Design of vaccine adjuvants incorporating TNF superfamily ligands and TNF superfamily molecular mimics

Gupta, Sachin; Termini, James M.; Kanagavelu, Saravana; Stone, Geoffrey W.

doi:10.1007/s12026-013-8443-6

Cited by 11 publications

(10 citation statements)

References 66 publications

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“…prior to vaccination with IMA950. In light of the relatively low magnitude and transient immune responses, enhancement of the vaccination regimen, including selection of the most effective adjuvant partner(s), is necessary; for example by using alternate or additional adjuvants such as locally applied poly-ICLC (37), imiquimod (38) or systemically administering CD40 ligand (39) or cyclophosphamide (40). Combining cancer vaccines such as IMA950 with immune checkpoint inhibitors such as anti-PD1/PD-L1 or anti-CTLA4 antibodies should also be expected to enhance anti-tumor immune responses.…”

Section: Discussionmentioning

confidence: 99%

A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma

Rampling

Peoples

Mulholland

et al. 2016

Clinical Cancer Research

130

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Statement of Translational RelevanceSurvival rates for patients with glioblastoma (GBM) are abysmal, with median overall survival of approximately 15 months. Immunotherapy of GBM is a promising area of investigation, although challenges around identification of novel and immunogenic target antigens exist. IMA950 is a GBM specific vaccine comprising 11 tumor-associated peptides (TUMAPs) developed to address this challenge. We have performed a phase 1 safety and immunogenicity study in newly diagnosed GBM patients using IMA950 plus GM-CSF alongside standard of care chemo-radiotherapy. Our results demonstrate that IMA950 is well tolerated with 90% of patients having a CD8+ T-cell immune response to at least one TUMAP, with 50% responding to two or more TUMAPs. No effect of pre-treatment regulatory T-cell levels on IMA950 immunogenicity was found and steroids did not appear to affect immune responses to the TUMAPs. This data provides evidence to support further development and optimization of IMA950 together with other immunotherapies for GBM. were multi-TUMAP responders, with no important differences between cohorts. No effect of pre-treatment Treg levels on IMA950 immunogenicity was observed and steroids did not affect TUMAP responses. PFS was 74% at 6 months and 31% at 9 months. CONCLUSION: IMA950 plus GM-CSF was well tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded.Further development of IMA950 is encouraged.

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Section: Discussionmentioning

confidence: 99%

A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma

Rampling

Peoples

Mulholland

et al. 2016

Clinical Cancer Research

130

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“…Particularly agonists of OX40 and CD27, mainly monoclonal antibodies, have been developed and are currently being tested in preclinical models and clinical trials to enhance the efficacy of antitumour immunotherapies [14,15]. Due to their critical role for the development of primary as well as memory responses against viral infections [16,17], their use as adjuvants in conventional vaccination has also been proposed [18] and both secreted OX40L-and CD70-based constructs have been shown to enhance immune responses to an HIV-1 DNA vaccine in a murine model [19].…”

Section: Introductionmentioning

confidence: 99%

Activation of OX40 and CD27 Costimulatory Signalling in Sheep through Recombinant Ovine Ligands

et al. 2020

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Members of the tumour necrosis factor (TNF) superfamily OX40L and CD70 and their receptors are costimulating signalling axes critical for adequate T cell activation in humans and mice but characterisation of these molecules in other species including ruminants is lacking. Here we cloned and expressed the predicted ovine orthologues of the receptors OX40 and CD27, as well as soluble recombinant forms of their potential ovine ligands, OaOX40L and OaCD70. Using biochemical and immunofluorescence analyses, we show that both signalling axes are functional in sheep. We show that oligomeric recombinant ligand constructs are able to induce signalling through their receptors on transfected cells. Recombinant defective human adenoviruses were constructed to express the soluble forms of OaOX40L and OaCD70. Both proteins were detected in the supernatant of adenovirus-infected cells and shown to activate NF-κB signalling pathway through their cognate receptor. These adenovirus-secreted OaOX40L and OaCD70 forms could also activate ovine T cell proliferation and enhance IFN-γ production in CD4+ and CD8+ T cells. Altogether, this study provides the first characterisation of the ovine costimulatory OX40L-OX40 and CD70-CD27 signalling axes, and indicates that their activation in vivo may be useful to enhance vaccination-induced immune responses in sheep and other ruminants.

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“…This phenomenon may go some way in explaining the enhanced production of NF-κB-regulated cytokines TNFα and IL-6 in the VACV-infected ear tissue of 54-wo mice (Figure 3C) as well as CCL2 in dLNs (Figure 4D). IL-6 and TNF superfamily ligands act as adjuvants and increase immunogenicity of vaccines (45, 46). Therefore, in the case of VACV vaccination, inflammaging might be beneficial by providing additional pro-inflammatory stimulus to drive the cascade of events leading to immune memory development.…”

Section: Discussionmentioning

confidence: 99%

Enhanced Efficacy of Vaccination With Vaccinia Virus in Old vs. Young Mice

2019

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Immunosenescence is believed to be responsible for poor vaccine efficacy in the elderly. To overcome this difficulty, research into vaccination strategies and the mechanisms of immune responses to vaccination is required. By analyzing the innate and adaptive immune responses to vaccination with vaccinia virus (VACV) in mice of different age groups, we found that immune cell recruitment, production of cytokines/chemokines and control of viral replication at the site of intradermal vaccination were preserved in aged mice and were comparable with younger groups. Analysis of cervical draining lymph nodes (dLN) collected after vaccination showed that numbers of germinal center B cells and follicular T helper cells were similar across different age groups. The number of VACV-specific CD8 T cells in the spleen and the levels of serum neutralizing antibodies 1 month after vaccination were also comparable across all age groups. However, following intranasal challenge of vaccinated mice, body weight loss was lower and virus was cleared more rapidly in aged mice than in younger animals. In conclusion, vaccination with VACV can induce an effective immune response and stronger protection in elderly animals. Thus, the development of recombinant VACV-based vaccines against different infectious diseases should be considered as a strategy for improving vaccine immunogenicity and efficacy in the elderly.

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Design of vaccine adjuvants incorporating TNF superfamily ligands and TNF superfamily molecular mimics

Cited by 11 publications

References 66 publications

A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma

A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma

Activation of OX40 and CD27 Costimulatory Signalling in Sheep through Recombinant Ovine Ligands

Enhanced Efficacy of Vaccination With Vaccinia Virus in Old vs. Young Mice

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