Preclinical evaluation of adoptive T cell therapy and liposomal tumour antigen vaccination as a combinatorial cancer immunotherapy

The immune system is designed to protect our bodies from infection by constantly surveying peripheral tissues for signs of infection. Immune effectors are activated and mobilized upon detection of components from pathogenic intruders, but the immune system can also recognize and eliminate transformed, cancerous cells if they appear foreign by expression of mutated antigens. The ability of the immune system to recognize and eliminate cancer cells have motivated the development of cancer immunotherapies that aim at mobilizing a tumour reactive immune response. Adoptive T cell therapy (ACT) is a type of cancer immunotherapy that has undergone extensive development during the past decades and now offers a curative option for subgroups of patients with malignant melanoma and haematological malignancies. ACT is based on treatment with autologous tumour-reactive, T cells that are isolated from the patient, expanded ex vivo and infused back to the patient. Despite impressive response rates, the majority of patients are not cured by ACT and currently the therapy is not effective for solid cancers other than melanoma. It is therefore necessary to continuously advance the procedure by identifying factors that influence the therapeutic efficacy of ACT. The phenotype of the infused T cells is known to influence the persistence and ability of T cells to sustain long-term tumourreactivity, and studies have shown that using minimally differentiated T cells for ACT improves the therapeutic outcome. Furthermore, providing post-infusion priming of T cells by tumour antigen vaccination has been found to enhance the persistence and functionality of the infused T cells. Motivated by these findings, this thesis provides a preclinical evaluation of a therapeutic strategy that aims at improving the therapeutic response of ACT by combining infusion of naïve, antigen-specific T cells with a liposomal tumour antigen vaccination consisting of tumour antigen and a toll-like receptor 7 (TLR7) agonist conjugated to a liposomal formulation. The ...