Purpose MAGE-A3 is a potential target for immunotherapy due to its tumor-specific nature and expression in several tumor types. Clinical data on MAGE-A3 immunotherapy have raised many questions that can only be addressed by using animal models. In the present study, different aspects of the murine anti-tumor immune responses induced by a recombinant MAGE-A3 protein (recMAGE-A3) in combination with different immunostimulants (AS01, AS02, CpG7909 or AS15) were investigated. Experimental Design and Results Based on cytokine profile analyses and protection against challenge with MAGE-A3-expressing tumor, the combination recMAGE-A3+AS15 was selected for further experimental work, in particular to study the mechanisms of anti-tumor responses. By using MHC class I-, MHC class II-, perforin-, B-cell- and IFN-γ- knock-out mice and CD4+ T cell-, CD8+ T cell- and NK cell- depleted mice, we demonstrated that CD4+ T cells and NK cells are the main anti-tumor effectors, and that IFN-γ is a major effector molecule. This mouse tumor model also established the need to repeat recMAGE-A3+AS15 injections to sustain efficient anti-tumor responses. Furthermore, our results indicated that the efficacy of tumor rejection by the elicited anti-MAGE-A3 responses depends on the proportion of tumor cells expressing MAGE-A3. Conclusions The recMAGE-A3+AS15 cancer immunotherapy efficiently induced an antigen-specific, functional and long-lasting immune response able to recognize and eliminate MAGE-A3-expressing tumor cells up to several months after the last immunization in mice. The data highlighted the importance of the immunostimulant to induce a Th1-type immune response, as well as the key role played by IFN-γ, CD4+ T cells and NK cells in the anti-tumoral effect.
Pertussis is underdiagnosed and underreported in adults and patients with underlying conditions. Patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of severe pertussis. Understanding the true prevalence of pertussis infections in such patients is important. We therefore evaluated the seroprevalence of anti-pertussis toxin (PT) antibodies in a cohort of 40–85-year-old patients diagnosed with moderate, severe or very severe COPD enrolled (between June 2011 and June 2012) in the prospective, observational "Acute Exacerbation and Respiratory InfectionS in COPD" (AERIS; NCT01360398) study, conducted in England. Serum anti-PT antibodies were measured in 104 patients using an enzyme-linked immunosorbent assay on samples collected 12 months (M12) and 24 months (M24) after enrollment. Overall, 14/104 (13.5%) patients had anti-PT concentrations ≥50 IU/mL at M12 or M24, indicative of exposure to Bordetella pertussis during the preceding 2–3 years. Of these, 6/104 (5.8%) had anti-PT ≥70 IU/mL, of whom 3/104 (2.9%) had anti-PT ≥120 IU/mL, indicative of exposure within 12 and 6 months, respectively. These results show a high circulation of B. pertussis in 40–85-year-old patients with moderate, severe or very severe COPD in England between 2012 and 2014, and call for enhanced immunization to prevent pertussis infections in such patients.
We assessed potential toxic effects of the MAGE-A3 Cancer Immunotherapeutic on female fertility and embryo-fetal, pre- and post-natal development in rats and on male fertility in rats and monkeys. Three groups of 48 female (Study 1) or 22 male (Study 2) CD rats received 5 or 3 injections of 100 μL of saline, AS15 immunostimulant, or MAGE-A3 Cancer Immunotherapeutic (MAGE-A3 recombinant protein combined with AS15) at various timepoints pre- or post-mating. Male Cynomolgus monkeys (Study 3) received 8 injections of 500 μL of saline (n = 2) or the MAGE-A3 Cancer Immunotherapeutic (n = 6) every 2 weeks. Rats were sacrificed on gestation day 20 or lactation day 25 (Study 1) or 9 weeks after first injection (Study 2) and monkeys, 3 days or 8 weeks after last injection. Injections were well tolerated. Female rat mating performance or fertility, pre- and post-natal survival, offspring development up to 25 days of age, and male mating performance (rats) or fertility parameters (rats and monkeys) were unaffected.
As vaccine-induced immunity and protection following natural pertussis infection wane over time, adults and adolescents may develop pertussis and become transmitters to unprotected infants. In Russia, diphtheria and tetanus but not pertussis-containing vaccines are registered for older children, adolescents, or adults. The reduced-antigen-content diphtheria toxoid, tetanus toxoid, and acellular pertussis (dTpa) vaccine (Boostrix, GSK) was developed for booster vaccination of children ≥4 years of age, adolescents, and adults. A phase III, open-label, non-randomized study was performed in eight centers in Russia between January and July 2018. The objective of this study was to assess immunogenicity, reactogenicity and safety of a single dose of dTpa vaccine in healthy Russian participants ≥4 years of age (age categories 4–9 years, 10–17 years, 18–64 years, and ≥65 years). At 1 month post-booster vaccination, across all age groups, >99.0% of participants were seroprotected against diphtheria and tetanus and >96.0% of participants were seropositive for anti-pertussis antibodies. For all antibodies across all age groups, antibody GMCs increased from pre- to 1 month post-booster vaccination and booster responses to diphtheria (in 71.5% of participants), tetanus (85.3%), and pertussis antigens (≥85.6%) were observed. One serious adverse event that was not causally related to the study vaccine was reported. No fatal cases were reported throughout the study period. In conclusion, administration of the dTpa vaccine as a booster dose in healthy Russian participants induced a robust immune response to all vaccine antigens and was generally well tolerated across all age groups.
The PRAME tumor antigen is a potential target for immunotherapy. We assessed the immunogenicity, the antitumor activity, and the safety and the tolerability of a recombinant PRAME protein (recPRAME) combined with the AS15 immunostimulant (recPRAME+ AS15) in preclinical studies in mice and Cynomolgus monkeys. Four groups of 12 CB6F1 mice received 4 injections of phosphate-buffered saline (PBS), recPRAME, AS15, or recPRAME+AS15. Immunized mice were injected with tumor cells expressing PRAME (CT26-PRAME) 2 weeks or 2 months after the last injection. The mean tumor surface was measured twice a week. Two groups of 10 monkeys received 7 injections of saline or recPRAME+ AS15. T-cell responses were measured by flow cytometry using intracellular cytokine staining (ICS). In CB6F1 mice, repeated injections of recPRAME+ AS15 induced high PRAME-specific antibody titers and mostly CD4+ T cells producing cytokines. This immune response was long-lasting in these animals and was associated with protection against a challenge with PRAME-expressing tumor cells (CT26-PRAME) applied either 2 weeks or 2 months after the last injection; these data indicate the induction of an immune memory. In HLA-A02.01/HLA-DR1 transgenic mice, recPRAME+ AS15 induced both CD4+ and CD8+ T-cell responses, indicating that this antigen can be processed by the human leukocyte antigen and is potentially immunogenic in humans. In addition, a repeated-dose toxicity study in monkeys showed that 7 biweekly injections of recPRAME+ AS15 were well tolerated, and induced PRAME-specific antibodies and T cells. In conclusion, these preclinical data indicate that repeated injections of the PRAME cancer immunotherapeutic are immunogenic and have an acceptable safety profile.
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