Chimeric antigen-receptor (CAR) engineered natural killer cells in a chronic myeloid leukemia (CML) blast crisis
Jusuf Imeri1, Paul Marcoux1, Matthias Huyghe1
1INSERM UMR-S-1310, Université Paris Saclay, Villejuif, France and ESTeam Paris Sud, Université Paris Saclay, Villejuif, France.
Abstract:
During the last two decades, the introduction of tyrosine kinase inhibitors (TKIs) to the therapy has changed the natural history of CML but progression into accelerated and blast phase (AP/BP) occurs in 3-5% of cases, especially in patients resistant to several lines of TKIs. In TKI-refractory patients in advanced phases, the only curative option is hematopoietic stem cell transplantation. We and others have shown the relevance of the expression of the Interleukin-2-Receptor α subunit (IL2RA/CD25) as a biomarker of CML progression, suggesting its potential use as a therapeutic target for CAR-based therapies. Here we show the development of a CAR-NK therapy model able to target efficiently a blast crisis cell line (K562). The design of the CAR was based on the scFv of the clinically approved anti-CD25 monoclonal antibody (Basiliximab). The CAR construct was integrated into NK92 cells resulting in the generation of CD25 CAR-NK92 cells. Target K562 cells were engineered by lentiviral gene transfer of CD25. In vitro functionality experiments and in vivo leukemogenicity experiments in NSG mice transplanted by K562-CD25 cells showed the efficacy and specificity of this strategy. These proof-of-concept studies could represent a first step for further development of this technology in refractory/relapsed (R/R) CML patients in BP as well as in R/R acute myeloblastic leukemias (AML).
Insights
A new CAR-NK therapy effectively targets Interleukin-2-Receptor α subunit (CD25) positive cells in advanced leukemia. This approach shows promise for treating TKI-resistant chronic myeloid leukemia and acute myeloid leukemia.
Area of Science:
- Immunotherapy
- Hematologic Oncology
- Cell Therapy
Background:
- Tyrosine kinase inhibitors (TKIs) have improved chronic myeloid leukemia (CML) outcomes, but 3-5% of patients progress to advanced phases, often resistant to TKIs.
- Hematopoietic stem cell transplantation is the only curative option for TKI-refractory advanced CML.
- Interleukin-2-Receptor α subunit (IL2RA/CD25) is a relevant biomarker for CML progression and a potential therapeutic target.
Purpose of the Study:
- To develop and evaluate a chimeric antigen receptor (CAR)-Natural Killer (NK) cell therapy targeting CD25.
- To assess the efficacy of CD25-targeted CAR-NK cells against CML blast crisis and acute myeloid leukemia (AML) models.
Main Methods:
- A CAR construct was designed using the scFv from Basiliximab (an anti-CD25 antibody) and integrated into NK92 cells to create CD25 CAR-NK92 cells.
- K562 cells, a blast crisis cell line, were engineered to express CD25 via lentiviral gene transfer.
- In vitro functionality assays and in vivo leukemogenicity studies in NSG mice were performed.
Main Results:
- CD25 CAR-NK92 cells demonstrated efficient and specific targeting of CD25-expressing K562 cells in vitro.
- In vivo experiments showed the efficacy of the CD25 CAR-NK therapy in reducing leukemic burden in mice engrafted with K562-CD25 cells.
Conclusions:
- This study presents a proof-of-concept for a novel CAR-NK therapy targeting CD25 in advanced leukemia.
- This strategy holds potential for treating refractory/relapsed (R/R) CML in blast phase and R/R acute myeloid leukemias (AML).
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