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.
OBJECTIVE
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.


METHODS
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 micro g/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-gamma 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-gamma) 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-gamma T-cell response (type 1). ALVAC-KSA seems to be an interesting candidate as a cancer vaccine for future clinical development.
Ullenhag
Gustav J
GJ
Department of Oncology, Radiology and Clinical Immunology, Section of Oncology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
Frödin
Jan-Erik
JE
Mosolits
Szilvia
S
Kiaii
Shahryar
S
Hassan
Moustapha
M
Bonnet
Marie Claude
MC
Moingeon
Philippe
P
Mellstedt
Håkan
H
Rabbani
Hodjattallah
H
D000368:Aged; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000627:therapeutic use*; D028121:Canarypox virus / Q000235:genetics*; D019496:Cancer Vaccines; D002277:Carcinoma / Q000188:drug therapy*; D015815:Cell Adhesion Molecules / Q000627:therapeutic use*; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014765:Viral Vaccines / Q000627:therapeutic use*
C078788:ALVAC vaccine; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D007074:Immunoglobulin G; D014765:Viral Vaccines; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor