346 Pre-clinical characterization of AZD0240, a CRISPR-engineered autologous TCR-T cell product targeting KRAS-G12D/HLA-A11:01 that is multi-armored to increase epitope sensitivity

BackgroundKRAS is one of the most mutated genes in human cancer, with the G12D mutation having the highest frequency, occurring in 28% and 12% of pancreatic cancer (PDAC) and colorectal cancer (CRC), respectively. KRAS G12D-containing peptides are presented by the common HLA allele HLA-A*11:01, maki...

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Published in:Journal for immunotherapy of cancer Vol. 13; no. Suppl 2; p. A396
Main Authors: Kok Lianne, Eshuis Sander, Kong Xiangjun, Ma, Jennifer, Mojadidi Michelle, Hall, Elizabeth, Grace Sun Ka Hei, Kroon, Paula, Tubb, Vanessa, Schumacher, Ton, Perez, Arianne, Linnemann Carsten, Cobbold, Mark, Heijst Jeroen van, Bendle Gavin
Format: Journal Article
Language:English
Published: London BMJ Publishing Group LTD 01.11.2025
Subjects:
Cancer
CRISPR
Lymphocytes
ISSN:2051-1426
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Summary:BackgroundKRAS is one of the most mutated genes in human cancer, with the G12D mutation having the highest frequency, occurring in 28% and 12% of pancreatic cancer (PDAC) and colorectal cancer (CRC), respectively. KRAS G12D-containing peptides are presented by the common HLA allele HLA-A*11:01, making this cancer neoantigen a highly attractive target for the development of adoptive TCR-T cell therapy. However, the levels of cancer neoantigen presentation are typically low and combined with the immunosuppressive tumor microenvironment this compromises the activation and reactivity of TCR-engineered T cells, posing a major hurdle for these cells to eradicate tumor lesions.MethodsTo establish a TCR-T cell therapy intended for the treatment of solid cancers, including PDAC and CRC, we developed AZD0240, a CRISPR-engineered autologous TCR-T cell product targeting KRAS-G12D/HLA-A*11:01. To improve the reactivity of AZD0240 to the KRAS-G12D neoantigen, we developed a novel multi-armoring strategy, involving the combined disruption of a key negative regulator of T cell function and the introduction of a positive enhancement of TCR signaling.ResultsEmploying this multi-armoring strategy, we observed enhanced cytokine production in response to low levels of exogenously loaded KRAS-G12D peptide, as well as to HLA-A*11:01+ tumor cells that express the KRAS-G12D mutation. Moreover, assessment of the in vitro and in vivo proliferative and cytotoxic capacity revealed that the AZD0240 armoring strategy profoundly increased both the clonal expansion and the anti-tumor efficacy of TCR-engineered T cells. Notably, the armored AZD0240 T cells were unable to respond to the KRAS G12 wild-type epitope, and no signs of increased TCR cross- or allo-reactivity, or malignant transformation were detected, derisking the clinical use of this armoring strategy.ConclusionsTaken together, AZD0240 is a KRAS-G12D/HLA-A*11:01-targeted TCR-T cell therapy that employs a novel multi-armoring strategy and is currently in preparation for clinical testing, with encouraging signs of pre-clinical efficacy and safety.
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ISSN:2051-1426
DOI:10.1136/jitc-2025-SITC2025.0346