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- Mosolits, Szilvia
(författare)
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Natural and induced immunity against the tumour-associated antigen, Ep-CAM
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The tumour-associated antigen (TAA), Ep-CAM is overexpressed on various human carcinomas, including colorectal carcinoma (CRC). TAAs or their immunodominant epitopes that are spontaneously recognised by the immune system might constitute a suitable target for immunotherapy. Fifteen % of sera of CRC patients with no previous immunotherapy elicited IgG antibodies against Ep-CAM. No Ep-CAM specific antibodies were detected in healthy controls or patients with Crohn's disease or colitis ulcerosa. Further analyses revelaed that 50% of the Ep-CAM-reactive sera bound to peptide residues 29-46 of Ep-CAM. The results provide evidence for spontaneous immune recognition of Ep-CAM in CRC patients and identify an immunodominant B cell epitope of human Ep-CAM. Anti-idiotypic antibodies (anti-Id) may serve as surrogate TAAs for vaccination. The optimal design of an anti-Id vaccine, however remains unclear. Moreover, whether vaccination with anti-Id or the original antigen is superior is controversial. SM262 is a human anti-Id raised against mAb 17-1A that recognises Ep-CAM. Vaccination of mice with anti-Id induced antibodies that shared idiotopes with mAb 17-1A and recognised Ep-CAM. Fusion of GM-CSF to anti-Id enhanced the magnitude of the antibody responses, while xenogeneic Fc domain had no significant modulatory effect. Recombinant anti-Id protein vaccine evoked a more potent humoral immunity as compared to DNA delivered by gene gun. Our study provides the fist evidence that immune tolerance in mice expressing the transgene for human Ep-CAM can be circumvented by anti-Id vaccination. The results may have implications for future anti-Id vaccine design. Vaccination of CRC patients with recombinant Ep-CAM protein, in combination with GM-CSF, induced Ep-CAM specific T and NK-like T cells producing cytotoxic cytokines. In addition, a long-lasting Th1 biased humoral and proliferative T cell response was elicited against Ep-CAM. The original antigen, Ep-CAM induced a more potent overall immune response as compared to anti-Id mimicking Ep-CAM. Analysis of TCR BV gene repertoire revealed that BV19+ CD8+ T cells might be involved in the vaccine induced anti-Ep-CAM immune response. The results collectively suggest that immunisation with Ep-CAM protein may serve as a novel approach to CRC immunotherapy. Furthermore, immunogenic MHC class I and II restricted Ep-CAM epitopes were identified that may provide new opportunities for developing effective multiepitope cancer vaccines targeting Ep-CAM. Vaccination with a recombinant canarypox virus (ALVAC) encoding human Ep-CAM in combination with GM-CSF induced a potent Ep-CAM specific, type 1 cellular immune response in CRC patients. However, no anti-Ep-CAM antibody or proliferative T cell responses were elicited. Combining ALVAC-Ep-CAM and recombinant Ep-CAM in a prime-boost vaccination approach may represent an effective strategy to induce a coordinated antigen specific cellular and humoral immune response. In conclusion, the results suggest that Ep-CAM is a promising target structure for immunotherapy. The present studies may form a basis for further enlarged clinical trials targeting Ep-CAM by active specific vaccination.
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| 2. |
- Staff, Caroline, et al.
(författare)
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Induction of IgM, IgA and IgE Antibodies in Colorectal Cancer Patients Vaccinated with a Recombinant CEA Protein
- 2012
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Ingår i: Journal of Clinical Immunology. - : Springer Science and Business Media LLC. - 0271-9142 .- 1573-2592. ; 32:4, s. 855-865
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Tidskriftsartikel (refereegranskat)abstract
- Previous clinical studies have indicated that natural IgM antibodies have the ability to induce apoptosis of tumor cells but IgE and IgA may also mediate tumor cell killing (in addition to IgG). The aim of the study was to analyse induction of IgM, IgA and IgE antibodies in patients vaccinated with the tumor associated antigen CEA. Twenty-four resected CRC patients without macroscopic disease were immunized seven times with CEA +/- GM-CSF. Four different dose schedules were used over a 12-month period. IgM, IgA and IgE antibody responses against recombinant CEA were determined by ELISA. Patients were monitored immunologically for 36 months and clinically for 147 months. GM-CSF significantly augmented the anti-CEA response for all three antibody classes. Low dose of CEA tended to induce a higher IgM, IgA or IgE anti-CEA antibody response than higher. Anti-CEA IgA antibodies could lyse CEA positive tumor cells in antibody dependent cellular cytotoxicity (ADCC) as well as in complement dependent cytotoxicity (CDC). A significant correlation between survival and high IgA anti-CEA titers was noted (p = 0.02) irrespective of GM-CSF treatment. The observation that IgA anti-CEA antibodies were cytotoxic and associated with improved survival might indicate that also these antibodies may exert a clinical anti-tumor effect.
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| 3. |
- Ullenhag, Gustav, et al.
(författare)
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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
- 2003
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 9:7, s. 2447-2456
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Ullenhag, Gustav J, et al.
(författare)
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Durable carcinoembryonic antigen (CEA)-specific humoral and cellular immune responses in colorectal carcinoma patients vaccinated with recombinant CEA and granulocyte/macrophage colony-stimulating factor.
- 2004
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 10:10, s. 3273-3281
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Previous studies have indicated that carcinoembryonic antigen (CEA) might be a suitable immunotherapeutic target in colorectal carcinoma (CRC). The aim of the present study was to analyze the immunological and clinical effects of vaccination with CEA together with the adjuvant granulocyte/macrophage colony-stimulating factor (GM-CSF).EXPERIMENTAL DESIGN: Twenty-four resected CRC patients without macroscopic disease were immunized seven times with recombinant CEA at four different dose levels over a 12-month period. Half of the patients received GM-CSF (80 microg/day for 4 consecutive days) at each immunization. Patients were monitored immunologically for 36 months and clinically for 76 months. T-cell response was evaluated by a [(3)H]thymidine incorporation assay, and IgG response was determined by ELISA.RESULTS: Minor local side effects were common. All 12 patients (100%) in the GM-CSF group developed a CEA-specific T-cell as well as an IgG response. The corresponding figures in the CEA alone group were 9 of 12 (75%) and 8 of 12 (66%), respectively. GM-CSF significantly augmented the amplitude of the T-cell response and the IgG titers. No dose-response relationship was noted. The immune responses at 12 months persisted 24 months after the last vaccination. Anti-CEA IgG titers were associated with increased survival (P < 0.05), whereas standard prognostic factors had no relationship, with the exception of serum CEA value.CONCLUSIONS: Vaccination with recombinant CEA and GM-CSF appears to be a nontoxic regimen inducing potent and durable antigen-specific IgG and T-cell response. The results of this study justify more extensive trials with recombinant CEA protein for immunotherapy of CRC.
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