Epitope editing enables targeted immunotherapy of acute myeloid leukaemia.
Gabriele CasiratiAndrea CosentinoAdele MucciMohammed S MahmoudIratxe Ugarte ZabalaJing ZengScott B FicarroDenise KlattChristian BrendelAlessandro RambaldiJerome RitzJarrod A MartoDanilo PellinDaniel E BauerScott A ArmstrongPietro GenovesePublished in: Nature (2023)
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.
Keyphrases
- bone marrow
- liver failure
- acute myeloid leukemia
- respiratory failure
- dendritic cells
- crispr cas
- aortic dissection
- drug induced
- cancer therapy
- amino acid
- mesenchymal stem cells
- monoclonal antibody
- hepatitis b virus
- stem cells
- binding protein
- acute lymphoblastic leukemia
- gene expression
- poor prognosis
- immune response
- genome wide
- cell death
- multiple myeloma
- extracorporeal membrane oxygenation
- high throughput
- tyrosine kinase
- high resolution
- intensive care unit
- dna methylation
- drug delivery
- transcription factor
- genome wide identification
- free survival