Identification of MAGE-A1 TCRs that confer function to CD8 and CD4 T cells for the advancement of T cell immunotherapy
Megan McAfee1*, Daniel Hunter1, Tom Schmitt1 & Aude Chapuis1,2
1Fred Hutchinson Cancer Research Center
2University of Washington Medical Center
Transfer of tumor-specific CD8 cytotoxic T cells (CTL) can safely mediate direct anti-tumor activity in select patients. However, efficacy is limited, in part by inadequate avidity of isolated CTL and by the absence of CD4 T cell engagement. Native, self-antigen/tumor-reactive T cells are rare and mostly of low avidity, owing to central and peripheral tolerance mechanisms. CD4 T cells may enhance CTL responses via IL-2 production, CD40L expression and direct cytolytic activity, but many tumors do not engage CD4 T cells as they do not express necessary major histocompatibility complex (MHC) Class II molecules. These facts present a strong rationale for isolating high-affinity Class I, tumor-specific TCRs that can engage CD8 and CD4 T cells. Melanoma-associated antigen gene A1 (MAGE-A1) is a desirable T cell therapy target, with abnormally increased expression in high-grade tumors and advanced disease, providing a relatively safe single target for the concurrent recruitment of therapeutic CD8 and CD4 T cells. To identify a high affinity, native HLA- A*0201-restricted MAGE-A1 T cell receptor (TCR) for human translation, we screened CTL lines from 12 HLA-matched normal donors with high-throughput TCR sequencing. We preferentially selected one, TCRMAGE-A1, after sorting with lower concentrations of peptide-MHC multimers, which correlates with higher TCR affinity. TCRMAGE-A1 alone activates transduced CD8, but not CD4 T cells. To confer both helper and cytolytic function to CD4 T cells, we co-transduced CD4 T cells with CD8alpha/beta co-receptor. Evolving data will be presented to support the efficacy of co-localizing CD8 and CD4 cells to the same target and to address whether second generation chimeric co-stimulatory CD8 constructs enhance TCR-transduced CD4 T cell activity in a humanized mouse model. Our platform streamlines the isolation of high affinity TCRs for a broad application to a range of malignancies.
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