MyD88 L265P Mutation-Specific TCR Gene Therapy for Treatment of B-Cell Lymphoma and Leukemia

Adoptive transfer of engineered T cells has shown remarkable success in hematopoietic malignancies. However, the current most common strategy of targeting lineage-specific antigens often leads to undesirable side effects and a high relapse rate. Therefore, novel treatment approaches are still needed. Oncogenic somatic mutations represent ideal targets because of tumor specificity: such (neo)antigens can be recognized by T cell receptors (TCR) in the context of MHC-peptide presentation. Here we have generated T cell lines from multiple healthy donors targeting one of the most common driver mutations found in B-cell lymphomas; a missense mutation on adaptor protein MyD88 changing leucine at position 265 to proline (L265P). T cell lines generated by autologous in vitro priming were reactive selectively against the predicted mutant epitope restricted to HLA-B7, but not against the corresponding wild-type peptide. Cloned TCRs from these lines led to mutation-specific and HLA-restricted reactivity with varying functional avidity. T cells engineered with mutation-specific TCR (TCR-T cells) recognized and killed cell lines of diffuse large B-cell lymphoma characterized by intrinsic MyD88 L265P. Furthermore, TCR-T cells showed promising therapeutic efficacy in xenograft mouse models, while initial safety screening did not indicate any sign of cross- or allo-reactivity risk. Taken together, our data suggest that mutation-specific TCRs can be used to target MyD88 L265P mutation, and hold promise for precision therapy for a significant subgroup of B-cell malignancies.