor MAb plus chemotherapy against xenografts of human tumors in nude mice. These experiments are critical for our planned clinical trials. 3) to explore additional agents (other than chemotherapy) which can contribute to the antitumor activity produced by MAb-mediated EGF receptor blockade. The primary agents under study will be the tyrphostins, chemical antagonists of receptor tyrosine kinases. 4) to explore the mechanisms accounting for the antitumor activity of anti- EGF receptor MAbs against a colon adenocarcinoma cell line, DiFi, which we observe to display an unusual sensitivity to EGF receptor blockade.
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| Xiang, R; Lode, H N; Dreier, T et al. (1998) Induction of persistent tumor-protective immunity in mice cured of established colon carcinoma metastases. Cancer Res 58:3918-25 |
