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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
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
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2003 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, no 7, 2447-2456 p.Article in journal (Refereed) Published
Abstract [en]

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 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.

Place, publisher, year, edition, pages
2003. Vol. 9, no 7, 2447-2456 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-90342PubMedID: 12855617OAI: oai:DiVA.org:uu-90342DiVA: diva2:162660
Available from: 2003-04-30 Created: 2003-04-30 Last updated: 2013-06-13Bibliographically approved
In thesis
1. Vaccine Therapy of Colorectal Cancer Patients with Tumor Associated Antigens
Open this publication in new window or tab >>Vaccine Therapy of Colorectal Cancer Patients with Tumor Associated Antigens
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, two different vaccines were evaluated as adjuvant therapy for patients with colorectal cancer. The ability of the two candidate vaccines to generate antigen-specific cellular and humoral responses, respectively, was studied. The effectiveness of granulocyte colony stimulating factor (GM-CSF) as a cytokine adjuvant to augment the immune response was also examined.

The first vaccination strategy involved immunization with the recombinant tumor-associated protein, carcinoembryonic antigen (CEA). Recombinant CEA was administered at 4 different dose levels 7 times during one year. Peripheral blood samples were regularly analyzed during 36 months. This vaccination regimen induced a strong immunoglobulin 1 (IgG1) and IgG4 response, a moderate IgG2 response and a weak IgG3 response against CEA. GM-CSF markedly augmented the effect on IgG1 and IgG4 as well as the T cell response. In contrast, dose of rCEA had no or modest effect on induced immune responses. The response gradually increased during the 12 months immunization period. Responses of all three IgG subclasses and of T cells were protracted up to 36 months. The anti-CEA IgG titers related significantly to survival. Functional HLA-DR epitopes of CEA could be defined. These major histocompatibility class II epitopes may serve as putative components of a peptide-based vaccination strategy.

The other vaccine strategy consisted of the tumor-associated antigen epithelial cell adhesion molecule (Ep-Cam) expressed as a transgene in a viral vector, ALVAC. Patients were immunized subcutaneously/intradermally 3 times over 6 weeks and monitored for immune responses for 46 weeks. No anti-Ep-Cam specific humoral response was induced, but Ep-Cam specific type 1 T cells (interpheron-gamma production) were induced, mainly in the GM-CSF group. The cytotoxic cellular response appeared late, or a few months after the last immunization.

Both vaccines were well tolerated. Since GM-CSF was an important component for both regimens, immungenicity of this cytokine was assessed. Multiple immunizations with low dose GM-CSF were associated with a low incidence of GM-CSF antibodies that did not neutralize the biological effect of GM-CSF.

In conclusion, both vaccines are promising candidate vaccines. GM-CSF is necessary to induce a strong humoral and cellular immune response. Large clinical trials are urgently warranted to evaluate the clinical efficacy.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 94 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1260
Oncology, Oncology, Colorectal cancer, GM-CSF, vaccination, CEA, ALVAC-KSA, IgG subclass, epitopes, Onkologi
National Category
Cancer and Oncology
Research subject
urn:nbn:se:uu:diva-3399 (URN)91-554-5626-X (ISBN)
Public defence
2003-05-24, Sal IV, Universitetshuset, Uppsala, 09:15
Available from: 2003-04-30 Created: 2003-04-30Bibliographically approved

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