1039 Vaccination with a single dose of a novel delivery platform confers durable >8 month immune responses, with lasting protection against tumour and metastases in preclinical models

Abstract

Background Treatments that expand or activate anti-cancer cytotoxic T cells, key players in tumour control, have improved clinical outcome, but are costly, complex and remain only partially effective. Increasingly, the ultimate goal of prolonged cancer remission appears to be contingent on sustained T cell responses, however few therapies are able to achieve this.

We developed a vaccine delivery platform where a single priming immunisation reliably generates a high magnitude, systemic anti-tumour CD8+ T cell response, which importantly, is durable out to >8 months. Up to 80% of mice were protected from tumour challenge, even upon implantation at 5 months post-vaccination.

Methods Mice were vaccinated intravenously (i.v.) with 10⁸ IU of a proprietary vector encoding cancer or control antigens prior to or following tumour implantation with 2x10⁵ (subcutaneous) or 1x10⁴ (i.v.) tumour cells. Implanted tumours were measured every 2–3 days using digital calipers and mice culled when tumours approached 1.2 cm³. Blood, spleen, tumours and other organs were sampled at indicated timepoints. Vaccine-specific T cells were characterised by surface staining and/or intracellular cytokine staining flow cytometry, RNA sequencing, peptidomics and microscopy.

Results Across three tumour models, a single vaccination significantly expanded antigen-specific CD8⁺ T cells, with high magnitude acute responses followed by a consistent baseline observed out to 98–112 days of 2–3% of total circulating T cells (median 2.775 + IQR 4.84, p<0.01), reflecting a highly durable vaccine response. These responses significantly halted or delayed tumour progression without checkpoint-inhibitor co-treatment (p<0.01). Antigen-specific T cells displayed elevated granzyme-B and reduced expression of exhaustion markers (Lag-3, Tim-3 and PD-1) both peripherally and intratumourally (p<0.05). Broadening the tumour-specific T cell response with an immunopeptidomically-identified epitope conferred unusually long-lived protection, protecting mice from tumour challenge 5 months post-vaccination (p=0.0031). Antigen-specific T cells were observed across blood, lungs, livers, spleens and lymph nodes of all surviving mice, at a median frequency of 2.75% of CD8⁺ T cells (range 1.4–4.4), being significantly enriched in the CD103⁺ CD69⁺ Trm population (p=0.0011). This regimen also prevented development of lung tumour nodules in a therapeutic metastatic model, (p=0.031).

Conclusions We developed a vector platform that reliably generates antigen-specific CD8⁺ T cell responses of a high magnitude and duration, with a dual-epitope vaccine delivering 80% protection in tumour models at >5 months post-vaccination. A first-in-human Ph1/2a trial using our lead asset, ITOP-1, will be initiated in 2024 across 4 sites in the UK.

Ethics Approval All work was performed under UK Home Office license PPL P874AC0F0, PP3430109, PBA43A2E4 or 40/3636 in accordance with the UK Animal (Scientific Procedures) Act 1986. All work was performed by trained and licensed individuals.