Providence Health & Services - Oregon

REDESIGNING SERVICE DELIVERY THROUGH THE TRI-COUNTY HEALTH COMMONS

COLUMBIA RIVER ONCOLOGY PROGRAM

HIGH DOSE RADIATION THERAPY TO DIRECT IMMUNE RESPONSES TO PANCREATIC CANCER

PHASE II CLINICAL DEVELOPMENT OF GALECTIN-3 INHIBITION AND ANTI-PD-1: IMMUNE MONITORING AND TUMOR RESPONSE - PROJECT SUMMARY/ABSTRACT DUE TO RECENT ADVANCES, IMMUNOTHERAPY IS NOW PART OF THE STANDARD OF CARE FOR PATIENTS WITH METASTATIC MELANOMA (MM) AND HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC). IMMUNE CHECKPOINT BLOCKADE WITH DRUGS SUCH AS PEMBROLIZUMAB (PEMBRO; ANTI-PD-1) RELEASE THE BRAKES ON SPECIALIZED WHITE BLOOD CELLS (T CELLS) TO BOOST ANTI-TUMOR IMMUNITY. UNFORTUNATELY, ANTI-PD-1 MONOTHERAPY INFREQUENTLY CURES PATIENTS WITH ADVANCED MALIGNANCY, THUS CURATIVE REGIMENS ARE STILL CRITICALLY NEEDED FOR THESE PATIENTS. THERE ARE MANY MECHANISMS OF RESISTANCE TO IMMUNOTHERAPY, BUT TUMOR-INDUCED IMMUNE SUPPRESSION IS LIKELY ONE OF THE MOST IMPORTANT. TWO WAYS ANTI-TUMOR IMMUNITY IS SUPPRESSED ARE THROUGH PD-1/PD-L1 INTERACTIONS AND THE SECRETION OF AN INHIBITORY PROTEIN CALLED GALECTIN-3 (GAL-3) BY THE TUMOR. GIVEN THE ABILITY OF PD-1/PD-L1 AND GAL-3 TO SUPPRESS ANTI-TUMOR IMMUNITY, THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT RELIEVING TWO MECHANISMS OF IMMUNE SUPPRESSION BY TREATMENT WITH A NOVEL GAL-3 INHIBITOR (GR-MD-02; BELAPECTIN) PLUS PD-1 BLOCKADE WILL ENHANCE TUMOR REGRESSION IN PATIENTS WITH MM AND HNSCC. THIS INNOVATIVE APPROACH TARGETS A UNIQUE REGULATORY PATHWAY CAPABLE OF CHANGING THE TUMOR MICROENVIRONMENT (TME) AND ENHANCING T CELL ACTIVITY. IMPORTANTLY, OUR RECENT PHASE 1 TRIAL (NCT02575404) PROVIDED EVIDENCE OF CLINICAL BENEFIT IN PATIENTS WITH MM (ORR 50%) AND HNSCC (ORR 33%) FOLLOWING GR-MD-02+APD-1 THERAPY, WHICH COMPARED FAVORABLY WITH THE 15-20% (10% IN HNSCC) RESPONSE RATE EXPECTED IN THIS POPULATION OF HEAVILY PRE-TREATED PATIENTS. MOREOVER, COMBINATION THERAPY WAS ASSOCIATED WITH SIGNIFICANTLY FEWER IMMUNE-MEDIATED ADVERSE EVENTS THAN ANTICIPATED WITH PEMBRO MONOTHERAPY. RESPONDING PATIENTS EXPERIENCED SIGNIFICANTLY INCREASED EFFECTOR MEMORY T CELL ACTIVATION AND REDUCED MONOCYTIC MYELOID-DERIVED SUPPRESSOR CELLS (M-MDSCS) COMPARED TO NON-RESPONDING PATIENTS, LEADING US TO HYPOTHESIZE THAT COMBINATION THERAPY INCREASES RESPONSES BY BOOSTING THE FUNCTION OF TUMOR-REACTIVET CELLS AND DIMINISHING M-MDSC-MEDIATED IMMUNE SUPPRESSION. THESE DATA PROVIDE A STRONG RATIONALE FOR COMPARING THE CLINICAL AND IMMUNOLOGICAL ACTIVITY OF GR-MD-02+PEMBRO VS. PEMBRO MONOTHERAPY IN PATIENTS WITH MM OR HNSCC. THIS RESEARCH IS SIGNIFICANT BECAUSE IMPROVEMENT TO THE ORR AND REDUCTION OF POTENTIAL SIDE EFFECTS ASSOCIATED WITH PEMBRO MONOTHERAPY WILL CONSIDERABLY ENHANCE CLINICAL CARE. OUR OBJECTIVE IS TO PERFORM A RANDOMIZED PHASE II CLINICAL TRIAL TO EVALUATE THE EFFICACY OF GR-MD-02 PLUS PEMBRO COMPARED TO PEMBRO MONOTHERAPY IN PATIENTS WITH MM OR HNSCC. OUR GOALS ARE TO: 1) DETERMINE THE OBJECTIVE RESPONSE OF THIS NOVEL COMBINATION FOR PATIENTS WITH MM OR HNSCC; AND 2) ELUCIDATE THE UNDERLYING MOLECULAR MECHANISMS BY WHICH COMBINED GR-MD-02+PEMBRO IMMUNOTHERAPY AUGMENTS ANTI-TUMOR IMMUNITY AND INFLUENCES GALECTIN-3-INDUCED IMMUNE SUPPRESSION. THESE STUDIES WILL HELP ELUCIDATE THE MECHANISMS FOR THE ANTI-TUMOR EFFECT OF GR-MD- 02+PEMBRO THERAPY, WHICH WILL PROVIDE CRITICAL INSIGHT INTO THE UNDERLYING MECHANISMS BY WHICH COMBINATION THERAPY, IN COMPARISON TO ANTI-PD-1 MONOTHERAPY, SUPPORTS ANTI-TUMOR IMMUNITY.

TARGETING RHEOSTATIC MECHANISMS OF MELANOMA PROGRESSION

(PQ11) TARGETING STING IN THE CONTEXT OF CHEMORADIATION THERAPY TO OVERCOME POOR PREEXISTING IMMUNITY IN MOUSE MODELS OF PANCREATIC CANCER.

TO UNDERSTAND/AUGMENT OX40-MEDIATED TUMOR IMMUNOTHERAPY

REWIRING THE MYELOID CELL RESPONSE TO ADJUVANTS TO IMPROVE TUMOR CONTROL

MECHANISMS THAT REGULATE TUMOR-SPECIFIC IMMUNE RESPONSES

ENHANCING THE EFFICACY OF RADIATION BY SPATIALLY RESTRICTING ANTI-TGFB TREATMENT TO THE TUMOR - PROJECT SUMMARY/ABSTRACT SELF-RENEWING STEM-LIKE CD8+ T CELLS (TSTEM-LIKE), DEFINED BY EXPRESSION OF TRANSCRIPTION FACTOR TCF1/LEF, DWELL IN LYMPHOID TISSUES AND ARE CRITICAL FOR ANTI-TUMOR IMMUNE RESPONSES. THE ROLE OF TSTEM-LIKE CELLS IN LOCAL AND DISTANT RADIATION RESPONSE HAS NOT BEEN DEFINED. PRELIMINARY SINGLE-CELL RNA SEQUENCING DATA DEMONSTRATES TSTEM-LIKE CELLS EXPAND TO REPOPULATE THE TUMOR WITHIN 3 DAYS OF RADIATION. IN OUR FIRST AIM WE WILL DETERMINE WHETHER TSTEM- LIKE CELLS FROM THE TUMOR-DRAINING LYMPH NODE ARE REQUIRED FOR RADIATION RESPONSE. RADIATION AND TRANSFORMING GROWTH FACTOR BETA (TGFΒ) INHIBITION ARE A PROMISING THERAPEUTIC COMBINATION. HOWEVER, TGFΒ HAS OPPOSING EFFECTS IN ANTI-TUMOR CD8+ T CELL DIFFERENTIATION, SUPPORTING TSTEM-LIKE CELLS IN THE TUMOR-DRAINING LYMPH NODE, WHILE SIMULTANEOUSLY PROMOTING EXHAUSTION OF TUMOR-INFILTRATING CD8+ T CELLS. IN AIMS 2 AND 3, WE WILL TEST RADIATION WITH 2ND GENERATION TGFΒ TARGETING THERAPEUTICS THAT SPATIALLY RESTRICT THE ACTIVITY TO THE TUMOR MICROENVIRONMENT AND RELATIVELY SPARE THE TUMOR-DRAINING LYMPH NODE, TO DETERMINE WHETHER SPATIAL RESTRICTION OF TGFΒ INHIBITION IS ABLE TO PRESERVE TSTEM-LIKE CELLS AND THEREBY ENHANCE THE EFFICACY OF COMBINATION THERAPY.

THE IMPORTANCE OF T CELL SURVIVAL IN TUMOR IMMUNITY

TELEHEALTH NETWORK GRANT PROGRAM

PRODUCTION AND CHARACTERIZATION OF A NOVEL OX40 LIGAND FOR CLINICAL USE

PRODUCTION OF A NOVEL 0X40 LIGAND FOR CLINICAL USE

COMMUNITY PROJECT FUNDING/CONGRESSIONALLY DIRECTED SPENDING - CONSTRUCTION

SPATIOTEMPORAL MOLECULAR ELUCIDATION OF RADIATION-INDUCED TUMOR MICROENVIRONMENT REMODELING TO EN-HANCE IMMUNOTHERAPY IN HEAD AND NECK CANCER - PROJECT SUMMARY RECENTLY WE SHOWED IN HNSCC MODELS THAT EFFECTIVE CHECKPOINT BLOCKADE IS DEPENDENT UPON INTACT LYMPHATIC DRAINAGE FOR DENDRITIC CELL TRAFFICKING AND THAT ELECTIVE NODAL RADIATION ABROGATED THE EFFECTIVENESS OF IMMUNOTHERAPY, POSSIBLY EXPLAINING THE LACK OF EFFICACY SEEN IN PRIOR STUDIES. NEOADJUVANT IMMUNOTHERAPY PRESERVES DRAINING LYMPHATICS, HOWEVER, EMERGING TRIALS TESTING PD-1I PRIOR TO SURGERY HAVE DOCUMENTED MAJOR PATHOLOGICAL RESPONSE RATES OF ONLY 5%. TO ENHANCE THE EFFECTIVENESS OF SINGLE AGENT PD-1I, IMPROVE CLINICAL OUTCOMES AND EXPLORE THE IMMUNOMODULATORY CAPACITY OF HYPOFRACTIONATED RADIATION, WE RECENTLY COMPLETED A FIRST IN HUMAN PHASE I TRIAL TESTING NEOADJVUANT IMMUNORADIOTHERAPY (NIRT) IN LOCALLY ADVANCED HPV+ AND HPV- HNSCC PATIENTS. PATIENTS RECEIVED NIVOLUMAB X 3 DOSES IN COMBINATION WITH STEREOTACTIC BODY RADIATION THERAPY (SBRT) TO GROSS TUMOR VOLUME OF 8GY X5 OR 8GY X3, FOLLOWED BY DEFINITIVE SURGICAL RESECTION. ASTONISHINGLY, THE PATHOLOGIC COMPLETE RESPONSE RATE IN HPV+ PATIENTS WAS 90% AND NO PATIENT REQUIRED ADJUVANT RADIATION OR CHEMORADIATION. A COHORT OF 5 PATIENTS WITH STAGE III-IVA HPV-NEGATIVE HNSCC TREATED WITH 8GYX3 PLUS NIVOLUMAB DEMONSTRATED A 60% MAJOR PATHOLOGIC (>25%) RESPONSE AND CLINICAL TO PATHOLOGIC DOWNSTAGING OF 100%. TRANSCRIPTIONAL SIGNATURES FROM THESE SURGICAL SPECIMENS COMPARED TO BASELINE ARE CHARACTERIZED BY INCREASED PHAGOCYTIC AND MACROPHAGE ACTIVATION PATHWAYS, TH1 AND TH2 CELL DIFFERENTIATION, ANTIGEN PRESENTATION AND PEPTIDE LOADING ONTO MHC CLASS I, AS WELL AS A LOSS OF CELL PROLIFERATION PATHWAYS THAT ARE DISTINCTLY DIFFERENT FROM THOSE TREATED WITH RADIATION ALONE, STRONGLY SUGGESTING A SYNERGISTIC EFFECT. GIVEN OUR PREVIOUS WORK SHOWING THAT PROGNOSIS OF PATIENTS WITH HPV- HNSCC IS SIGNIFICANTLY AFFECTED BY SPATIAL INTERACTIONS BETWEEN THE IMMUNE EFFECTOR AND SUPPRESSOR CELLS IN THE TUMOR MICROENVIRONMENT (TME), PARTICULARLY TUMOR-REACTIVE, ANTIGEN-SPECIFIC CD8 T-CELLS, WE HYPOTHESIZE THAT PRESERVATION OF IMMUNOLOGIC FUNCTION IN REGIONAL DRAINING LYMPH NODES DURING NIRT WILL IMPROVE PATHOLOGIC RESPONSE BY ENHANCING ANTI-TUMOR IMMUNE CELL PRIMING, AND THEREBY IMMUNE-MEDIATED KILLING OF TUMOR CELLS. TO TEST THIS HYPOTHESIS, WE RECENTLY LAUNCHED A PHASE 2 NEOADJUVANT CLINICAL TRIAL OF SBRT 8GY X3 + PEMBROLIZUMAB - IN STAGE III-IVA HPV- HNSCC PATIENTS THAT UNIQUELY INCLUDES PREOPERATIVE SENTINEL LYMPH NODE BIOPSY AT THE TIME OF DEFINITIVE SURGERY. THE AIMS OF THESE PROPOSED STUDIES ARE TO 1) DETERMINE WHETHER PATHOLOGIC RESPONSE TO NIRT IS ASSOCIATED WITH IMMUNE CELL ACTIVATION AND PRIMING OF THE ANTI-TUMOR RESPONSE IN THE SENTINEL LYMPH NODES; AND 2) USE RECENTLY DEVELOPED NEXT-GENERATION MULTI-OMIC SPATIOTEMPORAL MODELS TO TEST THE HYPOTHESIS THAT NIRT INDUCES TME REMODELING AND ENHANCES T-CELL INFILTRATION IN PRIMARY HNSCC. SUCCESSFUL COMPLETION OF THESE AIMS WILL ELUCIDATE THE MECHANISMS RESPONSIBLE FOR TUMOR CONTROL IN RESPONDERS AND NON-RESPONDERS, POTENTIALLY LEADING TO THE DEVELOPMENT OF A PREDICTIVE BIOMARKER AND NOVEL TARGETS FOR IMMUNE MODULATION.

OX40 MEDIATED CO-STIMULATION OVERCOMING TUMOR-INDUCED CD8 T CELL PERIPHERAL TOLER

PREVENTION OF METASTATIC CANCER USING A NOVEL VITAMIN E ANALOG

CLINICAL TRIAL OF DRIBBLE VACCINE IN NSCLC

PROVIDENCE HEALTH & SERVICES DBA PROVIDENCE WILLAMETTE FALLS MEDICAL CENTER PROPOSES A THREE-YEAR PROJECT TO INCREASE COMMUNITY CONNECTIONS WITH SANE SERVICES THROUGH BUILDING PARTNERSHIPS WITH COMMUNITY-BASED SEXUAL ASSAULT/DOMESTIC VIOLENCE ADVOCATES IN CLACKAMAS, MULTNOMAH, YAMHILL, CLATSOP, HOOD RIVER AND WASHINGTON COUNTIES IN OREGON. PROPOSAL EXPANDS ON EXISTING PROVIDENCE HEALTH & SERVICES SANE PROGRAMMING IN WASHINGTON AND MULTNOMAH COUNTIES. OUTCOMES INCLUDE COMPREHENSIVE MEDICAL FORENSIC EXAMS; SUBRECIPIENT CO-LOCATING AND MANAGING TWO HOSPITAL-BASED ADVOCATES IN PROVIDENCE WILLAMETTE FALLS MEDICAL CENTER; A MORE FORMAL PARTNERSHIP WITH SUBRECIPIENT TO FORMALLY INTEGRATE COMMUNITY-BASED SEXUAL ASSAULT/DOMESTIC VIOLENCE ADVOCATES WITHIN THE PROVIDENCE FORENSIC NURSE EXAMINER PROGRAM; INCREASED NUMBER AND AVAILABILITY OF SEXUAL ASSAULT NURSE EXAMINERS; IMPROVED ACCESS TO TRAINING AND CLINICAL EDUCATION; AND COORDINATED SEXUAL ASSAULT RESOURCE TEAM. ACTIVITIES AND DELIVERABLES INCLUDE INTEGRATION BETWEEN ENTITIES TO PROVIDE AN ESTIMATED 1,200 FORENSIC EXAMS OVER 3-YEAR PROJECT; WRITTEN POLICIES TO STANDARDIZE CARE; COLLABORATIVE CASE MANAGEMENT AMONG THE FOUR COUNTIES; INFRASTRUCTURE FOR DIRECT COMMUNITY DISPATCH OF FORENSIC NURSE EXAMINERS; TRAINING PLAN DEVELOPED AND IMPLEMENTED FOR SEXUAL ASSAULT NURSE EXAMINERS PROFESSIONAL DEVELOPMENT; AND COLLABORATIVE EFFORTS FOR SEXUAL ASSAULT RESOURCE TEAM ACROSS THE SIX COUNTIES, INCLUDING CULTURALLY SPECIFIC ORGANIZATION INVOLVEMENT SUCH AS FOR THE LATINO/A POPULATION.

EXPLOITING LYMPHOPENIA TO AUGMENT THE ADOPTIVE IMMUNOTHERAPY OF MELANOMA PATIENTS

CONTRIBUTION OF THE INFLAMMASOME TO RADIATION RESPONSE IN PANCREATIC CANCER - PROJECT SUMMARY/ABSTRACT THE CENTRAL THEME OF MY POSTDOCTORAL FELLOWSHIPS HAS BEEN TO INVESTIGATE MECHANISMS BY WHICH MYELOID CELLS ARE RECRUITED AND ACTIVATED TO PROMOTE INFLAMMATION AND IMMUNOSUPPRESSION DURING CANCER. CHRONIC INFLAMMATION IS A RECOGNIZED HALLMARK OF CARCINOGENESIS AND MY RESEARCH FOCUS IS TO IDENTIFY CRITICAL INFLAMMATORY PATHWAYS FOR COMBINATORIAL THERAPEUTIC STRATEGIES, SUCH THAT THE IMMUNE SYSTEM CAN BE HARNESSED FOR ANTITUMOR IMMUNITY. MY CURRENT RESEARCH FOCUS IS ON PANCREATIC CANCER, WHICH IS LARGELY RESISTANT TO CHEMOTHERAPY, RADIATION THERAPY (RT), AND IMMUNE CHECKPOINT BLOCKADE. RT ELICITS AN IMMUNOGENIC CELL DEATH WHEREBY RESIDENT AND RECRUITED LEUKOCYTES RESPOND TO DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS) RELEASED BY DYING CELLS. MACROPHAGES ARE CENTRAL MEDIATORS OF THIS RESPONSE AND RECOGNIZE DAMPS VIA INNATE ADJUVANT SENSORS, INCLUDING THE TOLL-LIKE RECEPTOR (TLR)/MYD88 PATHWAY. SPECIFICITY IN THIS PATHWAY IS REGULATED BY EXPRESSION OF VARIOUS NFB SUBUNITS THAT HOMO- OR HETERODIMERIZE TO DRIVE TRANSCRIPTIONAL PATHWAYS INVOLVED IN IMMUNE ACTIVATION OR IMMUNE SUPPRESSION. MY CURRENT WORK IS TO UNDERSTAND HOW MERTK-DEPENDENT UPREGULATION OF NFB P50 REGULATES MACROPHAGE IMMUNE SUPPRESSION POST-RT, AND SUPPRESSES LOCAL ANTITUMOR IMMUNITY BY REWIRING MACROPHAGE RESPONSE TO ADJUVANT SIGNALS THROUGH MYD88 SIGNALING. THIS PROPOSAL EXTENDS ON THESE FINDINGS TO TEST THE CENTRAL HYPOTHESIS THAT INFLAMMASOME ACTIVATION IN TUMOR- ASSOCIATED MACROPHAGES RESTRICTS RT-INDUCED ANTITUMOR CD8+ T CELL RESPONSES IN PANCREATIC CANCER. AS THE FIRST STEP OF INFLAMMASOME ACTIVATION, MYD88 SIGNALING REGULATES TRANSCRIPTION OF IL1 AND IL18 WHILE THE SECOND STEP INVOLVES ADDITIONAL ACTIVATION OF INFLAMMASOME RECEPTORS BY FACTORS RELEASED BY DYING CELLS IN RESPONSE TO RT. OUR PRELIMINARY DATA IMPLICATE INFLAMMASOME ACTIVATION IN MACROPHAGES AS A CRITICAL MECHANISM REGULATING IMMUNOSUPPRESSION FOLLOWING RT. THUS, WE AIM TO (1) DETERMINE THE FUNCTIONAL SIGNIFICANCE OF INFLAMMASOME ACTIVATION IN RT-MEDIATED TUMOR CLEARANCE AND (2) IDENTIFY INFLAMMASOME SIGNATURES AND PHENOTYPES IN MACROPHAGES RESPONDING TO RT AND DETERMINE WHETHER THIS SIGNATURE CORRELATES WITH POOR OUTCOMES IN PATIENTS. STUDIES UTILIZING LINEAGE-SPECIFIC KNOCKOUT MICE WILL IDENTIFY THE CELL TYPES IN WHICH INFLAMMASOME ACTIVATION OCCURS AND ITS FUNCTIONAL CONSEQUENCES ON REGULATING CD8+ T CELL RESPONSES IN RESPONSE TO RT. MY LONG-TERM CAREER GOAL IS TO BECOME AN INDEPENDENT INVESTIGATOR STUDYING DOMINANT IMMUNE MECHANISMS REGULATING CANCER DEVELOPMENT AND HOW CERTAIN ASPECTS OF INNATE IMMUNITY IMPART BARRIERS TO EFFECTIVE THERAPEUTIC STRATEGIES, INCLUDING BOTH TRADITIONAL CYTOTOXIC AND IMMUNE-BASED THERAPIES. DURING THE K22 AWARD PERIOD I PLAN TO GAIN ADDITIONAL TRAINING TO EXPAND MY SKILL SET IN BIOINFORMATICS, STATISTICS, LAB MANAGEMENT, AND COMMUNICATION SKILLS, AND TO DEVELOP MY INDEPENDENT RESEARCH PROGRAM SO THAT I MAY ESTABLISH A RECORD OF INDEPENDENT RESEARCH PROJECT GRANT PROGRAM FUNDING.

DISSECTING THE ROLES OF FAT1 AND NEAT1 IN SOFT TISSUE SARCOMA DEVELOPMENT AND METASTASIS USING NOVEL IN VIVO SARCOMA MODELS - SOFT TISSUE SARCOMAS (STSS) ARE RARE HETEROGENEOUS MESENCHYMAL TUMORS THAT HAVE MORE THAN 75 SUBTYPES. STSS ARE UNDERSTUDIED TUMORS FOR WHICH THERE ARE FEW ESTABLISHED RESEARCH MODELS AND A LACK OF FUNDING SOURCES. OVER DECADES, THERE HAS BEEN LITTLE IMPROVEMENT IN THE THERAPEUTIC STRATEGIES FOR STSS, WHICH ARE OFTEN RESISTANT TO CURRENT THERAPIES AND CAN BE FREQUENTLY FATAL AS 50% OF PATIENTS DEVELOP METASTASIS IN DISTANT ORGANS. TO SOLVE THIS UNMET CLINICAL PROBLEM, IN VIVO MODELS THAT ACCURATELY RECAPITULATE THIS SPECTRUM OF CANCERS PROVIDE A UNIQUE AND EFFECTIVE PLATFORM FOR STUDYING SARCOMA BIOLOGY AND PRECLINICAL TRIALS BEFORE NOVEL THERAPEUTIC STRATEGIES TRANSLATE TO LIMITED POPULATION OF SARCOMA PATIENTS. HOWEVER, THERE ARE VERY FEW IN VIVO SARCOMA MODELS AVAILABLE BECAUSE THE TUMOR SUPPRESSOR AND ONCOGENIC DRIVERS FOR SARCOMA DEVELOPMENT AND METASTASIS REMAIN UNKNOWN. THEREFORE, I PERFORMED GENOME-WIDE IN VITRO GENETIC SCREENS AND DIRECT IN VIVO CRISPR/CAS9 KNOCKOUT SCREENS IN WILD TYPE MICE TO IDENTIFY DRIVER GENES WHOSE MUTATION IS REQUIRED FOR SARCOMA INITIATION. FROM THESE SCREENS, I GENERATE A NOVEL IN VIVO SARCOMA MODEL DRIVEN BY THE MUTATION OF FAT1 WHICH IS FREQUENTLY MUTATED IN HUMAN STSS. THIS IS A DE NOVO IN VIVO MODEL THAT RECAPITULATES A SUBSET OF HUMAN STSS AND, TO OUR KNOWLEDGE, THE FIRST DETERMINATION THAT FAT1 IS A POTENT TUMOR SUPPRESSOR IN HUMAN STSS. FURTHERMORE, USING IN VIVO SARCOMA MODELS AND HIGH THROUGHPUT RNA SEQUENCING, I ALSO IDENTIFIED THE LONG NON-CODING RNA (LNCRNA) NEAT1 AS AN ONCOGENIC DRIVER FOR SARCOMA METASTASIS. THIS K22 AWARD WILL ALLOW ME TO BUILD MY OWN RESEARCH PLATFORM TO FURTHER CHARACTERIZE THE CRITICAL SIGNALING PATHWAYS AND TARGET GENES IN SARCOMA DEVELOPMENT AND METASTASIS USING THESE UNIQUE IN VIVO SARCOMA MODELS. IN SPECIFIC AIM 1, WE WILL DISSECT THE MECHANISM BY WHICH THE HIPPO PATHWAYS AND THEIR EFFECTORS YAP1/TAZ DRIVE SARCOMAS THROUGH THE MUTATION OF FAT1. IN ADDITION, WE WILL USE MY NOVEL IN VIVO SARCOMA MODELS TO TEST AND OPTIMIZE THE BEST COMBINATION TREATMENT STRATEGIES THAT SUPPRESS SARCOMA TUMOR GROWTH. IN SPECIFIC AIM 2, WE WILL DETERMINE THE MECHANISMS BY WHICH LNCRNA NEAT1 DRIVES SARCOMA METASTASIS. MY PRELIMINARY RESULTS SUGGEST THAT RNA SPLICING REGULATING GENES, SUCH AS KHSRP, INTERACT WITH NEAT1 AND PROMOTE SARCOMA METASTASIS. WE WILL USE MY UNIQUE IN VIVO SARCOMA MODELS TO DISSECT THE MECHANISMS GOVERNING SARCOMA METASTASIS AND THE IMPLICATIONS OF THESE GENES FOR TARGETED THERAPIES IN TREATING METASTATIC SARCOMA PATIENTS. IN CONCLUSION, COMPLETION OF THIS PROPOSAL WILL DETERMINE THE FUNCTIONAL CONSEQUENCES OF EXPRESSION OF THE CODING GENE FAT1 AND THE NON-CODING GENE NEAT1 IN SARCOMA DEVELOPMENT AND METASTASIS AND PROVIDE NOVEL CANDIDATE PATHWAYS AND GENES FOR DESIGNING EFFECTIVE TARGETED THERAPIES TO IMPROVE OUTCOMES FOR SARCOMA PATIENTS.

INCREASING THE POTENCY OF LISTERIA MONOCYTOGENES-BASED VACCINES BY ELIMINATING VACCINE-RELATED GAMMA DELTA T CELL RESPONSES.

UNVEILING THE ORIGIN OF TUMOR-REACTIVE REGULATORY T CELLS IN PATIENTS WITH MISMATCH REPAIR PROFICIENT COLON CANCER - PROJECT SUMMARY THE CRITICAL PRELIMINARY DATA FOR THIS PROPOSAL RELATES TO THE NATURE OF REGULATORY T CELLS (TREG) THAT INFILTRATE TUMORS IN PATIENT WITH COLORECTAL CANCER (CRC) AND THEIR RELATIONSHIP WITH TUMOR-REACTIVE CONVENTIONAL CD4+ T CELLS (CD4+ TCONV). WE DISCOVERED THAT TUMOR-INFILTRATING CD4+ TCONV EXPRESSING PD-1 AND ICOS RECOGNIZE TUMOR ANTIGENS. SUBSEQUENTLY, USING BULK TCR SEQUENCING ON SORTED T CELL POPULATIONS, WE FOUND TCR CLONOTYPES THAT ARE SHARED BETWEEN TUMOR-INFILTRATED PD-1+ICOS+ CD4+ TCONV AND TREGS, SUGGESTING A COMMON ORIGIN. THIS OBSERVATION WAS FURTHER SUPPORTED BY THE PRESENCE OF SHARED TCR CLONOTYPES BETWEEN TUMOR-INFILTRATING CD4 TCONV AND TREGS IN OUR SINGLE CELL RNA SEQUENCING AND SINGLE CELL TCR DATASET FROM 5 CRC PATIENTS. FURTHERMORE, WE OBSERVED THAT IN VITRO EXPANSION OF TUMOR-INFILTRATING TREGS RESULTS IN THE SIGNIFICANT LOSS OF FOXP3 EXPRESSION ON A SUBSET OF CELLS, SUGGESTING THE PRESENCE OF A POPULATION OF UNSTABLE TREGS IN THE TUMOR. WE HYPOTHESIZE THAT SOLUBLE FACTORS PRESENT IN THE TUMOR MICROENVIRONMENT (TME) CAN PROMOTE THE CONVERSION OF TUMOR-REACTIVE CD4+ TCONV INTO TREGS FOLLOWING TCR-MEDIATED ACTIVATION AND THAT THIS TREG PHENOTYPE IS UNSTABLE AND CAN BE REVERSED BY EFFECTOR CYTOKINES. THE SPECIFIC AIMS OF THIS STUDY ARE TO 1: ASSESS CONVERSION OF TUMOR-REACTIVE CD4+ TCONV INTO TUMOR-INDUCED TREG IN CRC TUMORS; 2: IDENTIFY THE FACTORS THAT REGULATE CD4+ TCONV TO TREG PLASTICITY. OUR STUDY DESIGN INCORPORATES THE USE OF SINGLE CELL RNA SEQUENCING, SINGLE CELL TCR SEQUENCING AND TOTALSEQ TO APPREHEND THE COMPLEXITY OF THE CD4+ TCONV AND TREG COMPARTMENTS IN CRC TUMORS. THESE RESULTS WILL PROVIDE ESSENTIAL INFORMATION REGARDING THE ORIGIN OF TUMOR- INFILTRATING TREGS AND HIGHLIGHT THE LEVEL OF CD4 T CELL PLASTICITY IN TUMORS. ANALYSIS OF THE TCR REPERTOIRE OF BLOOD MEMORY CD4+ TCONV AND TREG WILL FURTHER DEFINE IF CD4+ TCONV CONVERT INTO TREG IN THE TME. TO DETERMINE IF THIS PHENOMENON IS ASSOCIATED WITH TUMOR REACTIVITY, WE WILL CLONE THE TCRS SHARED BETWEEN CD4+ TCONV AND TREG AND INTRODUCED THEM INTO AUTOLOGOUS CD4+ TCONV TO DETERMINE WHETHER THEY RECOGNIZE TUMOR-SPECIFIC SOMATIC MUTATIONS IDENTIFIED BY WHOLE EXOME SEQUENCING AND RNA SEQUENCING. TO IDENTIFY EXTRACELLULAR SOLUBLE FACTORS THAT COULD PARTICIPATE IN THE CD4+ TCONV TO TREG CONVERSION, WE WILL ANALYZE THE COMPOSITION OF THE TUMOR SECRETOME DIRECTLY EX VIVO USING THE OLINK PLATFORM. WE WILL DETERMINE THE SPATIAL DISTRIBUTION OF THE CELLS SECRETING THOSE FACTORS AND THEIR RELATIONSHIP WITH CD4+ TCONV AND TREGS IN THE TME USING SEQUENTIAL IMMUNOFLUORESCENCE AND RNASCOPE. WE WILL EVALUATE IF THE IDENTIFIED FACTORS CAN PROMOTE CD4+ TCONV TO TREG CONVERSION IN VITRO AND WHETHER THEY SYNERGIZE WITH THE IMMUNOSUPPRESSIVE CYTOKINE TGF-Β. FINALLY, WE WILL DETERMINE THE STABILITY OF TUMOR-INDUCED TREGS AND WHETHER THIS TREG PHENOTYPE CAN BE REVERTED BY EFFECTOR CYTOKINES. THE FINDINGS FROM THIS PROPOSAL WILL REVEAL IF THE CONVERSION OF TUMOR-REACTIVE CD4+ T CELLS INTO TREGS OCCURS IN CRC TUMORS. IF OUR PROPOSAL IS SUCCESSFUL, IT WILL PROVIDE AN OUTSTANDING OPPORTUNITY TO BOTH REMOVE A NEGATIVE SIGNAL AND DELIVER A POSITIVE SIGNAL BY PREVENTING CONVERSION (OR REVERSING IT), WHICH MAY BE SUPERIOR TO SIMPLE TREG DEPLETION.

ELUCIDATING THE ROLE OF INTRATUMORAL MICROBIOTA ON IMMUNOTHERAPY EFFICACY - PROJECT SUMMARY/ABSTRACT MICROBES LIVE IN PRIMARY TUMORS ACROSS ORGAN SYSTEMS AND IN TUMOR METASTASES, MAKING THE MICROBES AN INTRINSIC AND ESSENTIAL COMPONENT OF THE TUMOR MICROENVIRONMENT, YET WHAT TYPES OF MICROBES RESIDE IN TUMORS AND HOW THEY CONTRIBUTE TO THE TUMOR MICROENVIRONMENT, T CELL FUNCTION, AND IMMUNOTHERAPY RESPONSE ARE UNKNOWN. WE MODELED ESTIMATED TUMOR BACTERIAL BURDEN AGAINST THE KNOWN OBJECTIVE RESPONSE RATE TO IMMUNOTHERAPY ACROSS TUMOR TYPES AND OBSERVED A REMARKABLE CORRELATION BETWEEN HIGH BACTERIAL BURDEN AND HIGH RESPONSE RATES TO IMMUNOTHERAPY, SUGGESTING THAT THE COMMUNITY OF MICROBES IN THE TUMOR, OR TUMOR MICROBIOTA, PLAYS A PIVOTAL ROLE IN INFLUENCING THE RESPONSE RATE TO IMMUNOTHERAPY. OUR PRELIMINARY DATA SUPPORTS THIS HYPOTHESIS, SHOWING THAT INCREASED NUMBERS OF MICROBIAL SPECIES IN TUMOR MICROBIOTA CORRELATE WITH INCREASED NUMBERS OF IMMUNE CELLS IN THE TUMOR AND RESPONSE TO IMMUNOTHERAPY IN HEAD AND NECK SQUAMOUS CELL CARCINOMA PATIENTS. HOWEVER, THE MICROBIAL COMPOSITION OF AND THE MECHANISMS BY WHICH INTRATUMORAL MICROBIOTA INFLUENCE THESE CLINICAL OUTCOMES ARE CURRENTLY UNKNOWN. WHILE INTRATUMORAL MICROBIOTA COMMUNITIES REMAIN A MYSTERY, RECENT STUDIES HAVE IMPLICATED THE INFLUENCE OF INTESTINAL MICROBIOTA ON IMMUNOTHERAPY OUTCOME, WHEREBY RESPONDING PATIENTS HARBOR SPECIFIC INTESTINAL MICROBIAL COMMUNITIES ASSOCIATED WITH ENHANCED SYSTEMIC IMMUNITY AND INTRATUMORAL IMMUNE INFILTRATION. INTERESTINGLY, MICROBES FROM THE GASTROINTESTINAL TRACT TRAFFIC TO DISTANT TUMORS, THUS POTENTIALLY SEEDING THE INTRATUMORAL MICROBIOTA. FOR EXAMPLE, BIFIDOBACTERIA, A BACTERIAL GENERA ASSOCIATED WITH IMMUNOTHERAPY EFFICACY, IS KNOWN TO TRANSLOCATE FROM THE INTESTINE TO DISTANT TUMORS. THUS, INTESTINAL MICROBIOTA MAY INFLUENCE IMMUNOTHERAPY RESPONSE THROUGH MICROBIAL DISSEMINATION TO TUMORS. HEREIN WE PROPOSE TO TEST WHETHER INTESTINAL MICROBES ASSOCIATED WITH IMMUNOTHERAPY EFFICACY PROMOTE BACTERIAL OR BACTERIAL PRODUCT TRANSLOCATION FROM THE INTESTINE TO THE LYMPH NODES AND/OR TUMOR. FURTHER, WE AIM TO UNCOVER UNIQUE MECHANISMS BY WHICH INTRATUMORAL MICROBIOTA, THROUGH EITHER DIRECT IMMUNE CELL INTERACTION OR THE MODULATION OF TUMOR MICROENVIRONMENT, INFLUENCE IMMUNOTHERAPY EFFICACY. THIS KNOWLEDGE MAY UNCOVER UNIQUE OPPORTUNITIES TO DEVELOP NEW THERAPEUTIC OPTIONS FOR PATIENTS WITH CANCER, EITHER BEFORE STANDARD OF CARE TREATMENTS OR SYNERGISTICALLY THROUGH AUGMENTATION OF CURRENT IMMUNOTHERAPY REGIMENS. TOWARD THIS END, WE HOPE TO LEVERAGE THE KNOWLEDGE WE GAIN FROM THIS PROPOSAL WITH RESPECT TO INTRATUMORAL MICROBIOTA TO DEVELOP BACTERIAL DRUGS IN THE LOCALIZED, INTRATUMORAL SETTING THUS MINIMIZING SYSTEMIC EFFECTS OF POTENTIALLY DETRIMENTAL DISRUPTIONS TO INTESTINAL MICROBIAL COMMUNITIES. THUS, OUR MECHANISTIC APPROACH HAS THE POTENTIAL TO LEAD TO INNOVATIVE MICROBIOME-BASED TREATMENTS THAT MAY INCREASE THE NUMBER OF PATIENTS RESPONDING TO IMMUNOTHERAPY.

DNASE1L3 REGULATION OF ANTI-TUMOR IMMUNE RESPONSES FOLLOWING RADIATION THERAPY - PROJECT SUMMARY THE CRITICAL PRELIMINARY DATA FOR THIS PROPOSAL RELATES TO DENDRITIC CELLS, A CRITICAL IMMUNE CELL THAT LINKS INNATE DETECTION OF INFECTION TO ADAPTIVE IMMUNE RESPONSES THAT CAN UNIQUELY TARGET AND DESTROY TARGETS. THESE SAME PRINCIPLES APPLY TO INITIATE AND CONTROL IMMUNE RESPONSES TO CANCER. WE DISCOVERED THAT IN TUMORS THAT ARE UNABLE TO GENERATE ADAPTIVE IMMUNITY TO ASSIST IN TUMOR CURE FOLLOWING RADIATION THERAPY, DENDRITIC CELLS FAIL TO MATURE. THESE DENDRITIC CELLS THAT FAIL TO MATURE EXPRESS A NOVEL TARGET GENE CALLED DNASE1L3, WHICH HAS BEEN SHOWN TO NEGATIVELY REGULATE INNATE STIMULI, AND TO NEGATIVELY REGULATE AUTOIMMUNE RESPONSES. THIS PROPOSAL IS AN INNOVATIVE INVESTIGATION INTO THE ROLE OF THIS GENE IN ANTI-TUMOR IMMUNITY, AND THE MECHANISMS BY WHICH IT IS REGULATED IN DENDRITIC CELLS IN TUMORS. WE HYPOTHESIZE THAT DNASE1L3 REPRESSES INNATE AND ADAPTIVE IMMUNE RESPONSES IN THE TUMOR ENVIRONMENT. THE SPECIFIC AIMS OF THIS STUDY ARE TO 1: DETERMINE THE CONSEQUENCE OF MYELOID EXPRESSION OF DNASE1L3 ON THE IMMUNE RESPONSE TO RADIATION THERAPY; 2: UNBIASED ANALYSIS OF THE CONSEQUENCE OF MYELOID EXPRESSION OF DNASE1L3 ON THE TUMOR IMMUNE ENVIRONMENT FOLLOWING RADIATION THERAPY. OUR STUDY DESIGN INCORPORATES CT- GUIDED RADIATION THERAPY OF MULTIPLE AUTHENTIC PANCREATIC TUMOR MODELS AND USING A RANGE OF RT DOSES AND FRACTIONATIONS. THESE ARE COMBINED WITH UNIQUE KNOCKOUTS AND ASSAYS THAT ALLOW US TO IDENTIFY DIVERGENT RESPONSES IN VITRO AND IN VIVO. OUR ANALYSES OF CLINICAL SAMPLES USE HIGH QUALITY BIOINFORMATIC APPROACHES THAT ALLOW US TO EVALUATE EFFECT OF THE TUMOR ENVIRONMENT ON THE BIOLOGICAL RESPONSE TO INNATE ADJUVANTS IN PATIENT SAMPLES.

CURING MODELS FOR PHOTOACTIVATED RESIN COMPOSITES

CHARACTERIZING AND REGULATING TUMOR-INDUCED REGULATORY T CELLS

DOCKING DRIBBLES TO DENDRITIC CELLS VIA C-TYPE LECTIN RECEPTORS

CLINICAL AND IMMUNOLOGICAL EFFECTS OF SBRT AND IL-2 IN METASTATIC MELANOMA

DLT GRANTS - SUBSTANCE USE DISORDER - MEDICAL

IPILIMUMAB PLUS A GALECTIN-3 INHIBITOR FOR METASTATIC MELANOMA

ARRA - EQUIPMENT TO ENHANCE TRAINING FOR HEALTH PROFESSIONALS

IMMUNOTHERAPY WITH DENDRITIC-ALLOGENEIC TUMOR CELLS

SYNERGY OF SOCS-1 INHIBITION AND MICROBIAL-BASED CANCER VACCINES

PACIFIC NORTHWEST MULTIPLE SCELROSIS REGISTRY AND NETWORK

TELEMEDICINE GRANT

DEVELOP A PET RADIOTRACER SUITABLE FOR IN VIVO IMAGING OF TGFΒ - PROJECT SUMMARY/ABSTRACT TRANSCRIPTION GROWTH FACTOR BETA (TGFΒ) IS A PLEIOTROPIC CYTOKINE WITH A SIGNIFICANT ROLE IN CREATING AN IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT. HIGH LEVELS OF TGFΒ ARE STRONGLY ASSOCIATED WITH POOR CANCER PROGNOSIS, BUT THERE ARE CURRENTLY NO NON-INVASIVE METHODS AVAILABLE TO QUANTIFY THE CYTOKINE IN VIVO. THIS PROPOSAL DESCRIBES THE DESIGN AND EVALUATION OF A NOVEL BIOLOGIC POSITRON EMISSION TOMOGRAPHY (PET) RADIOTRACER TO SELECTIVELY AND QUANTITATIVELY DETECT TGFΒ IN VIVO. THE PROPOSED BIOLOGIC CONSTRUCT IS A RECOMBINANT PROTEIN INCORPORATING THE EXTRACELLULAR DOMAIN OF HUMAN TGFΒ RECEPTOR II (TΒRII) LINKED TO THE FC FRAGMENT OF HUMAN IGG2 VIA THE ANTIBODY HINGE REGION. THIS RECOMBINANT PROTEIN WAS FURTHER MODIFIED BY APPENDING 1,4,7- TRIAZACYCLONONANE-1,4,7-TRIACETIC ACID (NOTA) COPPER CHELATOR VIA A P-SCN-BN REACTIVE MOIETY. THE RESULTING PRECURSOR MOLECULE WILL BE LABELED WITH 64CU TO PRODUCE THE ACTIVE RADIOTRACER, 64CU-FC:TΒRII. THE 64CU-FC:TΒRII RADIOTRACER WILL BE EVALUATED FOR PRECLINICAL EFFICACY BY IMAGING MICE USING SMALL ANIMAL PET-MRI. THIS PROPOSAL AIMS TO ASSESS THE EFFICACY OF 64CU-FC:TΒRII INCLUDING A DOSE TITRATION EXPERIMENT TO DETERMINE THE OPTIMAL DOSAGE AND INCUBATION TIME FOR THE RADIOTRACER, A BLOCKING STUDY, A COMPARISON OF IN VIVO PET STANDARDIZED UPTAKE VALUES (SUVS) WITH EX VIVO TUMOR LYSATE TGFΒ CONCENTRATIONS IN FOUR MURINE TUMOR MODELS, AND AN EXPERIMENT TO DETECT CHANGES IN TGFΒ EXPRESSION BEFORE AND AFTER RADIATION THERAPY.

GENERATION OF A NOVEL FUSION PROTEIN TO REDIRECT MACROPHAGE DIFFERENTIATION FOLLOWING RADIATION THERAPY.

OX40 MEDIATED CO-STIMULATION OVERCOMING TUMOR-INDUCED CD8 T CELL PERIPHERAL TOLER

TELEMEDICINE GRANT

ASSESSING THE IMPACT OF FINANCIAL INCENTIVES ON PROVISION OF INTERPRETIVE SERVICES IN MEDICAID - PROJECT SUMMARY/ABSTRACT BROAD ACCESS TO PROFESSIONAL INTERPRETIVE SERVICES IS A FUNDAMENTAL FIRST STEP IN IMPROVING ACCESS TO CARE FOR PEOPLE FACING LANGUAGE BARRIERS, INCLUDING INDIVIDUALS WHOSE PRIMARY PREFERRED LANGUAGE IS NOT ENGLISH AND THOSE WHO ARE DEAF OR HARD OF HEARING. FOR TOO LONG, THE U.S. HEALTH CARE SYSTEM HAS PRODUCED SIGNIFICANT DISPARITIES IN ACCESS, QUALITY, AND OUTCOMES FOR INDIVIDUALS WITH NON-ENGLISH LANGUAGE PREFERENCE (NELP). RESEARCH DEMONSTRATES THAT INDIVIDUALS WITH NELP HAVE DECREASED ACCESS TO HEALTH INSURANCE AND EXPERIENCE LONGER LENGTHS OF STAY IN THE HOSPITAL, HIGHER READMISSION RATES, POORER MANAGEMENT OF CHRONIC DISEASE, GREATER RISK OF ADVERSE EVENTS, AND LOWER SATISFACTION WITH THEIR CARE. FEDERAL POLICY MANDATES ACCESS TO INTERPRETIVE SERVICES BUT DOES NOT MANDATE THAT PAYERS REIMBURSE FOR INTERPRETATION, LEAVING MANY HEALTH CARE SYSTEMS ILL- EQUIPPED TO PROVIDE CARE TO NELP PATIENTS. AS PART OF ITS COMMITMENT TO HEALTH EQUITY, OREGON’S MEDICAID PROGRAM RECENTLY INTRODUCED AN INNOVATIVE FINANCIAL INCENTIVE TO INCREASE ACCESS TO INTERPRETIVE SERVICES. THE LONG-TERM GOAL OF THIS RESEARCH IS TO UNDERSTAND THE EXTENT TO WHICH FINANCIAL INCENTIVES FOCUSED ON HEALTH EQUITY CAN CHANGE SYSTEMS, AND TO CHARACTERIZE THE DOWNSTREAM IMPACT OF THESE POLICIES ON EXPERIENCES WITH AND PERCEPTIONS AND QUALITY OF HEALTH CARE. OUR SPECIFIC AIMS, WHICH ARE THE FIRST STEPS TOWARD ATTAINMENT OF THIS LONG-TERM GOAL, ARE TO (1) EXAMINE CHANGES IN THE FREQUENCY OF USE OF INTERPRETIVE SERVICES AMONG MEDICAID MEMBERS WITH NELP AFTER IMPLEMENTATION OF OREGON’S INCENTIVE POLICY FOR INTERPRETIVE SERVICES, AND (2) ASSESS DIFFERENCES IN USE OF INTERPRETIVE SERVICES BY SETTING, TYPE OF CARE, MODALITY OF INTERPRETATION, INTERPRETER TYPE, AND POPULATION. THIS STUDY WILL USE A LONGITUDINAL DESIGN TO UNDERSTAND THE IMPACT OF OREGON’S LANGUAGE ACCESS INCENTIVE POLICY ON RECEIPT OF INTERPRETIVE SERVICES AMONG MEDICAID MEMBERS WITH NELP. WE WILL USE QUARTERLY REPORTS SUBMITTED BY COORDINATED CARE ORGANIZATIONS (CCOS, OREGON’S MEDICAID MANAGED CARE ENTITIES) TO ASSESS CHANGES IN THE PROPORTION OF MEMBERS WITH A DOCUMENTED NEED FOR INTERPRETIVE SERVICES WHO RECEIVE THESE SERVICES, THE PROPORTION OF VISITS AMONG NELP MEDICAID MEMBERS AT WHICH INTERPRETATION WAS PROVIDED, AND THE YEARLY AVERAGE NUMBER OF VISITS WITH INTERPRETIVE SERVICES PER MEMBER WITH A FLAGGED NEED. IN ADDITION, WE WILL USE A COMPARATIVE INTERRUPTED TIME SERIES (CITS) APPROACH TO ANALYZE CHANGES OVER TIME IN THE PROPORTION OF FLAGGED MEDICAID MEMBERS RECEIVING INTERPRETIVE SERVICES ACROSS DIFFERENT SETTINGS, TYPES OF CARE, AND POPULATIONS. ULTIMATELY, BETTER UNDERSTANDING OF ACCESS TO INTERPRETIVE SERVICES IS A CRITICAL STEP IN EFFORTS TO REMOVE STRUCTURAL INEQUITIES, ENHANCE QUALITY OF HEALTH CARE, AND IMPROVE OUTCOMES.

RURAL HEALTH NETWORK DEVELOPMENT PLANNING GRANT PROGRAM

TELEMEDICINE GRANT

TELEMEDICINE GRANT