Combining adoptive T-cell therapy with cancer vaccines to enhance anti-tumour immune responses

Thesis

Adoptive T-cell therapy (ACT) consists of systemic infusion of cytotoxic tumour specific T cells aiming to control neoplasias. However, ACT still has very limited efficacy in humans. Cancer vaccines are promising immunotherapies to improve ACT, but the mechanisms underlying this combination are still poorly understood. To identify novel therapeutic approaches to improve ACT against solid tumours and to elucidate key factors responsible for immunotherapy efficacy, we have combined ACT with the chimpanzee adenovirus ChAdOx1 and poxvirus MVA vaccines encoding for specific tumour antigens. Strikingly, mice treated with the combination therapy showed a markedly higher tumour regression as compared to monotherapy controls. This efficacy was correlated with a superior tumour infiltration and expansion of tumour-reactive T cell populations in lymphoid organs. Surviving mice were rechallenged and monitored for 250 days and revealed that specific memory T cells populate lymph nodes, spleen and bone marrow. Interestingly, inflammation alone during ACT was sufficient to enhance T cell expansion and tumour control when followed by antigen-specific boosting. This synergy was abrogated when T cell trafficking to the lymph nodes was impaired. Importantly, we found that ChAdOx1 and MVA vaccination induces high levels of CXCL10. Crucially, blockade of its receptor, CXCR3, completely abrogated vaccine-mediated T cell expansion and tumour control. This suggests an essential role for CXCR3 signalling in the synergy between T-cell therapy and cancer vaccines. In conclusion, ChAdOx1 and MVA vaccination improves ACT against solid tumours by expanding transferred T cells that have long-lasting memory in a CXCR3-dependent manner.

Authors: Pereira Almeida, V

• DOI: 10.5287/ora-rb5nxzr1a
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: inflammation; tumour immunology; combination therapy; immunotherapy
• Subjects: Oncology; Immunology