ABSTRACT
The colorectal carcinoma (CRC)-associated GA733 antigen (also known as CO17-1A, KS1-4, KSA or EpCAM) has been the target of a phase II/III randomized trial of passive immunotherapy with monoclonal antibody CO17-1A and phase I active immunotherapy trials with polyclonal anti-idiotypic antibodies mimicking the CO17-1A or GA733 epitope on the antigen. The CO17-1A antigen was molecularly cloned and the extracellular domain expressed in baculovirus (BV) GA733-2E. Whereas, anti-idiotypic antibody mimics a single epitope on the antigen, BV GA733-2E expresses multiple potentially immunogenic epitopes. In animals, the immunogenicity of BV GA733-2E in aluminum hydroxide was superior to that of anti-idiotype in the same adjuvant. Here, we compared the immunogenicity of anti-idiotypic antibody and GA733-2E antigen in CRC patients. These studies indicate that the antigen is superior to the anti-idiotype antibody in inducing humoral and cellular immunity in CRC patients.
Subject(s)
Antibodies, Anti-Idiotypic/therapeutic use , Antigens, Neoplasm/therapeutic use , Cancer Vaccines , Colorectal Neoplasms/drug therapy , Antibodies, Anti-Idiotypic/administration & dosage , Antigens, Neoplasm/administration & dosage , Cell Adhesion Molecules/administration & dosage , Cell Adhesion Molecules/therapeutic use , Colorectal Neoplasms/immunology , Epithelial Cell Adhesion Molecule , Humans , Immunity, Cellular/drug effects , Immunotherapy , Molecular Mimicry , Recombinant Proteins/therapeutic use , Treatment OutcomeABSTRACT
Targeting the GA733 antigen (also known as CO17-1A, EGP, KS1-4, KSA, Ep-CAM) by monoclonal antibody CO17-1A or anti-idiotypic antibodies mimicking the CO17-1A or GA733 epitope has induced prolonged survival and specific immune responses to the antigen, respectively, in colorectal cancer (CRC) patients. In pre-clinical studies in mice and rabbits, recombinant baculovirus-derived GA733-2E antigen was superior to anti-idiotypic antibodies at modulating specific immune responses. Our aim was to evaluate the immunogenicity and potential toxicity of alum-precipitated GA733-2E in a phase I trial in patients with resected CRC or pancreatic cancer. Six patients with advanced pancreatic carcinoma and 6 with CRC Dukes' stage A, B or C received between 4 and 7 doses of alum-precipitated GA733-2E at 50, 200 or 800 microg/dose at monthly intervals. Antibody binding to GA733-2E or antigen-positive CRC cells was determined, as were antigen-specific proliferative, cytolytic T-lymphocyte and delayed-type hypersensitivity responses. Six of the 12 patients developed antigen-specific humoral immune responses after immunotherapy, and 8 developed cellular immune responses. The overall immune response rate, including patients with humoral and/or cellular immune responses, was 83%. Median overall survival of the CRC and pancreatic cancer patients was 39.8 and 11.2 months, respectively. Following 18 years of single-epitope targeting of the GA733 antigen, immunization of patients against multiple epitopes of the antigen frequently induces an immune response in the absence of significant toxicity, despite relatively widespread expression of this antigen on normal epithelial cells.
Subject(s)
Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Cell Adhesion Molecules/immunology , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/immunology , Immunotherapy , Vaccines, Synthetic/immunology , Aged , Antibodies, Monoclonal/immunology , Antibody Formation , Antigens, Neoplasm/genetics , Cancer Vaccines/adverse effects , Cancer Vaccines/therapeutic use , Cell Adhesion Molecules/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/therapy , Cytokines/analysis , Epithelial Cell Adhesion Molecule , Female , Humans , Hypersensitivity, Delayed , Immunity, Cellular , Lymphocyte Activation , Male , Middle Aged , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/therapy , Recombinant Proteins/immunology , T-Lymphocytes, Cytotoxic/immunology , Treatment Outcome , Tumor Cells, Cultured , Vaccines, Synthetic/adverse effects , Vaccines, Synthetic/therapeutic useABSTRACT
Soluble CD44standard (sCD44s) and CD44v6 (sCD44v6) cannot only be detected in sera of patients with pancreatic carcinoma but also of healthy blood donors. To investigate whether sCD44s and sCD44v6 are derived from white blood cells, we stimulated whole blood with phytohemagglutinin and interleukin-2, which induced expression of CD44v6 only on monocytes. For further investigations, we used the promyelocytic leukemia cell line Hl-60. Only Hl-60 cells differentiating along the macrophage pathway showed increased expression of CD44s and CD44v6. Furthermore, only macrophages showed increased secretion of sCD44s and sCD44v6. Our data suggest that CD44s and CD44v6 are common adhesion molecules on macrophages and macrophage-like cells.
Subject(s)
Glycoproteins/metabolism , Hyaluronan Receptors/metabolism , Macrophages/immunology , Alternative Splicing , Cell Differentiation , Cell Membrane/immunology , Cholecalciferol/pharmacology , Dimethyl Sulfoxide/pharmacology , Genetic Variation , Glycoproteins/blood , Glycoproteins/genetics , HL-60 Cells , Humans , Hyaluronan Receptors/blood , Hyaluronan Receptors/genetics , In Vitro Techniques , Interferon-gamma/pharmacology , Interleukin-2/pharmacology , Lymphocytes/drug effects , Lymphocytes/immunology , Macrophages/cytology , Macrophages/drug effects , Monocytes/drug effects , Monocytes/immunology , Phytohemagglutinins/pharmacology , Protein Isoforms/blood , Protein Isoforms/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Recombinant ProteinsABSTRACT
The baculovirus-derived extracellular domain of the CO17-1A antigen induced cellular and/or humoral immune responses in curatively resected colorectal and pancreatic cancer patients after at least three applications of the vaccine. The vaccine application was safe and non-toxic. The clinical efficacy of the vaccine needs to be evaluated in larger, randomized clinical trials.
