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.

ObjectivesTo determine the potential costs and health benefits of a serum-based spectroscopic triage tool for brain tumours, which could be developed to reduce diagnostic delays in the current clinical pathway.DesignA model-based health pre-trial economic assessment. Decision tree models were constructed based on simplified diagnostic pathways. Models were populated with parameters identified from rapid reviews of the literature and clinical expert opinion.SettingExplored as a test in both primary and secondary care (neuroimaging) in the UK health service, as well as application to the USA.ParticipantsCalculations based on an initial cohort of 10 000 patients. In primary care, it is estimated that the volume of tests would approach 75 000 per annum. The volume of tests in secondary care is estimated at 53 000 per annum.Main outcome measuresThe primary outcome measure was quality-adjusted life-years (QALY), which were employed to derive incremental cost-effectiveness ratios (ICER) in a cost-effectiveness analysis.ResultsResults indicate that using a blood-based spectroscopic test in both scenarios has the potential to be highly cost-effective in a health technology assessment agency decision-making process, as ICERs were well below standard threshold values of £20 000–£30 000 per QALY. This test may be cost-effective in both scenarios with test sensitivities and specificities as low as 80%; however, the price of the test would need to be lower (less than approximately £40).ConclusionUse of this test as triage tool in primary care has the potential to be both more effective and cost saving for the health service. In secondary care, this test would also be deemed more effective than the current diagnostic pathway.

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HighlightsThe manuscript details the rationale, design and protocol for PARADIGM-2.PARADIGM-2 comprises two parallel phase I, dose escalation studies of the PARP inhibitor olaparib in combination with radiotherapy (for MGMT unmethylated patients) and radiotherapy-temozolomide (for MGMT methylated patients) in newly diagnosed glioblastoma.This is a novel approach to phase I dose escalation trial design that maximises the potential for patients with glioblastoma to benefit from the addition of the radio- and chemosensitizing drug olaparib.