Abstract
Cancer immunotherapy with T-cells that carry chimeric antigen receptors is currently on cutting edge of modern oncology. Autotransplantation of T-lymphocytes with chimeric receptor specific for certain tumor antigen proves to be clinically effective, but costly. Linear carriers of chimeric antigen receptors based on natural killer NK-92 cell culture may be an affordable alternative, however, this culture is resistant to lentiviral transduction. Recently, lentiviral vectors, pseudotyped with surface glycoproteins of the measles virus vaccine strain, have recently been successfully applied for transduction of primary immune cells. The aim of the work was to assess the efficiency of transduction of NK-92 cells with lentivirus vectors, pseudotyped with measles F and H surface glycoproteins, as well as to establish optimal conditions for selection of NK-92 transduced with the chimeric receptor against CD20 and to evaluate the culture’s cytotoxic potential. The results showed that the maximum infectious titer is achieved using the H∆18 variant in combination with F∆30, and the use of the TBK1/IKKɛ inhibitor BX795 results in additional 3-fold increase in the infectious titer. CAR-expressing NK-92 were able to suppress the proliferation of CD20+ cell line Raji in lower effector-to-target ratios than unmodified NK-92.
Highlights
Cancer immunotherapy with T-cells that carry chimeric antigen receptors is currently on cutting edge of modern oncology
Treatment regimens based on chimeric antigen receptor (CAR)-T cells demonstrate good clinical efficacy, but the cost of therapy is often extremely high, which is due to the requirement for production of a personalized T-cell population for each patient
The aim of this work was to determine the efficicacy of transduction of NK92 cells with lentiviruses, pseudotyped F and H glycoproteins of the measles virus, as well as to determine the conditions for isolation and purification of NK-92 cells transduced with a chimeric receptor directed against the CD20 antigen, and to assess their cytotoxic potential
Summary
Cancer immunotherapy with T-cells that carry chimeric antigen receptors is currently on cutting edge of modern oncology. In research and clinical trials, the most frequent vehicle is the patient's own cytotoxic T-lymphocytes with induced specificity for a particular tumor antigen or their combination. These modifications are performed by expressing a chimeric antigen receptor (CAR), consisting of several intracellular signaling domains for T-lymphocyte activation and an extracellular region that recognizes a tumor antigen [2]. Treatment regimens based on CAR-T cells demonstrate good clinical efficacy, but the cost of therapy is often extremely high, which is due to the requirement for production of a personalized T-cell population for each patient. It is possible to overcome these drawbacks, but this will require a significant improvement in the field of cell culturing and production
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