Alsaieedi, Ahdab Abdulazim; (2017) T cell delivery of immune-stimulatory cytokines to enhance cancer immunotherapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Adoptive cell therapy using TCR-engineered T cells is an exciting area of research and has emerged as a promising strategy for treating cancer patients. However, the effector function of TCR-engineered T cells can be tuned down by local mechanisms of tumour-associated immunosuppression. The potential of cytokines to reverse local immune suppression and enhance tumour immunity has been described in the past. The main aim of this project was to engineer T cell specificity as well as effector cytokine production as a strategy to enhance cancer immunotherapy. This was achieved by combining TCR gene transfer with genetic engineering to achieve IL-12 and IL-27 production in therapeutic T cells. In vitro validation data demonstrated not only an enhanced production of IL-12 and IL-27 by the engineered T cells but also an enhanced effector function upon antigen-specific stimulation. In order to circumvent previously described toxic side effects observed with systemic IL-12 delivery, a tet-regulated gene expression system was utilised to regulate cytokine production by engineered T cells in vivo. Adoptive transfer of TCR-redirected T cells expressing regulated IL-12 in B16F10 melanoma-bearing mice resulted in an enhanced accumulation of transferred CD8+ T cells in the tumour and in a change of the innate immune cell composition in the tumour microenvironment. Importantly, regulated IL-12 delivery resulted in enhanced therapeutic efficacy of the transferred T cells without causing systemic toxicity. IL-27 delivery in engineered T cells also showed some effectiveness when combined with TCR gene therapy, although the therapeutic benefit of IL-27 was inferior to IL-12. The data in this study demonstrate the potency of additional genetic manipulation to tailor the TCR-redirected T cell effector function which can result in a substantial enhancement in their therapeutic efficacy, and thus, enhanced antitumor immune response.

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