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

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

Monoclonal antibodies (MoAbs) that block signal transduction pathwaysactivated 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-KetteringCancer Center.

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

The MoAbs 225 IgG1 and 528 IgG2A bind to the EGF receptor withaffinity comparable to the natural ligands. In so doing, theycompete with ligands for binding and thus block ligand-inducedactivation of tyrosine kinase, Dr. Mendelsohn said at a symposiumon MoAbs and cancer therapy sponsored by the Cancer Research Institute.

Blocking EGF receptors inhibits the growth of normal cells withoutcausing injury, he said. However, in cells that require EGF forsurvival or that have been damaged by chemotherapy, the blockadeappears to induce apoptotic cell death.

Although EGF receptor is not a tumor-specific antigen, it is highlyexpressed in tumor cells. "Receptor blockade can inhibitproliferation of a variety of tumor cell types in culture, andcan prevent growth of human tumor cell xenografts in nude miceif administered twice a week, beginning soon after tumor cellimplantation," he said.

Well-established tumor cells resist the blockade, however. Growthmay be slowed, but it is not halted. The researchers theorizedthat combining receptor blockade with concurrent chemotherapymight overcome this resistance, since the two therapies appearto act synergistically to cause tumor cell death.

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

In the first human study, a single dose of murine MoAb 225 achievedexcellent tumor uptake without systemic toxicity, he said. A subsequentphase I trial employing a single dose of human chimeric MoAb C225showed similar results.

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