Liechtenstein, TM; (2015) Lentivector-based cancer immunotherapy silencing PD-L1 and modulating cytokine priming; development of ex vivo myeloid-derived suppressor cells to assess therapeutic efficacy. Doctoral thesis , UCL (University College London).

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Abstract

Cancer immunotherapy strategies based on lentiviral vector (lentivector) transduction have recently been shown to be safe and effective in the clinic. The objective of cancer immunotherapy is to induce anti-cancer immune responses. Cytotoxic T cell (CTL) responses are particularly effective at recognizing and eradicating cancer cells and their activation is the main objective of most cancer immunotherapy treatments. Effective CTL responses depend on activation by antigen presenting cells (APCs), presenting tumour-associated antigens (TAAs) in the context of appropriate co-stimulatory and cytokine signals. In general, cancer immunotherapy has largely been ineffective due to tumour-induced immune suppression. One immunosuppressive mechanism employed by tumours relies on the accumulation of tumour-infiltrating myeloid-derived suppressor cells (MDSCs). Effective cancer immunotherapy treatments therefore need to stimulate tumour-specific CTLs as well as counteract the activity of tumour-infiltrating immunosuppressive cells. The first part of this thesis is based on the construction and evaluation of lentivector vaccines. The lentivector vaccines simultaneously expressed TAAs and cytokines, combined with silencing of the co-inhibitory molecule programmed death 1 ligand 1 (PD-L1). A collection of lentivector vaccines expressing an array of different T cell-polarising cytokines was generated and their T cell stimulatory and anti-tumour efficacies were assessed in vitro and in vivo. In the second part of this thesis a highly efficient and rapid method to produce large numbers of melanoma-infiltrating MDSCs ex vivo was developed, without inducing tumours in mice. Ex vivo MDSC phenotype, differentiation, and immunosuppressive activities were extensively studied. The novel ex vivo melanoma MDSCs were further used to evaluate the lentivector vaccines generated in the first part of this thesis. Simultaneous delivery of IL12 and a PD-L1-silencing microRNA was the only combination that could counteract ex vivo MDSC suppressive activities, correlating with therapeutically relevant anti-melanoma activities in a syngeneic B16 melanoma mouse model.

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