CD38 knockout natural killer cells expressing an affinity optimized CD38 chimeric antigen receptor successfully target acute myeloid leukemia with reduced effector cell fratricide
| Autor: | Subhashis Sarkar, Eva Szegezdi, Emma Nolan, Sonja Zweegman, Lucy Kirkham-McCarthy, Stanislav Khoruzhenko, Niels W.C.J. van de Donk, Mark Gurney, Rama Shivakumar, Tuna Mutis, Arwen Stikvoort, Michael O'Dwyer |
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| Přispěvatelé: | Hematology, AII - Cancer immunology, CCA - Cancer biology and immunology, Hematology laboratory |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cytotoxicity Immunologic Myeloid medicine.medical_treatment Biology CD38 Immunotherapy Adoptive Cell therapy 03 medical and health sciences Gene Knockout Techniques 0302 clinical medicine immune system diseases Cell Line Tumor hemic and lymphatic diseases medicine Cytotoxic T cell Humans Membrane Glycoproteins Receptors Chimeric Antigen Myeloid leukemia hemic and immune systems Hematology Immunotherapy medicine.disease ADP-ribosyl Cyclase 1 Chimeric antigen receptor Killer Cells Natural Leukemia Leukemia Myeloid Acute 030104 developmental biology medicine.anatomical_structure Cancer research 030215 immunology |
| Zdroj: | Gurney, M, Stikvoort, A, Nolan, E, Kirkham-McCarthy, L, Khoruzhenko, S, Shivakumar, R, Zweegman, S, van de Donk, N W C J, Mutis, T, Szegezdi, E, Sarkar, S & O'Dwyer, M 2020, ' CD38 knockout natural killer cells expressing an affinity optimized CD38 chimeric antigen receptor successfully target acute myeloid leukemia with reduced effector cell fratricide ', Haematologica, vol. Online ahead of print . https://doi.org/10.3324/haematol.2020.271908 Haematologica, Online ahead of print. Ferrata Storti Foundation |
| ISSN: | 0390-6078 |
| DOI: | 10.3324/haematol.2020.271908 |
| Popis: | There is a strong biological rationale for the augmentation of allogeneic natural killer (NK) cell therapies with a chimeric antigen receptor (CAR) to enhance acute myeloid leukemia (AML) targeting. CD38 is an established immunotherapeutic target in multiple myeloma and under investigation as a target antigen in AML. CD38 expression on NK cells and its further induction during ex vivo NK cell expansion represent barriers to the development of a CD38 CAR-NK cell therapy. We set out to develop a CD38 CAR-NK cell therapy for AML, first by using an NK cell line which has low baseline CD38 expression and subsequently NK cells expanded from healthy donors. To overcome anticipated fratricide due to NK cell CD38 expression when using primary expanded NK cells, we applied CRISPR/Cas9 genome editing to disrupt the CD38 gene during expansion, achieving a mean knockdown efficiency of 84%. The resulting CD38 knockdown expanded NK cells, after expression of an affinity optimized CD38 CAR, showed reduced NK-cell fratricide and an enhanced ability to target primary AML blasts. Furthermore, the cytotoxic potential of CD38 CAR-NK cells was augmented by pretreatment of the AML cells with all-trans retinoic acid which drove enhanced CD38 expression, offering a rational combination therapy. These findings support the further investigation of CD38 knockdown - CD38 CAR-NK cells as a viable immunotherapeutic approach to the treatment of AML. |
| Databáze: | OpenAIRE |
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