Journal Article

Epitope editing enables targeted immunotherapy of acute myeloid leukaemia

Zeng, Jing, Salah Mahmoud, Mohammed, Marto, Jarrod A., Brendel, Christian, Genovese, Pietro, Rambaldi, Alessandro, Cosentino, Andrea, Pellin, Danilo, Ficarro, Scott B., Klatt, Denise, Bauer, Daniel E., Armstrong, Scott A., Ugarte Zabala, Iratxe, Mucci, Adele, Casirati, Gabriele, Ritz, Jerome

2023

Overview

Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia 1 , 2 , the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens 3 – 5 . Acute myeloid leukaemia immunotherapies target genes expressed by haematopoietic stem/progenitor cells (HSPCs) or differentiated myeloid cells, resulting in intolerable on-target/off-tumour toxicity. Here we show that epitope engineering of donor HSPCs used for bone marrow transplantation endows haematopoietic lineages with selective resistance to chimeric antigen receptor (CAR) T cells or monoclonal antibodies, without affecting protein function or regulation. This strategy enables the targeting of genes that are essential for leukaemia survival regardless of shared expression on HSPCs, reducing the risk of tumour immune escape. By performing epitope mapping and library screenings, we identified amino acid changes that abrogate the binding of therapeutic monoclonal antibodies targeting FLT3, CD123 and KIT, and optimized a base-editing approach to introduce them into CD34 + HSPCs, which retain long-term engraftment and multilineage differentiation ability. After CAR T cell treatment, we confirmed resistance of epitope-edited haematopoiesis and concomitant eradication of patient-derived acute myeloid leukaemia xenografts. Furthermore, we show that multiplex epitope engineering of HSPCs is feasible and enables more effective immunotherapies against multiple targets without incurring overlapping off-tumour toxicities. We envision that this approach will provide opportunities to treat relapsed/refractory acute myeloid leukaemia and enable safer non-genotoxic conditioning. Epitope engineering of donor haematopoietic stem/progenitor cells endows haematopoietic lineages with selective resistance to CAR T cells or monoclonal antibodies, without affecting protein function or regulation, enabling the targeting of genes that are essential for leukaemia survival and reducing the risk of tumour immune escape.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/1 / 13/31 / 42/41 / 45/100 / 45/23 / 631/250/251 / 631/532/1542 / 631/61/201 / 631/67/1990/283/1897 / 64/60 / 96/106 / 96/44 / Acute myeloid leukemia / Amino acids / Animals / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - therapeutic use / Antigens / Antigens, CD34 - metabolism / Bone marrow / Bone Marrow Transplantation / CD123 antigen / CD19 antigen / CD34 antigen / Cell differentiation / Chimeric antigen receptors / Editing / Engineering / Epitope Mapping / Epitopes - genetics / Epitopes - immunology / Flow cytometry / Gene Editing / Genes / Genotoxicity / Hematopoiesis / Hematopoietic Stem Cells - immunology / Hematopoietic Stem Cells - metabolism / Hemopoiesis / Heterografts - immunology / Humanities and Social Sciences / Humans / Immunotherapy / Immunotherapy - adverse effects / Immunotherapy - methods / Kinases / Leukemia / Leukemia, Myeloid, Acute - immunology / Leukemia, Myeloid, Acute - therapy / Ligands / Lymphocytes / Lymphocytes T / Monoclonal antibodies / multidisciplinary / Mutation / Myeloid cells / Phosphorylation / Progenitor cells / Receptors, Chimeric Antigen - immunology / Recurrence / Science / Science (multidisciplinary) / T-Lymphocytes - immunology / Transplantation Conditioning / Tumor Escape / Xenograft Model Antitumor Assays / Xenotransplantation