Liposome-based mRNA cancer immunotherapy targeting ion channels

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PROJECT SUMMARY Immune checkpoint inhibitors like monoclonal blocking antibodies against programmed cell death 1 (PD1) have revolutionized the way solid malignancies are treated. However, despite a dramatic response in some patients, the majority either have no response or develop resistance. The focus of our research is on head and neck squamous cell carcinoma (HNSCC), an aggressive cancer with high mortality rates and high resistance to checkpoint inhibitors. Our goal is to develop new treatment options that improve immunosurveillance and reduce the resistance to PD1 therapy in HNSCC patients. The efficacy of immunotherapy in cancer relies on the therapy's capability to increase their migration of tumor- specific T cells into the tumor, and sustain their cancer killing capacity despite the immunosuppressive tumor microenvironment (TME). Improving the ability of the T cells to infiltrate the tumor and to function in the hostile TME remains the greatest challenge of immunotherapy. These functions of T lymphocytes rely on Kv1.3 and KCa3.1 potassium channels that control the membrane potential and facilitate the Ca2+ influx necessary for cytokine production, cytotoxicity and chemotaxis. We have discovered that these channels contribute to the failure of immune surveillance and the resistance to immunotherapy in HNSCC. KCa3.1 channels are inhibited by adenosine, an immunosuppressive molecule present in the TME, and this mechanism limits T cell infiltration into the tumors. In addition, Kv1.3 channels are reduced in tumor infiltrating T cells and contribute to inefficient cytotoxicity. Lastly, we observed that cytotoxic T cells of HNSCC patients that respond to PD1 blockade display a characteristic increase in Kv1.3 and loss of response to adenosine. Therefore, a therapy that enhances Kv1.3 and confer resistance to adenosine selectively in T cells would be highly beneficial in HNSCC. We will develop lipid nanoparticles (LNPs) for targeted delivery to T cells of a messenger RNA (mRNA) encoding Kv1.3 and a peptide that confers resistance to adenosine through liposomal nanoparticles. The adenosine- blocking peptide blocks the signaling pathway downstream to the adenosine receptor. Herein, will test the hypothesis that a cell-targeted liposomal mRNA formulation that induces overexpression of Kv1.3 channels and loss of adenosine-sensitivity in T lymphocytes can reduce the resistance to anti-PD1 therapy in HNSCC patients. In Aim 1, we will produce LNPs that carry an mRNA encoding Kv1.3 and a peptide that blocks the effect of adenosine and are decorated with antibodies for targeted delivery to T lymphocytes. In Aim 2, we will determine the impact of these LNPs on tumors utilizing HNSCC patient-derived organoids and humanized mice. These studies will establish the feasibility of a new formulation that can improve the T cell cytotoxicity and confer resistance to the TME, and its validity for single-agent or combinatorial cancer immunotherapy.