PhD in Infection & Immunity - Modifying human cytomegaloviruses to drive expansion of effector natural killer and cytotoxic T cells

Natural Killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTL) are immune cells known to kill cancerous and virus-infected cells and are being used to treat forms of these diseases. Both cell types are used or have been proposed for use in adoptive immunotherapy against multiple cancers following ex vivo expansion of mature or chimaeric-antigen receptor engineered effectors, with NK cells also allowing for re-targeting using monoclonal, bispecific and trispecific antibodies [1]. One shortfall limiting application remains the failure of infused cells to expand and persist in vivo. This study aims to generate new understanding and reagents that will enable the expansion of highly functional NK cells and CTL for immunotherapy. We will achieve this by studying the capacity of genes encoded by human cytomegalovirus (HCMV) to expand these cell types.

HCMV is unique in that it infects for life and drives the largest in vivo expansions of NK cells and CTL known to man [2]. Such cells exhibit highly cytotoxic function and a signature ’effector’ phenotype. Despite the pathogenic nature of HCMV, redirection of such CMV-induced immune responses have cured or prevented infection of the animal equivalents of HIV and tuberculosis respectively [3,4], thus attenuated forms of HCMV are being investigated as novel vaccine vectors in humans. Our laboratories have developed unique reagents and state-of-the-art proteomic, virological, immunological and molecular biological techniques to study the impact of HCMV genes on immune function [5-7]. Preliminary work has identified HCMV gene families that alter the phenotype of responding NK cells and CTL. We will use these cutting edge approaches and samples from healthy individuals and cancer patients to define the underlying molecular mechanisms that drive differentiation of NK cells and CTL towards different phenotypes and functions in response to this virus. This will aid in our understanding of how to generate immune cells to protect at-risk individuals from HCMV, and also help inform the development of safe and effective HCMV-based vaccine vectors to counter different cancers and pathogens.