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Principal Investigator: LAURA CONFORTI
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2023
Award: $189,338
Funding agency: National Cancer Institute
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.
Terms: <Address><Adenosine><Adenosine Receptors><Antibodies><Artificial nano particles><Artificial nanoparticles><Assay><Bioassay><Biologic Assays><Biological Assay><Blocking Antibodies><COVID-19><COVID19><CV-19><CV19><Cancer Patient><Cancers><Cell Body><Cell Function><Cell Locomotion><Cell Migration><Cell Movement><Cell Process><Cell physiology><Cell-Mediated Lympholytic Cells><Cells><Cellular Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Characteristics><Checkpoint inhibitor><Chemotaxis><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Disease model><Effectiveness><Electrophysiology><Electrophysiology (science)><Experimental Therapies><Failure><Formulation><Goals><HNSCC><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Immune><Immune Surveillance><Immune checkpoint inhibitor><Immune infiltrates><Immune mediated therapy><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunologically Directed Therapy><Immunosurveillance><Immunotherapy><In Vitro><Infiltration><Investigational Therapies><Investigational Treatments><Ion Channel><Ionic Channels><K channel><Laboratories><Liposomal><Liposomes><Lytotoxicity><Malignant Cell><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Mediating><Membrane Channels><Membrane Potentials><Messenger RNA><Methods><Mice><Mice Mammals><Motility><Murine><Mus><Nature><Neurophysiology / Electrophysiology><Oncologist><Operative Procedures><Operative Surgical Procedures><Organoids><P1 Purinoceptors><PD 1><PD-1><PD-1 antibody therapy><PD-1 therapy><PD1><PD1 antibody therapy><PD1 based treatment><Patients><Peptides><Potassium Channel><Potassium Ion Channels><Production><Property><Purinergic P1 Receptors><RNA vaccine><RNA-based vaccine><Radiation therapy><Radiotherapeutics><Radiotherapy><Relapse><Research><Resistance><Resistance development><Resistant development><Resting Potentials><SCCHN><Shapes><Signal Pathway><Solid><Solid Neoplasm><Solid Tumor><Specificity><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell infiltration><T cell targeted therapeutics><T cell therapy><T-Cells><T-Lymphocyte><Testing><Toxic effect><Toxicities><Transmembrane Potentials><Tumor Burden><Tumor Load><Up-Regulation><Upregulation><aPD-1 therapy><aPD-1 treatment><aPD1 therapy><aPD1 treatment><adoptive T cell transfer><adoptive T-cell therapy><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD1 therapy><anti-PD1 treatment><anti-cancer immunotherapy><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1 therapy><anticancer immunotherapy><cancer cell><cancer immunotherapy><cancer infiltrating T cells><cancer microenvironment><cancer progression><cell motility><chemotherapy><combinatorial><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytokine><cytotoxicity><design><designing><developing resistance><disorder model><electrophysiological><engineered nano particle><engineered nanoparticle><experimental therapeutic agents><experimental therapeutics><fighting><head and neck squamous carcinoma><head and neck squamous cell cancer><high risk><humanized mice><humanized mouse><immune cell infiltrate><immune check point inhibitor><immune microenvironment><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><interest><killer T cell><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA vaccine><mRNA-based vaccine><malignancy><melanoma><migration><mortality><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm progression><neoplasm/cancer><neoplastic progression><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><patch clamp><programmed cell death 1><programmed cell death protein 1><programmed cell death protein 1 therapy><programmed death 1><radiation treatment><resistant><response><side effect><site targeted delivery><sle2><surgery><systemic lupus erythematosus susceptibility 2><targeted delivery><therapeutic T-cell platform><thymus derived lymphocyte><trafficking><treatment with radiation><tumor><tumor immune microenvironment><tumor infiltrating T cells><tumor microenvironment><tumor progression><tumor-immune system interactions>