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