Engineering CAR-T cells to overcome the immunosuppressive microenvironment of solid tumours

Panetti, Silvia ORCID: 0000-0003-0176-7636 (2023). Engineering CAR-T cells to overcome the immunosuppressive microenvironment of solid tumours. University of Birmingham. Ph.D.

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Abstract

Chimeric antigen receptor (CAR)-T cell therapies have revolutionised the treatment landscape for cancer patients. However, engineered adoptive lymphocyte-based therapies face significant resistance in solid tumour microenvironments due to amino acid and nutrient scarcity, as well as significant infiltration of suppressive myeloid cells. Here, we investigated the microenvironment of different solid tumours and assessed the detrimental effects of myeloid-derived suppressor cells (MDSCs) on the autologous and engineered anti-cancer immunity. We demonstrated a novel strategy to improve CAR-T cell efficacy and tumour clearance by depleting MDSCs with a repurposed CD33-directed immunoconjugate, Gemtuzumab Ozogamicin. In addition, we designed metabolically enhanced CAR-T cell constructs, to endow the T cells with increased L-arginine catabolic activity. We found that arginase-transduced CAR-T cells were able to recognise and lyse target cells in a comparable fashion to the anti-GD2 control. However, they presented an enhanced bioenergetic flexibility, evidenced by the increased maximal respiration achieved during the MitoStress test (p = 0.010), and a higher intracellular abundance of key metabolites, such as pyruvate (p = 0.028) and glutamine (p = 0.003). Ultimately, the novel CAR-T cells were shown to have a proliferative advantage upon antigen stimulation (p = 0.015) and induce superior tumour reduction in vivo (p = 0.010) compared to the standard CAR-T cells.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):