By ecancer reporter Saira Ahmed
A study published in the journal Nature reports that tumour-associated antigens shared by normal tissue can be precisely modified, resulting in selective resistance to targeted immunotherapies and generating artificial leukaemia-restricted antigens. This improves the safety and efficacy of targeted immunotherapies in acute myeloid leukaemia (AML).
Despite several promising adoptive immunotherapies, the absence of safely actionable tumour-restricted markers hinders their application to other haematological malignancies, such as acute myeloid leukaemia.
AML shares most surface markers with normal haematopoietic stem/progenitor cells (HSPCs) or differentiated myeloid cells and targeted immunotherapies can increase toxicity and health risks considerably.
Moreover, due to intratumoural heterogeneity and plasticity in AML, targeting more than one surface antigen may be required, therefore increasing the risk of overlapping toxicity.
In this study amino acid changes that abrogate the binding of therapeutic monoclonal antibodies targeting FLT3, CD123 and KIT were identified by performing epitope mapping and library screenings. Through base-editing, they were introduced in CD34+ HSPCs. In-vivo screenings and ex-vivo experiments showed that the functionality of these receptors is not affected by this mutation.
The CD34+ HSPCs were also treated with CAR T cell therapy which confirmed resistance of epitope-edited haematopoiesis and concomitant eradication of patient-derived acute myeloid leukaemia xenografts.
The study results show that introducing a single amino acid substitution within FLT3, CD123 and KIT ECDs is enough to abrogate their recognition by monoclonal antibodies and CAR T cells.
By restricting the on-target activity to leukaemia cells, epitope-editing reduced the antigen burden to which CAR T cells were exposed. The reduced PD-1 levels observed in vivo suggested a decrease in the undesired CAR T cell stimulation and excessive cytokine release or exhaustion.
Moreover, this study's epitope engineering by base editing was multiplexed, which showed a synergistic on-tumour effect while avoiding overlapping toxicities. This proved that targeting multiple molecules could eliminate AML with heterogeneous or low-level antigen expression and further reduce the risk of relapse.
Dr Gabriele Casirati (Dana-Farber Cancer Institute, Boston, USA), an author of this study noted that “epitope editing is a really promising new technology that can definitely be translated to clinical practice”.
He further states “The outlook of this study is that high-risk patients who do not fare well with…first-line treatments could receive an edited transplant, and after the transplant, they have the possibility to receive a very potent CART cell therapy without having the risk of on-target toxicity.”
Watch the interview here.
Reference: Casirati, G., Cosentino, A., Mucci, A. et al. Epitope editing enables targeted immunotherapy of acute myeloid leukaemia. Nature 621, 404–414 (2023).
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