Targeting cancer neoantigens in patients with myeloid malignancies

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Objective 1. Our initial screening of PBMCs from five patients with myeloid disorders using conventional in vitro sensitization methods with peptides and tandem minigenes was negative. To overcome limitations such as poor in vitro expansion of T cells in patients with myeloid cancers, we initiated a collaborative study to use single-cell technology to identify TCRs that recognize candidate neoantigens in MDS. Preliminary analysis of 11 MDS and 5 CMML patients revealed suitable populations for TCR profiling. To address the low mutational burden and expand our screening libraries, we initiated another collaboration to analyze and identify tumor- and patient-specific splicing aberrations in U2AF1-, SF3B1-, and SRSF2-mutated MDS patients. Bioinformatic analysis of candidates for screening is underway. Objective 2. We screened 10 healthy donors with common class I HLAs and found reactive TCRs against several driver mutations in 4 of them. Validation of whether these TCRs can lyse relevant tumor cells is in progress. We also vaccinated a total of 50 HLA-transgenic mice and identified two TCRs that recognize a driver mutation in AML and mediate robust, specific lysis of primary AML cells bearing both the mutation and one of the common HLAs. Validation in a xenograft model is in progress.