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Principal Investigator: Rajan P. Kulkarni
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2024
Award: $705,441
Funding agency: National Institute of Dental and Craniofacial Research
Immune related adverse events (irAEs) secondary to checkpoint blockade inhibition (CBI) or other immune
modulatory therapy for cancer, including head and neck cancers, are a significant problem given the increasing
use of CBI and other immunomodulatory agents. It is therefore of critical importance to improve understanding
and optimize treatment regimens for irAEs. Oral mucosal irAE toxicity is relatively understudied despite the
potentially significant morbidity to patients. Understanding oral mucosal irAEs is an immediately accessible
window into the autoimmune pathology caused by ICB. Lessons from oral mucosal irAEs thus can inform
approaches to other irAEs. Our objective is to define T cell-based mechanisms of oral mucosal irAEs due to anti-
PD-1 therapy. This work will also further our goal to identify predictive markers of oral mucosal irAEs through
improved knowledge of their pathogenesis. Our central hypotheses are that regulatory T cell (Treg) plasticity is
a major driver of oral mucosal irAEs, with IL-17A being a key cytokine driver of mucosal toxicity. These
hypotheses build on prior work to define molecular signatures of T cells causative of muco-cutaneous eruptions.
We will test these hypotheses using an innovative combination of approaches including analysis of human
samples, mouse models that can generate similarly behaving irAEs, and generation and analysis of patient-
derived organoids (PDOs). Our team of experts in immunology, immunotherapy, head and neck cancer, and
bioinformatics will test this central hypothesis and achieve our objective via the following specific aims: 1)
Determine functional significance of Treg and Th17 balance in oral mucosal irAEs. 2) Investigate mechanistically
focused strategies to mitigate mucosal irAEs in murine models. 3) Validate therapeutic strategies to mitigate
irAEs in patient-derived irAE organoid models. We will utilize our expertise in single cell RNA sequencing and
PDOs to accomplish these aims. At the end of the project, the expected outcome is to better understand the
pathophysiological mechanisms of oral mucosal irAEs and have identified strategies that can treat or modulate
these, for future clinical trials. We will also be able to generate the mechanistic basis for future strategies to
rapidly mitigate or even prevent these irAEs, which will ultimately benefit HNSCC and other cancer patients.
Terms: <(TNF)-α><3-D><3-Dimensional><3D><Adrenal Cortex Hormones><Adverse Experience><Adverse event><Air><Atopic Dermatitis><Atopic Eczema><Atopic Neurodermatitis><Autoimmune><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bio-Informatics><Bioinformatics><Biologic Models><Biological Models><Biopsy><Body Tissues><Buccal Cavity><Buccal Cavity Head and Neck><Buccal Mucosa><Bullous Pemphigoid><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cachectin><Cancer Patient><Cancer Treatment><Cancers><Cavitas Oris><Cell Body><Cells><Clinical><Clinical Management><Clinical Trials><Colitis><Complex><Corticoids><Corticosteroids><Cutaneous><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Data Set><Development><Disseminated Neurodermatitis><Endocrine Diseases><Endocrine Diseases and Manifestations><Endocrine System Diseases><Equilibrium><Evidence based treatment><Exhibits><Expression Signature><Future><Gene Expression Profile><Generations><Goals><HNSCC><HPGF><Head and Neck Cancer><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-6><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL6 Protein><IMiD><Immune><Immune Modulation Therapy><Immune mediated therapy><Immune modulatory therapeutic><Immunes><Immunologic Stimulation><Immunological Stimulation><Immunologically Directed Therapy><Immunology><Immunostimulation><Immunotherapy><In Vitro><Inbred NOD Mice><Incidence><Inflammation><Inflammatory><Informatics><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-17><Interleukin-6><Interruption><Investigation><Knowledge><Licheniform Eruptions><Lichenoid Eruptions><Liquid substance><MGI-2><Macrophage-Derived TNF><Malignant Head and Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Methods><Model System><Modeling><Modern Man><Molecular Fingerprinting><Molecular Profiling><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Mouth><Mouth Mucosa><Mucosa><Mucosal Inflammation><Mucosal Tissue><Mucositis><Mucous Membrane><Myeloid Differentiation-Inducing Protein><NOD Mouse><Non-Obese Diabetic Mice><Nonobese Diabetic Mouse><Operative Procedures><Operative Surgical Procedures><Oral><Oral Mucosa><Oral cavity><Oral health><Oral mucous membrane structure><Organoids><Outcome><PD 1><PD-1><PD-1 antibody therapy><PD-1 therapy><PD1><PD1 antibody therapy><PD1 based treatment><Pain><Painful><Pathogenesis><Pathologic><Pathology><Patients><Pattern><Pemphigoid><Personalized medical approach><Phenotype><Plasmacytoma Growth Factor><Preventative strategy><Prevention strategy><Preventive strategy><Psoriasis><Publishing><QOL><Quality of life><Regulatory T-Lymphocyte><Reporting><Research Specimen><SCCHN><Sampling><Secondary to><Sialadenitis><Sialoadenitis><Specimen><Stomatitis><Surgical><Surgical Interventions><Surgical Procedure><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Thyroiditis><Tissues><Toxic effect><Toxicities><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treg><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ulcer><Ulceration><Validation><Work><aPD-1><aPD-1 therapy><aPD-1 treatment><aPD1><aPD1 therapy><aPD1 treatment><allergic dermatitis><allergic eczema><anti programmed cell death 1><anti-PD-1><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD-1/PD-L1><anti-PD1><anti-PD1 therapy><anti-PD1 treatment><anti-cancer therapy><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 therapy><antiPD-1><antiPD1><balance><balance function><cancer therapy><cancer-directed therapy><cell type><check point blockade><checkpoint blockade><clinical relevance><clinically relevant><cytokine><dental health><developmental><dimensional analysis><endocrine disorder><experience><fluid><gene expression pattern><gene expression signature><head and neck squamous carcinoma><head and neck squamous cell cancer><head/neck cancer><high dimensionality><human tissue><immune check point blockade><immune checkpoint blockade><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulating therapies><immune modulatory agents><immune modulatory drugs><immune modulatory therapies><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immune-mediated adverse events><immune-modulation treatment><immune-related adverse effect><immune-related adverse events><immune-related adverse reaction><immuno therapy><immunological diversity><immunomodulating agents><immunomodulating drugs><immunomodulation therapy><immunomodulation treatment><immunomodulator agent><immunomodulator drug><immunomodulator medication><immunomodulator prodrug><immunomodulator therapeutic><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><improved><individualized approach><innovate><innovation><innovative><insight><interferon beta 2><liquid><malignancy><malignant head and neck tumor><molecular profile><molecular signature><mouse model><murine model><neoplasm/cancer><non-obese diabetic (NOD) mice><nonobese diabetic (NOD) mice><novel><oral mucosae><oral mucosal><personalized approach><pharmacologic><precision approach><predictive biomarkers><predictive marker><predictive molecular biomarker><prevent><preventing><programmed cell death 1><programmed cell death protein 1><programmed cell death protein 1 therapy><programmed death 1><prospective><psoriasiform><psoriatic><regulatory T-cells><salivary gland inflammation><scRNA-seq><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><success><surgery><systemic lupus erythematosus susceptibility 2><tailored approach><therapy optimization><three dimensional><thymus derived lymphocyte><transcriptional profile><transcriptional signature><treatment optimization><treatment strategy><tumor><validations><αPD-1><αPD1>