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Antibody-based therapy - Chemotherapy has not been highly successful in the treatment of metastatic colorectal cancer, and mainstream chemotherapy is still built around one of the earliest agents used, 5- flurouracil. With this background, considerable effort has gone into developing biological-based therapies, but with limited success. It might be thought that in part this may reflect the heterogeneity (lack of specificity of the antibodies used) of tumor antigens that have been targeted. Among the papers approaching issues of antibody-based therapy, two recent ones in Cancer Research are of interest.
A paper from a multi-institutional group (University of Alabama at Birmingham, the National Cancer Institute, and the Medical College of Georgia in Augusta) which appeared in the October 1, 1995, issue of Cancer Research, may refute the explanation based on heterogeneity of antigens targeted. These investigators used a monospecific antibody termed mAb D612, which targets a protein highly expressed on primary and metastatic colorectal, gastric and pancreatic cancers. In the Phase II study (early clinical trial for antitumor activity) that is described, 14 patients with metastatic GI cancers (10 colon, 3 rectal, 1 stomach) received mAb D612 (40 mg/m2, days 4,7 and 11) in combination with recombinant human monocyte colony-stimulating factor (rhM-CSF; 80 micrograms/kg, days 1-14). M-CSF augments antibody-dependent cell cytotoxicity, mobilizing monocytes and potentiating their differentiation into macrophages. Ten of the patients experienced diarrhea, treatable in most with indomethacin, and there was monocytosis (release of monocytes), reduction in thrombocytes, and low to moderate levels of anti-D612 antibody developed in 11 patients. No antitumor effects were observed despite the fact that all patients showed some biological effects of these substances. The lesson of this study is that it is entirely possible such biological therapy may not work in the typical situation of a Phase II trial, where the disease is advanced and tumor burdens are high. If this is true, antibodies would be applied most appropriately to eradication of residual disease, or as an adjuvant approach to resolve ascites or local tumor deposits. In such situations, individual cancer cells are exposed and accessible to a higher ratio of antibody to antigen.
In this connection, a Phase I trial (an exploratory look at tolerance and dosage) of a monoclonal antibody (2B1) with specificity for both the protein product of the c-erbB-2 oncogene (implicated in many types of cancer) and a receptor (FcgammaRIII) on human natural killer cells, was published in the October 15, 1995, issue of Cancer Research. Doctors from the Fox Chase Cancer Center, Philadelphia, Pennsylvania, reported resolution of pleural effusions (tumor-cell containing fluids between the membranes around the lungs), ascites, and one of two liver metastases, in three patients with metastatic colon cancer, and reduction in chest wall disease in a breast cancer patient. These are the types of situation where cancer cells would be more accessible to the antibody. On the other hand, it is likely that bispecific antibodies are more effective than those which are monospecific, since other preliminary studies with such bispecific antibodies also have looked promising.
A preventive role for aspirin - The evidence in favor of a preventive role for aspirin continues to mount, the latest being the report in the September 7, 1995 issue of the New England Journal of Medicine from the Harvard Medical School and Brigham and Women's Hospital in Boston, of women enrolled in the Nurses' Health Study. It was widely publicized in the press. Women who took two or more aspirin tablets per week had the same risk of colorectal cancer as nonusers after 4 or 5 to 9 years. For those taking aspirin regularly for 10 to 19 years there was a non-significant reduction in risk, but after more than 20 years, the relative risk was significantly reduced to 0.56 (95% confidence interval 0.36-0.90) compared with nonusers. Controlling for other risk factors did not eliminate this protective effect. See also CANCERWEB for August, 1995, which includes a related abstract on aspirin consumption and breast cancer from the August CANCERLIT update.