Monday, May 6, 2024
5/6/2024
PROJECT SUMMARY/ABSTRACT The overarching goal of this R21 proposal is to explore the potential of nelfinavir, a widely used antiviral agent, as a modulator to significantly augment the efficacy of adoptive cell transfer (ACT) therapy against melanoma. Melanoma, one of the most aggressive and fatal neoplasms, is responsible for over 80% of skin cancer-related deaths. Despite recent advances in treatment for this devastating disease, including surgical resection, targeted therapy and chemotherapy, the prognosis of patients with melanoma remains dismal. Cellular therapy using ACT approach represents a particularly promising strategy to treatment of this malignancy; yet, the therapeutic outcomes remain elusive due to a variety of factors that limits the anti-tumor immunity. We recently revealed the critical roles of eukaryotic elongation factor-2 kinase (eEF-2K) in promoting the survival and cytocidal activity of CD8+ T cells and in augmenting the antitumor activity of CAR-T therapy, suggesting the potential of manipulating this kinase in boosting immunotherapy against melanoma. eEF-2K belongs to the family of atypical a-kinases and is an evolutionarily conserved regulator of protein synthesis. This kinase phosphorylates eEF-2, a 100 kDa protein that promotes ribosomal translocation from the A to the P-site, the reaction that induces movement of mRNA along the ribosome during translation. Phosphorylated eEF2 is unable to catalyze ribosomal translocation, thereby inhibiting peptide elongation. Notably, studies showed that eEF-2K can be activated by nelfinavir, an orally bioavailable antiviral agent that have been widely used in clinical treatment of human immunodeficiency virus infection such as HIV and AIDS, and that activation of eEF- 2K in tumor cells promotes tumor cell death and suppresses tumor progression. Thus, based on our observation of the role of eEF-2K in reinvigoration of cytotoxic CD8+ T cells as well as the above studies, we hypothesize that pharmacologic activation of eEF-2K by nelfinavir can be exploited as a novel and effective therapeutic approach to substantially augment the efficacy of ACT against melanoma. Addressing this hypothesis would provide a proof of concept and rationale for improving the efficacy of current anti-melanoma therapies through targeting eEF-2K by use of nelfinavir. To test this hypothesis, we will characterize the effects of nelfinavir on cytotoxic T lymphocytes including T cell functions, persistence, and stability, and evaluate the impact of nelfinavir on reinforcing the efficacy of ACT against melanoma through use of in vitro and in vivo melanoma models. Successful completion of this study may provide a rapid path to enter clinical trials of nelfinavir in treatment of patients with immune poor-responsive melanoma, yielding new therapeutic opportunities to significantly improve current melanoma treatment through use of nelfinavir.
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