Prostate cancer has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings for a decade. However, efficacy of the most advanced therapies, including the licensed cell-based immunotherapy Sipuleucel-T, does not offer a durable control or long-term survival in patients suffering from recurrent or metastatic disease.
The prostate cancer vaccine programme builds on the technology developed in the institute, the chimpanzee adenovirus ChAdOx1-MVA vaccination regimen, which allows generation of the strongest sustained CD8+ T cell immune responses recorded in humans and has uniquely provided CD8+ T cell mediated protection against infectious diseases.
The preclinical part of the programme addressed the question of whether these viral vectors encoding prostate-specific antigens can break immunological tolerance to self-antigens and induce antigen-specific protective tumour immune response. We have undertaken comparative immunogenicity and efficacy assessment of a range of new and old cancer antigens in mouse transplantable tumour models and in an autochthonous mouse model of prostate cancer, the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP). The ChAdOx1-MVA immunisation platform targeting a panel of prostate-specific antigens, including the oncofetal self-antigen 5T4, has been evaluated alone and in combination with checkpoint inhibitors and agonistic monoclonal antibodies (mAbs) in mouse tumour models. Immunisations induced potent antigen-specific immune responses attributable to CD8+ T cells. In the B16.h5T4 melanoma model, prophylactic 5T4-targeted vaccination resulted in complete protection against tumour challenge, while therapeutic vaccination significantly delayed tumour growth and increased overall survival of tumour-bearing mice when used in combination with the mAbs therapy. Preclinical findings strongly supported the clinical investigation of the heterologous ChAdOx1-MVA 5T4 immunisation regimen in prostate cancer settings.
The first-in-human trial VANCE (NCT02390063) recruited 40 patients, either newly diagnosed with early stage prostate cancer and scheduled for radical prostatectomy or patients with stable disease on active surveillance protocol, to receive the ChAdOx1-MVA 5T4 vaccine. The trial was completed in 2018 and demonstrated an excellent safety profile and exceptional immunogenicity of the vaccine.
Based on the encouraging results of the VANCE study and preclinical results obtained combining the ChAdOx1-MVA 5T4 vaccine with the PD-1 checkpoint inhibitor, we have started the phase I/II trial ADVANCE (NCT03815942), which is currently recruiting patients with intermediate-risk prostate cancer and patients with advanced metastatic disease, to receive the ChAdOx1-MVA 5T4 vaccine in combination with anti-PD-1 mAb (nivolumab). The study primary endpoints are the safety and efficacy of this combination immunotherapy. The data analysis will be completed by Q4 2020.