Monoclonal antibodies (MoAbs) show promise as a prognostic as well as therapeutic tool in some minimal residual cancers, said Gert Riethmüller, MD, of the University of Munich's Institute for Immunology.
Speaking at a symposium sponsored by the Cancer Research Institute, Dr. Riethmüller reported that an ongoing trial is using MoAbs to detect cytokeratin-positive cells in bone marrow as evidence of micrometastatic disease in patients with early cancers of the lung, breast, gastrointestinal tract, and urogenital system. A therapeutic trial with the 17-1A MoAb is also underway.
Acknowledging that primary prevention of cancer is still beyond reach, Dr. Riethmüller characterized the avoidance of metastatic disease as "secondary prevention," and called it a realistic goal. He pointed out that the systematic dissemination of tumor cells occurs early in many epithelial tumor types. Thus, the key to secondary prevention is the identification and treatment of minimal residual disease before it manifests clinically.
Dr. Riethmüller said that cytokeratin expression is not a tumor-specific characteristic; rather, it is ubiquitous in normal epithelial tissues. Nonetheless, the origin and malignant nature of the targeted cells in the bone marrow can be established through evidence of differentiation antigens and mutated oncogene proteins expressed by the tumor cells.
This method has been employed successfully in early cancers of the lung, breast, and large bowel, and clinical follow-up studies have confirmed the prognostic significance of cytokeratin-expressing cells as a marker for occult metastatic disease, he said.
Once identified, these micrometastases can be targeted for immunotherapy. Because the cells are located in the mesenchymal interstitia, they are accessible to IV injection of antibodies and secondary effector cells and molecules.
In a randomized prospective trial in which patients with colorectal cancer (Dukes stages C1 and C2) were treated with the 17-1A MoAb within 2 weeks of complete resection, the treated group showed an improved 7-year survival over the untreated group, Dr. Riethmüller said.
The therapeutic effect was most pronounced on manifestation of distant metastases, he said, whereas no effect was seen on local relapses. Toxic effects were minor, consisting of diarrhea of short duration in a few patients.
A new phase I/II trial is planned using chimerized MoABs to reduce the risk of rejection from repeated treatments, Dr. Riethmüller said. He noted that ongoing research into other antigen targets may make possible a multipronged approach, employing a defined combination of different antibodies in "preemptive strike" therapy.