Tolga Sutlu, Ph.D.
A century after the initial proposition that the immune system has the capacity to fight against tumors, evading destruction by immune cells is now well recognized as a hallmark of cancer. It is well established that during the development of malignancy, NK cell function is impaired and the phenotype is skewed due to the immunosuppressive pressure of the tumor. We have previously shown that the removal of NK cells from this milieu along with ex vivo cytokine stimulation can recover both the phenotype and the cytotoxic activity of the cells. Clinical studies have demonstrated significant anti-tumor responses generated by ex vivo activated NK cells both in the autologous and allogeneic settings in various cancers. However, understanding of the exact mechanisms of tumor recognition still presents a challenge since it is very much dependent on the phenotype and the composition of the tumor. We intend to characterize the exact phenotypic changes that are responsible for the recovery of NK cell functionality in such settings and pinpoint mechanisms of tumor recognition in a patient-specific setting by using genetically modified NK cells.
Although adoptive immunotherapy with genetically modified NK cells is a promising approach for cancer treatment, optimization of highly efficient gene transfer protocols for NK cells still presents a challenge. The efficiency of viral gene delivery to NK cells has always proven challenging and less efficient than other cells of the hematopoietic system. In fact, this is not to be unforeseen, since it is well established that NK cells are among the first-responders to viral infections and must have been evolutionarily selected to have high endurance against a virus infection. We have recently overcome this problem by developing a novel viral genetic modification method that relies on the use of small molecule inhibitors against signaling components of innate immune receptors that detect intracellular viral RNA and activate an anti-viral response in NK cells, negatively effecting the efficiency of lentiviral transduction. Our results present a proof-of-principle for the feasibility of such approaches to enhance lentiviral gene delivery to NK cells. We have also observed that the use of such inhibitors enhances lentiviral transduction efficiency in a number of human and mouse cell lines, indicating a broadly applicable, practical and safe approach that has the potential of being instrumental for various gene therapy protocols.
Our research aims to bring us closer to optimal ex vivo manipulation of NK cells for cancer immunotherapy. Clinical trials with ex vivo activated NK cells as well as further preclinical development of NK cell genetic modification processes are underway.