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MoAb to Block Growth Signals Plus Chemotherapy May Act Synergistically to Kill Tumor Cells

MoAb to Block Growth Signals Plus Chemotherapy May Act Synergistically to Kill Tumor Cells

An experimental approach combining immunotherapy with conventional chemotherapy may succeed in delivering a "one-two punch" to many common tumors of epithelial origin.

Monoclonal antibodies (MoAbs) that block signal transduction pathways activated by epidermal growth factor (EGF) receptor can slow, and even halt, the growth of these tumors, said John Mendelsohn, MD, chairman, Department of Medicine, Memorial Sloan-Kettering Cancer Center.

In ongoing clinical trials, he said, the MoAb is being given with three different chemotherapy agents in hopes of producing a synergistic tumor-killing effect.

The MoAbs 225 IgG1 and 528 IgG2A bind to the EGF receptor with affinity comparable to the natural ligands. In so doing, they compete with ligands for binding and thus block ligand-induced activation of tyrosine kinase, Dr. Mendelsohn said at a symposium on MoAbs and cancer therapy sponsored by the Cancer Research Institute.

Blocking EGF receptors inhibits the growth of normal cells without causing injury, he said. However, in cells that require EGF for survival or that have been damaged by chemotherapy, the blockade appears to induce apoptotic cell death.

Although EGF receptor is not a tumor-specific antigen, it is highly expressed in tumor cells. "Receptor blockade can inhibit proliferation of a variety of tumor cell types in culture, and can prevent growth of human tumor cell xenografts in nude mice if administered twice a week, beginning soon after tumor cell implantation," he said.

Well-established tumor cells resist the blockade, however. Growth may be slowed, but it is not halted. The researchers theorized that combining receptor blockade with concurrent chemotherapy might overcome this resistance, since the two therapies appear to act synergistically to cause tumor cell death.

To test this hypothesis, the Memorial Sloan-Kettering researchers used nude mice and xenografts of squamous cell carcinoma and adenocarcinoma. They administered receptor-saturating doses of MoAb in combination with maximum tolerated doses of cisplatin (Platinol), doxorubicin, or paclitaxel (Taxol). All animals were cured when observed over a period of up to 6 months.

In the first human study, a single dose of murine MoAb 225 achieved excellent tumor uptake without systemic toxicity, he said. A subsequent phase I trial employing a single dose of human chimeric MoAb C225 showed similar results.

Trials with repeated weekly doses of C225 in combination with paclitaxel, cis-platin, or doxorubicin are currently underway, Dr. Mendelsohn said, "to see if what works in mice will work in humans."

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