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Overcoming constraints on T cells in the HBV-infected liver (360G-Wellcome-101849_Z_13_A)

<p>My request for enhancement funding arises from the component of my existing award focused on developing T cell immunotherapy of hepatitis B and hepatocellular carcinoma using patient samples. We recently made important contributions to the testing of genetically redirected T cells for a first-in-man treatment of HBV-related hepatocellular carcinoma1. We are also collaborating with academic and pharmaceutical partners to develop immunotherapeutic vaccines aiming to boost antiviral T cells for hepatitis B control. However, these approaches remain limited by the profound exhaustion and other immune constraints imposed on T cells by high-level antigenic stimulation in the tolerogenic liver. Front-line candidates to revive T cells are checkpoint inhibitors such as PD-1 blockade. However, we have found that genetic knockdown of PD-1 can initiate detrimental effects in virus-specific T cells (Fig.1). The emerging concept that PD- 1 may actually be required to support long-term maintenance of T cells in the setting of persistent antigenic stimulation is underscored by recent work in murine models2, 3 and by our finding that liver-resident PD-1+T cells can remain highly functional (Pallett, in preparation). These discoveries underscore the need to investigate more fundamental drivers and mediators of T cell failure as alternatives or additions to checkpoint inhibition.</p>

£175,008

05 Dec 2016

Grant details
Amount Awarded 175008
Applicant Surname Maini
Approval Committee Science Enhancement Committee
Award Date 2016-12-05T00:00:00+00:00
Financial Year 2016/17
Grant Programme: Title Enhancement
Internal ID 101849/Z/13/A
Lead Applicant Prof Mala Maini
Planned Dates: End Date 2019-09-01T00:00:00+00:00
Planned Dates: Start Date 2017-03-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London
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