title: Antibody delivery and effector cell activation in a phase II trial of recombinant gamma-interferon and the murine monoclonal antibody CO17-1A in advanced colorectal carcinoma.
abstract: Murine monoclonal antibodies of the immunoglobulin G2a isotype interact with human effector cells to mediate antibody-dependent cellular cytotoxicity (ADCC) directed against malignant cells which express antigens recognized by these antibodies. gamma-Interferon enhances these effects in vitro. In a Phase I trial of murine monoclonal antibody CO17-1A and recombinant gamma-interferon (rIFN-gamma), we demonstrated that low doses of rIFN-gamma were superior to high doses in augmenting ADCC mediated by treated patients' monocytes. These results formed the basis for a Phase II trial of CO17-1A combined with low dose rIFN-gamma. Nineteen patients with metastatic colorectal carcinoma were treated with four consecutive daily infusions of 1.0 X 10(6) IU/m2 rIFN-gamma, with 150 mg of CO17-1A administered on days 2, 3, and 4. Therapy was tolerated well. Peripheral blood mononuclear cells were purified from patient samples obtained at baseline and at 1, 4, or 24 h following the start of the first rIFN-gamma infusion and were tested for their ability to lyse 111In-labeled cells of the SW1116 colorectal line. Enhancement of monocyte ADCC was seen by 24 h, while lymphocyte ADCC and natural killer activity directed against K562 cells were enhanced to a lesser extent. Nonspecific lysis of SW1116 cells by effectors was not seen at the time points examined. While CO17-1A antigen expression was observed in most biopsies, 131I-labeled CO17-1A imaged positively in less than one-half of the organs known to harbor metastases, and therapeutic antibody delivery was not always demonstrated by immunoperoxidase staining techniques of tissue obtained following therapy. In antigen-positive lesions, tissue pO2 levels appear to identify lesions which would image positively. No objective responses were seen. Our findings suggest that prolonged therapy with low doses of rIFN-gamma potentiates ADCC but that physiological obstacles to therapeutic antibody delivery are significant. In order to evaluate the validity of this therapeutic approach, measures to enhance antibody delivery are needed, starting with systematic evaluations of therapy with escalating doses of CO17-1A combined with low dose rIFN-gamma therapy.
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000032:analysis; D002277:Carcinoma / Q000628:therapy*; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000009:adverse effects / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010100:Oxygen / Q000032:analysis; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012004:Rectal Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D011994:Recombinant Proteins; D007371:Interferon-gamma; D010100:Oxygen