(1202-C) A Platform for Novel Target Discovery - Delivering Complexity & Robustness into Arrayed Immuno-Oncology Screens at AstraZeneca
Tuesday, February 6, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Chimeric Antigen Receptor (CAR)-T cell therapies have demonstrated remarkable efficacy in treating haematological cancers. However, challenges remain in solid tumours where the immuno-suppressive tumour microenvironment limits treatment responses. For instance, in prostate cancers a high level of the immuno-suppressive cytokine TGFβ is released in bone metastases, inhibiting the cytotoxic function of infiltrating CAR-T cells. Here, we describe an automated high-throughput immune cell target discovery platform to identify novel targets that upon inactivation rescue the antitumour functions of CAR-T cells in the presence of TGFβ. We performed arrayed CRISPR knockout screens in human CAR-T cells and developed a complex miniaturised co-culture system with multiparametric endpoints. We found that the loss of genes involved in the canonical TGFβ signalling pathway and other novel targets resulted in increased proliferation, cytokine production and importantly, restoration of tumour-killing activity despite the presence of TGFβ. These findings could provide additional arsenals for armouring next-generation autologous or allogeneic CAR-T/TCR-T cell therapies.