| 1. |
- 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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| 2. |
- Staff, Caroline
(författare)
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Vaccination in gastrointestinal cancer
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Advances in immunology have increased the possibility to develop therapeutic cancer vaccines (TCV), as a complementary approach to standard treatment. The goal of a successful cancer vaccine is to induce a potent long-lasting immune response against the tumour with limited toxicity on normal cells. Most tumour cells express tumour-associated antigens (TAA), which can act as targets for the immune system. However, most TAAs evade recognition by the immune system to avoid auto-immunity, as many TAAs coexist in normal tissues. Commonly expressed TAAs in gastrointestinal malignancies are Carcinoembryonic antigen (CEA) and telomerase which both have been used as targets in cancer immunotherapy. The aim of this thesis was to explore the immunogenicity and safety of a CEA based protein and DNA TCV in patients with colorectal cancer (CRC) in the adjuvant setting and telomerase vaccination (GV1001) in patients with advanced pancreatic adenocarcinoma (PC). A long-term follow-up of CRC patients immunized with recombinant (rCEA) ± Granulocyte-macrophage colony-stimulating factor (GM-CSF) was conducted. Induction of anti-CEA IgM, IgA and IgE antibodies was monitored from 36 months after start of immunization. GM-CSF significantly augmented the anti-CEA response for all three classes (p<0.05). A significant correlation between survival and high IgA anti-CEA titers was noted (p=0.02). Anti-CEA IgA antibodies could lyse CEA positive cells in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) assays. The type, severity and duration of side-effects of CEA66-DNA vaccination in combination with cyclophosphamide and GM-CSF, was evaluated in 10 CRC patients. CEA66-DNA was delivered by a needle-free device system (Biojector). Adverse events (AE) were mild and transient, without any grade 3 or 4 AEs. No clinical signs of autoimmunity were seen. In an explorative study using CEA66-DNA (producing unglycosylated CEA) and wild type (tetwt)-CEADNA (producing glycosylated CEA) for immunization in combination with cyclophosphamide and GM-CSF immune responses (proliferation assay, ELISPOT, cytokine secretion assay) were analyzed in the adjuvant setting of CRC patients. 10 patients received intradermal (i.d.) or intramuscular (i.m.) CEA66-DNA by Biojector at weeks 0, 2 and 6 (part 1). 10 patients; (part 2), received tetwt-CEADNA 400 μg i.d. by needle followed by electroporation at weeks 0 and 12. Part 3 (n=6) included patients primed with CEA66-DNA and boosted with tetwt-CEADNA. GM-CSF and cyclophosphamide was also included. In total, 16 out of 20 (80%) patients mounted a single assay cellular response; 10/10 (100%) in part 1 and in 6/10 (60%) of the patients in part 2 (p=0.025). Immune responses were weak but durable. We also assessed the safety and immunogenicity in advanced PC patients using a 16 aa telomerase peptide (GV1001) for vaccination in combination with GM-CSF and gemcitabine as first line treatment. Three different vaccine treatment schedules (groups A, B, C) were used. In groups A and B, differing only in the dose of GM-CSF, a total of 67% of the patients showed an induced telomerase response. An induced ras (antigenic spreading) specific immune response was noted. All responses were weak and transient. A significant decrease in regulatory T cells over time was noted in patients in groups A and B. In conclusion, durable weak anti-CEA immune responses were seen following rCEA and CEA-DNA vaccination in CRC patients in the adjuvant setting. Weak and transient anti-telomerase responses following peptide vaccination were induced in patients with advanced PC. To develop a therapeutic concept of clinical significance measures have to be taken to optimize vaccine strategies.
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| 3. |
- Tedner, Sandra G., et al.
(författare)
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Extract and molecular-based early infant sensitization and associated factors-A PreventADALL study
- 2021
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 76:9, s. 2730-2739
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Tidskriftsartikel (refereegranskat)abstract
- Background More knowledge about sensitization patterns in early infancy, including impact of molecular allergology, is needed to help predict future allergy development more accurately. Objective We aimed to determine the prevalence and patterns of allergic sensitization at 3 months of age, and explore possible associated factors. Methods From the Scandinavian antenatally recruited PreventADALL mother-child cohort, we included 1110 3-month infants with available serum. Sensitization was defined as s-IgE of >= 0.1 kU(A)/L by Phadiatop Infant(R) (ThermoFisher Scientific) including birch, cat, grass, dog, milk, egg, peanut and wheat. Further ImmunoCAP analyses to ovomucoid, casein, Ara h 1-3, omega-5-gliadin were performed in food extract s-IgE-positive children. Maternal sensitization was defined as s-IgE >= 0.35 kU(A)/L to Phadiatop(R) (inhalant allergen mix) and/or Fx5 (food allergen mix) at 18-week pregnancy. Results Overall 79 (7.3%) infants had specific sensitization, many with low s-IgE-levels (IQR 0.16-0.81 kU(A)/L), with 78 being sensitized to food extract allergens; 41 to egg, 27 to milk, 10 to peanut, and 25 to wheat. A total of 62/78 were further analysed, 18 (29%) had s-IgE to ovomucoid, casein, Ara h 1-3 and/or omega-5-gliadin. Eight infants (0.7%) were sensitized to inhalant allergens. Maternal sensitization to food allergens was associated with infant sensitization, odds ratio 3.64 (95% CI 1.53-8.68). Conclusion Already at 3 months of age, 7% were sensitized to food, mostly without detectable s-IgE to food allergen molecules, and <1% to inhalant allergens. Maternal food sensitization was associated with infants' sensitization.
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| 4. |
- Wärnberg Gerdin, Sabina, et al.
(författare)
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Impaired skin barrier and allergic sensitization in early infancy
- 2022
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Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 77:5, s. 1464-1476
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Tidskriftsartikel (refereegranskat)abstract
- Background: Factors predicting allergic sensitization in the first 6 months of life are poorly understood. We aimed to determine whether eczema, dry skin, and high transepidermal water loss (TEWL) at 3 months were associated with allergic sensitization at 6 months of age and, secondarily, to establish whether these characteristics predicted sensitization from 3 to 6 months of age.Methods: At 3 months of age, 1,994 infants from the population-based PreventADALL birth cohort in Norway and Sweden were assessed for eczema and dry skin on the cheeks and/or extensors; impaired skin barrier function, defined as TEWL in the upper quartile (>9.4 g/m(2)/h), and allergen-specific IgE levels <0.1 kU(A)/L, available in 830. At 6 months, we assessed allergic sensitization to any food (egg, cow's milk, peanut, wheat, soy) or inhalant (birch, timothy grass, dog, and cat) allergen by a skin prick test wheal diameter >= 2 mm larger than negative control.Results: Any sensitization was found in 198 of the 1,994 infants (9.9%), the majority to food allergens (n = 177, 8.9%). Eczema, dry skin, and high TEWL at 3 months increased the risk of sensitization at 6 months; adjusted odds ratios 4.20 (95% CI 2.93-6.04), 2.09 (95% CI 1.51-2.90) and 3.67 (95% CI 2.58-5.22), respectively. Eczema predicted sensitization with 55.6% sensitivity and 68.1% specificity; dry skin with 65.3% sensitivity and 57.3% specificity; and high TEWL with 61.7% sensitivity and 78.1% specificity.Conclusion: Eczema, dry skin, and high TEWL at 3 months predicted allergic sensitization at 6 months of age.
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