Epitope editing enables targeted immunotherapy of acute myeloid leukaemia

Gabriele Casirati, Andrea Cosentino, Adele Mucci, Mohammed Salah Mahmoud, Iratxe Ugarte Zabala, Jing Zeng, Scott B. Ficarro, Denise Klatt, Christian Brendel, Alessandro Rambaldi, Jerome Ritz, Jarrod A. Marto, Danilo Pellin, Daniel E. Bauer, Scott A. Armstrong and Pietro Genovese ()
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Gabriele Casirati: Division of Hematology/Oncology, Boston Children’s Hospital
Andrea Cosentino: Division of Hematology/Oncology, Boston Children’s Hospital
Adele Mucci: Division of Hematology/Oncology, Boston Children’s Hospital
Mohammed Salah Mahmoud: Division of Hematology/Oncology, Boston Children’s Hospital
Iratxe Ugarte Zabala: Division of Hematology/Oncology, Boston Children’s Hospital
Jing Zeng: Division of Hematology/Oncology, Boston Children’s Hospital
Scott B. Ficarro: Dana-Farber Cancer Institute
Denise Klatt: Division of Hematology/Oncology, Boston Children’s Hospital
Christian Brendel: Division of Hematology/Oncology, Boston Children’s Hospital
Alessandro Rambaldi: University of Milan and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII
Jerome Ritz: Division of Hematology/Oncology, Boston Children’s Hospital
Jarrod A. Marto: Dana-Farber Cancer Institute
Danilo Pellin: Division of Hematology/Oncology, Boston Children’s Hospital
Daniel E. Bauer: Division of Hematology/Oncology, Boston Children’s Hospital
Scott A. Armstrong: Division of Hematology/Oncology, Boston Children’s Hospital
Pietro Genovese: Division of Hematology/Oncology, Boston Children’s Hospital

Nature, 2023, vol. 621, issue 7978, 404-414

Abstract: Abstract Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia1,2, the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens3–5. 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.

Date: 2023
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DOI: 10.1038/s41586-023-06496-5

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