Author: Evelyn Ojo

Publisher:

Published: 2019

Total Pages: 218

ISBN-13:

Cancer is the second-leading cause of death in the United States and worldwide leading to 8.8 million deaths in 2015. Despite major advancements in science and health, patients at advanced stages of particular cancer types experience significant mortality. Cancer patients often relapse following treatment with conventional therapeutic modalities such as chemotherapy and radiation therapy. Conventional treatment approaches do not successfully address the heterogeneity present in most solid tumors, result in severe off-target effects resulting in severe side effects, and fail to kill dormant cancer cells. Immunotherapy is the use of immune cells as tools to combat diseases. Natural killer (NK) cells are lymphocytes that lyse tumor cells and virally-infected cells through diverse mechanisms including release of cytotoxic granules. NK cell therapy has shown much promise in preclinical studies however it fails to demonstrate efficacy in various cancer populations. This body of work tackles two crucial barriers to NK cell therapy in patients with solid tumors. NK cell numbers in the tumor has been correlated with good prognosis in cancer patients. Obtaining clinically efficacious numbers of NK cells is limited by the relatively small proportion of NK cells in peripheral blood. We, therefore, designed and engineered a novel IL-21-based NK cell expansion platform consisting of OCI-AML3 cells transduced with membrane-bound IL-21 (NKF cells). We demonstrated that NKF cells are effective at expanding NK cells. The NK cells expanded using NKF cells were able to lyse a wide array of tumor types and demonstrated a favorable metabolic signature as compared to non-expanded NK cells. Additionally, NKF-expanded NK cells significantly reduced the tumor burden in sarcoma cell-infected mice. Cancer cells have developed mechanisms to evade anti-tumor activities of NK cells, dampening the efficacy of NK cell-mediated lysis of cancer cells. Transforming growth factor-ß (TGF-ß) is an immunosuppressive cytokine abundantly secreted by cancer cells to modify the cancer landscape to support the growth and development of the tumor. We demonstrated that inhibition of TGF-ß using the clinical grade TGF-ß inhibitor, galunisertib, resulted in rescue of NK cell cytokine secretion and cytotoxic function. In conclusion, this work has evaluated the NKF expansion system and demonstrated its ability to robustly expand NK cells. NKF-expanded NK cells have increased glycolytic and oxidative phosphorylation rates and continue to expand beyond 5 weeks of expansion. Feeder cell-expanded NK cells demonstrate superior cytotoxic function following inhibition of TGF-ß signaling. Infusion of NKF-expanded NK cells coupled with TGF-ß inhibition has the potential to result in decreased tumor burden in cancer patients.