Expanding the scope of TCR gene therapy for AML and other cancers
Rachel Perret, Jennifer W. Cao, Karine Valliant-Saunders, Akshita Pillai, Philip D. Greenberg
Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle
Cancer treatments have changed little in the last 50 years, with non-specific and highly toxic chemo- and radiotherapy regimens leaving a lot of room for improvement. Targeted immunotherapies including adoptive T cell transfer are emerging as an alternative, relying on the exquisite specificity of the immune repertoire to target cancer cells without widespread off-target effects. TCR gene therapy accelerates the reproducible generation of tumor-specific T cells from patients, creating a promising avenue for treating hematological and solid tumors. Several hurdles remain to making this a broadly effective strategy, including variable target antigen expression, risk of tumor antigenic escape, and current therapies limited almost exclusively to HLA-A0201+ patients. We previously characterized WT1 and cyclin A1 as favorable T cell immunotherapy targets, based on high expression in malignant versus normal cells and roles in oncogenesis, reducing likelihood of loss variants. We currently have a high-affinity HLA-A0201/WT1-specific TCR in Phase I trials for the treatment of AML and NSCLC, and are selecting the best HLA-A0201/cyclin A1-specific TCR to advance to clinical development. We are also focused on developing WT1- and cyclin A1-specific TCRs for ~7 common HLA types, aiming to cover >90% of patients. T cell lines are generated by stimulating donor cells with overlapping peptide libraries to identify new epitopes. The highest affinity T-cell clones for each HLA/antigen combination are selected based on the strength of tetramer binding. TCRs are then cloned into lentiviral vectors for expression in CD8 T cells. Safety and efficacy of selected TCRs are rigorously tested using bioinformatics screens, in vitro assays, and humanized MHC-I mice. Our goal is to create a molecular toolbox of off-the-shelf TCR reagents, allowing us to rapidly produce the optimal T cell immunotherapy for each patient’s tumor antigenic profile and HLA type.
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