1502TiP A phase I/IIa trial of ChAdOx1 and MVA vaccines against MAGE-A3 and NY-ESO-1

While immunotherapy is a critical modality for the treatment of many cancers, many patients (pts) do not respond to checkpoint blockade. Vaccination against tumour antigens has potential to enhance this, and despite the historically limited success of vaccines in monotherapy, effective immune induction is observed. Prime-boost viral vaccination is a highly potent platform, priming immunity with the CHAdOx1 adenoviral vector, followed by MVA vaccinia vector boosting, against MAGE-A3 and NYESO-1. Nonclinical data to support the rationale for enhanced CHAdOx1-MVA efficacy, in combination with chemo- and immunotherapy, has been generated in an in vivo surrogate model ( McAuliffe J et al, 2021 ). The MAGE-A3 antigen is expressed on tumours of a high percentage of cancer patients including non-small cell lung cancer (NSCLC). NYESO-1, expressed on a subset of MAGE-A3+ tumours, has the additional advantage of being highly immunogenic in cancer patients, either spontaneously or in response to peptide vaccination. The safety, tolerability, efficacy and immunogenicity of ChAdOx delivery of MAGE-A3/NYESO-1 antigens, boosted by MVA-MAGE-A3 (MAGE-A3+ pts) or MVA-MAGE-A3 and MVA-NYESO-1 (MAGE-A3+NYESO-1+ pts) are explored in this trial. This is a multi-centre, first-in-human, phase I/IIa, randomised, open label trial, run in the UK, for patients scheduled to receive first-line chemo-immunotherapy containing pembrolizumab as standard of care (SoC) treatment, for Stage III/IV NSCLC (and potentially additional indications) expressing MAGE-A3 +/- NYESO-1 (NCT04908111). Patients receive trial vaccination from Cycle 3 of their SoC treatment. In the initial Safety Run-In Stage, opened in October 2021, all patients receive ChAdOx1-MAGE-A3-NYESO prime vaccination and either MVA-MAGE-A3 single boost (3 evaluable pts) or MVA-MAGE-A3 and MVA-NYESO double boost (3 evaluable pts) vaccinations with SoC. The currently expanding Rolling Recruitment Stage includes a NSCLC Randomised Cohort of approximately 80 pts, randomised 1:1 to addition of vaccination. The primary objective is safety and tolerability, with key secondary objectives of immunogenicity and clinical efficacy. Tertiary objectives include correlative translational analyses. CRUKD/20/001, Release date: 07 Dec 2020. Cancer Research UK Centre for Drug Development. Has not received any funding.