Abstract 5572: IMC-F106C, a novel and potent immunotherapy approach to treat PRAME expressing solid and hematologic tumors

Abstract

Abstract Background: Bispecific immunotherapies have been validated for the treatment of hematologic tumors but none have yet been approved for solid tumor indications, including high prevalent tumors such as non-small-cell lung carcinoma (NSCLC). Immunocore is developing ImmTAC® molecules, a new class of TCR/anti-CD3 bispecific fusion protein, that target intracellularly derived peptides presented at the tumor cell surface in complex with human leukocyte antigen (HLA). The ImmTAC IMC-F106C is in development for the treatment of advanced cancers that are positive for Preferentially Expressed Antigen in Melanoma (PRAME). PRAME is a cancer-testis antigen (CTA) that is highly expressed in normal testis and a range of solid and hematologic malignancies. The aim of this study was to characterise the expression of PRAME in a variety of human malignancies (mRNA and protein) and demonstrate that IMC-F106C can potently redirect T cells to eliminate indication-relevant tumor cells in vitro. Method: FFPE tumor samples were analysed by RT-qPCR and IHC for a number of tumor indications, to determine levels of PRAME mRNA and protein expression in patient samples for each indication. The activity of IMC-F106C was investigated in cellular assays using healthy donor PBMCs as effectors, targeting a variety of indication-relevant tumor cell lines expressing a PRAME-specific peptide complexed with HLA-A*02:01, including NSCLC non-small-cell lung carcinoma, ovarian carcinoma, and acute myeloid leukemia cell lines. T cell activation was assessed by cytokine release and T cell-mediated target-cell killing was evaluated by measurement of cell death (xCELLigence). Results: PRAME mRNA and protein expression was highly prevalent in samples of NSCLC, including both the adenocarcinoma and squamous cell carcinoma subtypes, SCLC, melanoma, ovarian, endometrial carcinoma samples, and in triple negative breast cancer (TNBC). Over 60% of samples demonstrated some level of PRAME expression by IHC and RT-qPCR in these 6 cancer indications. In the PRAME positive HLA-A*02:01 positive cell lines, IMC-F106C redirected donor effector cells to release IFNγ and GrB and kill tumor cells in a dose-dependent manner, with activity demonstrated as low as < 1 pM. By contrast, cell lines negative for PRAME or HLA-A*02:01 expression failed to induce responses < 1 nM of IMC-F106C. Conclusion: These data indicate that PRAME is expressed in a number of solid tumors, and is highly prevalent in lung tumours, irrespective of EGFR status, as well as female-oriented cancers. In conjunction, IMC-F106C efficiently redirects T cell activity against tumor cell lines that express PRAME across a range of tumor indications. Taken together, IMC-F106C could prove to be a highly effective immunotherapy option for HLA*02:01 positive patients with PRAME positive tumors. Citation Format: Sylvie Moureau, Alessio Vantellini, Florence Schlosser, Jacob Robinson, Jane Harper, Athiva Shankar, Greg Dobrynin, Gabrielle Le Provost, Amanda Williams, David Berman, Laure Humbert. IMC-F106C, a novel and potent immunotherapy approach to treat PRAME expressing solid and hematologic tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5572.