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Principal Investigator: Jared Michael Newton
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2019
Award: $28,091
Funding agency: National Institute of Dental and Craniofacial Research
Immunosuppressive microenvironments are a major hindrance to current immunotherapy applications in solid
tumor cancers. Patients with human papillomavirus (HPV)-induced oropharyngeal cancer (OPC) are an excellent
example of this as marked elevations in systemic immunosuppression result in less than 50% response rates to
immune checkpoint inhibitor (ICI) therapies, a new potent cancer immunotherapy. The long-term objective of this
application is to aid in the development of effective combination immunotherapy platforms for the treatment of
HPV-associated oral cancers. The overall goal of this research project, which is the next step in pursuit of that
objective, is to determine if solid tumor conditioning to remove intra-tumoral immunosuppressive cells can
enhance the efficacy of ICI therapies against HPV-induced OPC. To accomplish this goal three aims have been
developed. Aim 1 will optimize and characterize an immunomodulatory nanoparticle platform which we
hypothesize will promote significant activation of both innate and adaptive immune cell populations while
minimizing the suppressive effects of various immunosuppressive cell populations. Aim 2 will assess the
therapeutic efficacy and immunologic mechanism of our nanoparticles in combination with ICI therapies. We
hypothesize that combination nanoparticle treatment will significantly enhance the efficacy of ICIs in a murine
primary tumor challenge of HPV-related OPC by limiting immunosuppressive cells in the intra-tumoral space.
Aim 3 will then characterize the induced systemic and immunologic memory effects of our combination therapy,
which we hypothesize will both be greatly enhanced due to improved activation of tumor-specific T-cells. Various
immunologic, biologic, and bioengineering techniques will be used to test our overall working hypothesis. These
techniques include production and characterization of liposomal platforms, extensive use of preclinical murine
models of HPV-related OPC, and immune microenvironment and mechanism studies. Overall, this project will
help explain the role that immunosuppressive cell populations play in oral cancer immunologic avoidance. This
could greatly improve oral health but generating new approaches to enhance patient responses to
immunotherapies, thereby limiting the application of highly toxic treatment regimens used currently.
Terms: <Adverse effects><Agonist><Anogenital cancer><Antigen-Presenting Cells><Area><Biological><Biomedical Engineering><CD152><CD152 Antigen><CD152 Antigen Gene><CD152 Gene><CTLA 4><CTLA-4 Gene><CTLA-4 antigen><CTLA4><CTLA4 Protein><CTLA4 gene><CTLA4-TM><Cancer Biology><Cancer Patient><Cancers><Cell Body><Cells><Cervical><Checkpoint inhibitor><Combination immunotherapy><Combined Modality Therapy><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte Protein 4 Gene><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Antigen 4 Gene><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4 Gene><Development><Edodekin Alfa><Effectiveness><Experimental Therapies><Generalized Growth><Goals><Growth><HNSCC><HPV><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Health><Homolog of Drosophila TOLL><Human><Human Papilloma Virus><Human Papillomavirus><IL-12><IL12><IMiD><Immune><Immune checkpoint inhibitor><Immune memory><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Memory><Immunological><Immunological Memory><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunomodulators><Immunosuppressants><Immunosuppression><Immunosuppression Effect><Immunosuppressive Agents><Immunosuppressive Effect><Immunotherapy><In Vitro><In complete remission><Infectious Human Wart Virus><Interleukin-12><Intervention><Intervention Strategies><Investigational Therapies><Investigational Treatments><Knowledge><Lipid A><Liposomal><Liposomes><Malignant Neoplasms><Malignant Oral Cavity Neoplasm><Malignant Oral Cavity Tumor><Malignant Oral Neoplasm><Malignant Oropharyngeal Neoplasm><Malignant Oropharyngeal Tumor><Malignant Tumor><Memory><Mice><Mice Mammals><Modern Man><Mouth Cancer><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myeloid-derived suppressor cells><NKSF><Natural Killer Cell Stimulatory Factor><Operative Procedures><Operative Surgical Procedures><Oral Cancer><Oral Cavity Squamous Cell Carcinoma><Oral health><Oral squamous cell carcinoma><Oropharnyx Cancers><Oropharyngeal Cancer><Oropharyngeal Carcinoma><Oropharynx Cancer><Oropharynx Carcinoma><Outcome><PD 1><PD-1><PD1><PD1 gene><Patients><Play><Population><Pre-Clinical Model><Preclinical Models><Primary Neoplasm><Primary Tumor><Production><Public Health><R-Series Research Projects><R01 Mechanism><R01 Program><Radiation therapy><Radiotherapeutics><Radiotherapy><Regulatory T-Lymphocyte><Reporting><Research Grants><Research Project Grants><Research Projects><Role><SCCHN><SLEB2 gene><Safety><Solid Neoplasm><Solid Tumor><Surgical><Surgical Interventions><Surgical Procedure><T-Cells><T-Lymphocyte><TLR4><TLR4 gene><Techniques><Testing><Tissue Growth><Toll Homologue><Tonsil><Treatment Efficacy><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treg><United States><Work><accessory cell><anamnestic reaction><anti-cancer immunotherapy><anti-tumor immune response><anticancer immunotherapy><antitumor immune response><base><bio-engineered><bio-engineers><bioengineering><cancer immunotherapy><cancer microenvironment><cancer type><career development><check point immunotherapy><check point inhibitor therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint therapy><clinical investigation><combination therapy><combinatorial immunotherapy><combined modality treatment><combined treatment><complete response><conditioning><conventional therapy><conventional treatment><cytotoxic T-lymphocyte antigen 4><dental health><developmental><dual immunotherapy><experience><experimental therapeutic agents><experimental therapeutics><immune check point inhibitor><immune check point therapy><immune checkpoint therapy><immune drugs><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulation><immune modulatory agents><immune modulatory drugs><immune regulation><immune suppression><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogenic><immunologic reactivity control><immunomodulating agents><immunomodulatory><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoregulation><immunoregulatory><immunosuppressive><immunotherapy for cancer><immunotherapy of cancer><improved><insight><intervention efficacy><interventional strategy><liposomal delivery><liposome delivery><malignancy><malignant mouth neoplasm><malignant mouth tumor><malignant oropharynx neoplasm><malignant oropharynx tumor><mouse model><mouth SCC><mouth squamous cell carcinoma><multi-modal therapy><multi-modal treatment><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><ontogeny><oral cavity SCC><oral cavity cancer><oral squamous cancer><oral squamous carcinoma><patient response><pre-clinical><preclinical><programmed cell death 1><programmed cell death protein 1><programmed death 1><radiation treatment><radio-therapy><regulatory T-cells><response><response to treatment><responsive patient><secondary immune response><sexually transmitted virus><side effect><skills><sle2><social role><success><surgery><systemic lupus erythematosus susceptibility 2><therapeutic efficacy><therapeutic response><therapeutically effective><therapy efficacy><thymus derived lymphocyte><toll-like receptor 4><tongue base><tongue root><tonsillar><translational investigator><translational researcher><translational scientist><treatment response><treatment with radiation><tumor><tumor microenvironment><wart virus>