Abstract B67: Development of MyD88 L265P mutation-specific TCR gene therapy for treatment of B-cell lymphoma and leukemia

Abstract

Abstract Lymphoproliferative malignancies form a major group of cancers and are responsible for nearly 10% of all cancer deaths in developed countries. Adoptive transfer of engineered T cells has been shown to be a promising treatment approach; hence, screening and evaluation of cellular antigens for T-cell therapy with higher specificity and efficacy is a rapidly progressing area of research. Cancer-specific antigens derived by somatic mutations acquired during tumor development, so called “neoantigens,” represent a very advantageous target repertoire. Here we aimed to develop T-cell receptors (TCRs) targeting recurrent neoantigens in lymphoma and leukemia, for a truly cancer-specific immunotherapy. With this purpose, 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. TCR alpha and beta nucleotide sequences from these T-cell lines were successfully cloned into a retroviral vector and expressed on T cells of healthy donors for further characterization. All cloned TCRs have shown mutation-specific and HLA-restricted reactivity with varying functional avidity. TCR-transduced T cells were able to selectively recognize and kill engineered target cells expressing MYD88 mutation, proving that the mutant epitope can be naturally processed by human proteasome and presented on HLA-B7. In order to further evaluate the therapeutic potency, we tested TCR-transduced T cells with non-Hodgkin lymphoma cell lines naturally harboring MyD88 L265P, and again observed HLA-restricted and mutation-specific reactivity and cytotoxicity, accompanied by antigen-induced proliferation. Taken together, our data suggest that mutation-specific TCRs can be used to target cancer cells with MyD88 L265P, and hold promise for immunotherapy of B-cell malignancies. Therefore, an application to the European Patent Office for variable region sequences of the TCRs has been made (EP19152801.7) in collaboration with Charité Technology Transfer Office. Preclinical safety screening of the TCRs and in vivo efficacy assessment in mice are in progress. Citation Format: Özcan Çinar, Antonia Busse, Antonio Pezzutto. Development of MyD88 L265P mutation-specific TCR gene therapy for treatment of B-cell lymphoma and leukemia [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B67.