Award

More than 30% of children diagnosed with acute myeloid leukemia (AML) relapse after initial treatment, creating an urgent need for new treatment options. T-cell receptor (TCR) based therapies are a promising way to combat these cases due to their ability to target intracellular antigens that other therapies can’t reach. This proposal describes an approach to discover a set of known and novel AML-specific targets and new TCR drug candidates. A novel library-vs-library screening method will be used to screen repertoires of donor T-cells against 30 AML targets simultaneously for functional activation, with resolution of TCR-target interaction at the single-cell level. Beyond previously validated targets, novel AML targets will be selected across common MHC alleles for expression and presentation. Potential relationships between TCRs and AML targets can be identified through the analysis of single-cell sequencing data, and the most promising TCR candidates from the screen can be validated using gold-standard T cell assays. If successful, the TCRs identified by this proposal can be further developed into therapies for AML. Given the flexibility of TCRs, the method described in this proposal can also be applied to other cancers that lack treatment options for patients who fail frontline therapies.