Immunization of Colorectal Carcinoma Patients with a Recombinant Canarypox Virus Expressing the Tumor Antigen Ep-CAM/KSA (ALVAC-KSA) and Granulocyte Macrophage Colony- stimulating Factor Induced a Tumor-specific Cellular Immune Response

• Published in: Clinical cancer research 2003-07, Vol.9 (7), p.2447-2456
• Main Authors: Ullenhag, Gustav J, Frödin, Jan-Erik, Mosolits, Szilvia, Kiaii, Shahryar, Hassan, Moustapha, Bonnet, Marie Claude, Moingeon, Philippe, Mellstedt, Håkan, Rabbani, Hodjattallah
• Format: Article
• Language: English
• Subjects: Aged; Antigens, Neoplasm - biosynthesis; Antigens, Neoplasm - therapeutic use; Canarypox virus - genetics; Cancer Vaccines; Carcinoma - drug therapy; Cell Adhesion Molecules - therapeutic use; Cell Division; Colorectal Neoplasms - drug therapy; Enzyme-Linked Immunosorbent Assay; Epithelial Cell Adhesion Molecule; Female; Follow-Up Studies; Genetic Therapy - methods; Genetic Vectors; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Humans; Immunoglobulin G - metabolism; Immunotherapy - methods; Interferon-gamma - metabolism; Kinetics; Leukocytes, Mononuclear - metabolism; Male; Medicin och hälsovetenskap; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Viral Vaccines - therapeutic use
• ISSN: 1078-0432; 1557-3265; 1557-3265

Purpose: Colorectal carcinoma cells express the tumor-associated antigen epithelial cellular adhesion molecule (Ep-CAM)/KSA. Passive immunotherapy with monoclonal antibodies using this antigen has shown promising results. Ep-CAM might also be a target for active specific immunotherapy. Expression of the tumor antigen in a viral vector may facilitate appropriate antigen presentation. The feasibility of an Ep-CAM/KSA-specific therapeutic vaccination was investigated in cancer patients. Experimental Design: The full-length Ep-CAM gene was inserted into the avipox virus ALVAC (ALVAC-KSA). Twelve radically operated colorectal carcinoma patients without evidence of remaining macroscopic disease (stages I, II, and III) entered the study. The first 6 patients were immunized with three injections of ALVAC-KSA (10 7.09 CCID 50 per immunization) alone in weeks 0, 3, and 6. The subsequent 6 patients received the same schedule of ALVAC-KSA together with the adjuvant cytokine granulocyte macrophage colony-stimulating factor (GM-CSF; 75 μg/day for 4 consecutive days). Results: The adverse reactions to the vaccinations were mild except for local skin reactions. In the ALVAC-KSA group a weak T-cell response was induced in 2 of 6 patients. In the ALVAC-KSA/GM-CSF group a marked IFN-γ response (enzyme-linked immunospot) was induced in 5 of 6 patients. The T-cell response appeared late, 1 month after the last immunization, with a peak at 4–5 months after immunization. No IgG antibodies against Ep-CAM were detected. Before vaccination the majority of patients had a type 1 T-cell response (IFN-γ) against the vector, which was noted in healthy donors as well. All of the patients developed high titers of IgG antibodies against the vector, and the T-cell response was vigorously boosted. Conclusions: ALVAC-KSA, in combination with low dose local administration of GM-CSF may induce a strong, IFN-γ T-cell response (type 1). ALVAC-KSA seems to be an interesting candidate as a cancer vaccine for future clinical development.