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Clinical Translation of Gene Modified T-cell Therapy for Solid Tumours

Sophie Papa

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Medical Research Council (MRC)
Aim: The aim of this fellowship is to develop immunotherapy for prostate cancer for the purpose of clinical translation. Methodology: A chimeric antigen receptor (CAR) P28z, which selectively recognises the prostate cancer antigen prostate specific membrane antigen (PSMA) co-expressed in one retroviral open reading frame with a chimeric cytokine receptor 4ab and the human sodium iodide symporter (hNIS) (collectively known as PiN4) has been generated. The expansion, survival and homing of PiN4 T-cells requires optimisation. To this end two novel immunocytokines will be compared with interleukin-2 (IL-2) and IL-4 for their ability to support PiN4 cytotoxicity via the 4ab. PiN4 function will be evaluated by production of pro-inflammatory cytokines and destruction of tumour monolayers after co-culture. Cytotoxicity will be quantified by MTT assays. Homing, and persistence of PiN4 cells in vivo will be studied by SPECT and PET imaging of the adoptively transferred T-cells capitalising on expression of the hNIS. The optimal combination of PiN4, immunocytokine/cytokine support and treatment schedule will be determined in vivo by studies of tumour xenograft destruction quantified by bioluminescence imaging of established xenografts engineered to express luciferase. Scientific and medical opportunities of the research: The scientific opportunities of this work focus on overcoming hurdles to translation of CAR therapy in solid tumours. Specifically to improving T-cell homing and persistence in the tumour micro-environment, whilst reducing the risk of PiN4 T-cells damaging normal tissues in which low levels of PSMA can be found. If successful these techniques can be used to enhance the function and safety of CARs targeting different tumour associated antigens. Medically the generation of a protocol and regulatory documents for a first in man study is the ultimate goal of this fellowship.

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