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Long-term Cardiometabolic Disease in COVID-19

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Background: People with COVID-19 have increased risk of death and cardiometabolic disease including cardiovascular disease, diabetes mellitus, dyslipidemia and kidney disease. However, the evidence base is limited in 3 key aspects: (1) Existing studies have characterized the risks of adverse outcomes associated with earlier variants of SARS-CoV-2 and have limited follow-up. (2) It is not clear whether an annual vaccination for COVID-19 beyond the third dose reduces risk of adverse events. (3) Comparative analyses of COVID-19 vs. influenza are helpful to benchmarking risks but are only available for earlier variants and for limited follow up. Significance/Impact: Our proposal aims to answer key questions that are critical to guiding public health policy – including 1) characterizing short- and long-term risks of old, new and yet to emerge variants and subvariants of SARS-CoV-2 (proxied by the era in which they predominate); 2) on an ongoing annual basis, evaluate the effectiveness of COVID-19 vaccines in reducing risks of adverse health outcomes; and 3) on an ongoing basis, provide a comparative assessment of COVID-19 vs seasonal influenza. The proposal is specifically designed to address several key research questions outlined in the US Government National Research Action Plan on Long Covid. The results will have direct and substantial real-world impact in informing policy and clinical care. Innovation: The proposal leverages the unique power of the VA’s large-scale electronic health records and recent methodologic innovations in causal inference and clinical epidemiology to expand the evidence base about the health effects of COVID-19 and the role of vaccines. Specific Aims: To use healthcare data from the VA to: (1) characterize the acute and long-term risks of death and cardiometabolic disease in people with COVID-19 from 2020-2029, cohorted into variant-predominant eras, versus a matched historical control; (2) evaluate the effectiveness of receipt of the COVID-19 vaccine in each year (from 2022-2029) in reducing risk adverse health outcomes in the 12 months after receipt of the vaccine; and (3) comparatively evaluate the acute and long-term risks of death and cardiometabolic disease in people hospitalized for COVID-19, cohorted into variant-predominant eras, versus those hospitalized for seasonal influenza in each influenza season (from 2020 to 2029). Methodologies: VA electronic health record data will be used to construct independent cohorts for each aim and outcome being examined. COVID-19 test results and vaccination data will be collected form the COVID-19 Shared Data Resource, VA laboratory data and Medicare data. Incident outcome definitions validated for use with EHR data will be used. Inverse probability weighing will be used to balance for individual-level patient characteristics (predefined and algorithmically selected covariates), contextual characteristics, and characteristics related to the pandemic. Censoring weights will additionally be used to address situations that may result in informative loss to follow- up. Survival and mixed effect regression models will then be used to estimate differences in risk of outcomes between the COVID-19 exposure group of interest and reference groups, and estimates will be reported as hazard ratios and adjusted incidence rates, or differences in slopes. Implementation/Next Steps: Results from this proposal will inform public health policies (e.g. vaccine policies) and clinical care. Future studies will investigate optimizing care of people with cardiometabolic disease.

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United States Department of Veterans Affairs

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Mechanistic characterization of JNK2α variants in alcohol-caused heart failure

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National Institute on Alcohol Abuse and Alcoholism (NIAAA)

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Long-term excessive alcohol consumption leads to a significant prevalence of alcoholic cardiomyopathy (ACM) that is characterized by impaired cardiac function (heart failure, HF) in the absence of other cardiovascular diseases. During the COVID-19 pandemic, increased alcohol consumption due to social isolation has magnified the serious problem. Clinically, ACM is a leading cause of non-ischemic dilated cardiomyopathy increasing mortality and morbidity and puts a tremendous economic burden on our healthcare system. Sarcoplasmic reticulum (SR) Ca2+ ([Ca2+]SR) mishandling is known to play a key role in cardiac hypertrophy and HF development. The SR Ca2+ pump, SERCA2, is essential in [Ca2+]SR handling and reduced SERCA2 expression leading to depleted [Ca2+]SR load is a hallmark of HF. However, failed clinical trials of SERCA2 gene therapy in HF patients suggests that increasing the abundance of SERCA2 per se is insufficient to reverse HF. Although alcohol abuse is a significant risk factor for HF, it can take many years for an alcoholic individual undergoing adaptive cardiac changes with normal function to reach the point of ACM. The underlying mechanisms remain unclear to date. The goal of this proposal is to fill this knowledge gap by exploring a previously unknown mechanism of alcohol activated JNK2 acting as a driver of ACM onset. Our pilot findings show that JNK2, but not JNK1, is critical in alcohol-caused cardiac remodeling via a dynamic regulation of JNK2α variants in augmented SERCA2 pump activity (adaptive) followed by suppressed SERCA2 transcriptional activity (maladaptive). Our lab recently reported a critical role of JNK2 (not JNK1) in enhanced [Ca2+]SR uptake/load via enhanced SERCA2 activity. Aim 1 here will detail how JNK2 interacts/phosphorylates SERCA2 to augment its pump activity as an adaptive response to long-term alcohol exposure. JNK2 has multiple splicing variants (i.e. α, β). We identified that α1, α2, β2 (but not β1) are predominantly expressed in the human heart. And we found significantly increased JNK2α2, but reduced JNK2α1 correlated with reduced SERCA2 expression in human ACM LVs, while increased JNK2α2 suppressed the SERCA2 promoter activity, which is likely due to hypermethylated SERCA2 promoter through JNK2α2-upregulated DNA methyltransferase DNMT1 transcription activity. Thus, Aim 2 will define how JNK2α2 suppresses SERCA2 expression and onsets ACM, and test the translational potentials of blocking the JNK2α2 actions as an anti-ACM therapeutic strategy. Our multi-discipline team will use a unique combination of cutting-edge approaches (protein-SR-myocyte-heart-animal, in vitro to ex vivo to in vivo) including a novel battery of cardiac-specific JNK2α2 mouse models (JNK2act, MKK7D, MKK7D-JNK2dn, JNK2dn), in vivo gene transfer, and biochemical/proteomic/CUT&Tag-Seq/bioinformatics analyses to systematically fulfill the two Specific Aims. The scientific premise of this innovative proposal is strong given the integration of targeted functional measurements and paired with mechanistic experimental designs along with appropriate alternative approaches. Anticipated outcomes from the mechanistic and proof-of-concept translational studies will reveal causal role of JNK2α in ACM onset and provide translational insight into modulating JNK2α variants as a prospective anti-HF intervention.

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Optimizing methadone treatment strategies for opioid use disorder in the era of fentanyl

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Treatment with medications for opioid use disorder is a critical intervention with proven effectiveness for improving morbidity, mortality and quality of life, yet only a minority of patients with an opioid use disorder are engaged in treatment and ongoing use of fentanyl during treatment is common. Current methadone treatment protocols were developed and validated based on studies performed in populations with heroin use, with a focus on diversion prevention and minimizing overdose risk. A deadlier drug supply dominated by fentanyl has altered this risk-benefit assessment and evidence-based updates are urgently needed. Challenges of methadone initiation and maintenance in patients with fentanyl use are well-documented. Inadequate control of withdrawal and cravings at standard methadone doses due to higher levels of opioid tolerance and physical dependence in individuals with a history of fentanyl use may contribute to ongoing use of non-prescribed opioids and increased overdose risk. Failure to reach a therapeutic dose expediently can result in a perceived lack of efficacy, adding additional barriers to treatment engagement and retention. In response, some addiction medicine specialists have suggested that accelerated initiation trajectories combined with higher maintenance doses are needed, but there are no standardized protocols for patients using fentanyl and wide variability in methadone dispensing practice. Limited data suggest that higher doses and expanded ‘take-homes’ among people with a history of fentanyl use do not contribute to excess deaths from methadone, but these studies lack longitudinal patient-level effectiveness and safety data to draw firm conclusions to support practice change. This study seeks to evaluate the effectiveness and safety of different methadone treatment strategies, including dosing and expanded take- home flexibilities associated with the COVID-19 pandemic, on treatment retention and non-fatal/fatal overdose in a retrospective cohort of patients (n~10,000) initiating medication treatment for an opioid use disorder with methadone in the fentanyl era. The data-rich environment in Rhode Island and established relationships with non-profit opioid treatment programs and state agencies will be leveraged to assemble a single, comprehensive, longitudinal novel dataset that will include both electronic health record data (detailed patient characteristics and methadone dispensing data) and state administrative data (with emergency medical services and emergency department visits for non-fatal opioid overdose, medical examiner records for fatal overdoses, corrections, and controlled substance prescribing information) Results of this study will help resolve long-standing questions about the optimal methadone dosing strategies and directly inform opioid use disorder clinical treatment best practices for patients who use fentanyl, thereby reducing the risk of overdose and improving treatment retention.

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CTO1681 to prevent and mitigate cytokine release syndrome in multiple myeloma patients receiving CAR T-cell therapy

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CytoAgents is developing CTO1681 for the prevention and treatment of cytokine release syndrome (CRS) associated with chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy has emerged as a very promising treatment option for patients with relapsed or refractory (R/R) hematologic malignancies. However, CAR T-cell therapy can also result in a high incidence of severe and potentially life-threatening immune-mediated toxicity, including CRS and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is a systemic inflammatory response that has been reported as one of the most frequent and dangerous adverse events following CD19-directed CAR T-cell therapy. CRS is thought to be mediated by an initial release of proinflammatory cytokines, which activate bystander immune cells and endothelial cells, which in turn activate more immune cells, culminating in a cytokine storm. Because CytoAgents’ novel approach is focused on reducing the transcription of multiple proinflammatory cytokines, its compound is expected to mitigate, and in some cases even prevent, CRS. CTO1681 is an orally available, stable compound identical to beraprost sodium-314d (BPS-314d), the stereoisomer of the racemate beraprost sodium (BPS) that accounts for nearly all of BPS’s pharmacological activity. Because BPS can modulate the release of cytokines from human peripheral blood mononuclear cells, CytoAgents has investigated the use of BPS and its active isomer CTO1681 as a treatment for moderate virus-induced CRS, specifically influenza and COVID-19. All of the results to date indicate that CTO1681 has strong potential to reduce the CRS response, leading to better patient outcomes regardless of CRS etiology. Overall, BPS, BPS-314d, and CTO1681 formulations have been found to be well tolerated and to not completely suppress cytokine levels in healthy volunteers with normal serum levels. CytoAgents is currently conducting a Phase 1b trial of CTO1681, a multicenter, open-label, dose-escalating safety and pharmacokinetic (PK) MAD study in patients with diffuse large B cell lymphoma (DLBCL) receiving CD19- directed CAR T-cell therapy. This Direct to Phase II project will support additional drug manufacturing and initiation of an open-label Phase 2a trial in multiple myeloma (MM) patients. The company will undertake three specific aims: 1) Determine the preliminary efficacy of CTO1681 in preventing or reducing CRS or ICANS compared to historical data; 2) Determine the expanded safety profile of CTO1681 in patients with R/R MM receiving CAR T-cell therapy; 3) Investigate the potential impact of CTO1681 on antitumor activity of CAR T-cell therapy compared to historical data. This project will help support clinical assessment of CTO1681 in CAR T-cell therapy recipients, advancing a novel treatment with the potential to reduce hospitalization, intensity of supportive care, and mortality and to improve patients’ quality of life. Moreover, this therapeutic may allow more patients with R/R hematologic malignancies to have access to potentially life-saving CAR T-cell treatment.

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Small Business Innovation Research Grant

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large cell Diffuse non-Hodgkin's lymphoma

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Development of Novel RhoA Nitration Inhibitory Peptides for the Treatment of Acute Lung Injury

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National Heart Lung and Blood Institute (NHLBI)

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) manifest with acute lung inflammation with increased vascular permeability. Treatment of ALI/ARDS patients with low-volume mechanical ventilation is the only proven therapy for ALI/ARDS, and mortality rates remain unacceptable. Because the syndrome of acute respiratory failure is so common in the United States and worldwide, especially in the face of relatively new respiratory viruses such as SARS-CoV-2, ALI/ARDS is an unmet medical need. Novel pharmacological therapies need to be developed to further improve clinical outcomes in ALI/ARDS patients. RhoA and Rac1 exert distinct effects on epithelial and endothelial barrier function via selective structural and biochemical modulation of junctional proteins. Rac1 and RhoA have antagonistic effects on endothelial barrier function in the lung. Rac1 is required for the assembly and maturation of endothelial junctions, whereas RhoA destabilizes endothelial junctions by increasing the isometric tension at the cell membrane, increasing myosin contractility. Our prior studies have linked RhoA nitration at (Tyr (Y)34) with its activation, endothelial barrier disruption, the disruption of mitochondrial network dynamics, mitochondrial function, and the activation of NF-kb dependent inflammation. A strategy has been designed to shield RhoA from nitration at Y34, protect endothelial barrier function, preserve mitochondrial function, and reduce inflammation during conditions that can cause ALI/ARDS. This strategy identified a small peptide, NipR1, which protects RhoA from nitration at Y34 and prevents LPS-induced peroxynitrite attack. NipR1 contains nine amino acids from 31–39 of RhoA fused with the cell-permeable TAT sequence. Natural peptides have poor absorption, distribution, metabolism, and excretion (ADME) properties with rapid clearance, short half-life, low permeability, and sometimes low solubility. Thus, in response to this special NHLBI RFA, a chemical approach will be utilized to identify more potent peptidomimetics of NipR1. In the R61 phase, we will generate ~100 compounds based on our newly identified pharmacophores and screen them using both in vitro and in vivo assays in multiple mouse models of ALI. In the R33 phase, we will generate two optimized NipR1 derivatives, conduct pharmacokinetics/pharmacodynamics (PK/PD) and safety studies, and confirm therapeutic effects using a pig model of sepsis. We anticipate these studies will allow us to identify a lead compound with desired in vitro and in vivo characteristics as a novel therapy for ALI/ARDS.

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National Heart  Lung  and Blood Institute

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Impact of 12-month Postpartum Insurance Extensions on Maternal and Newborn Health

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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

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UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA

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The United States is experiencing a maternal health crisis. Maternal mortality and severe maternal morbidity (SMM) affect around 700 and 60,000 women, respectively, every year, and the numbers are increasing. Hidden in these averages are disparities with Black and American Indian women, women on Medicaid insurance, and women residing in rural areas bearing the disproportionate burden of maternal mortality and SMM. Over half of these maternal deaths occur in the postpartum period with maternal mortality and SMM remaining well elevated beyond 42 days postpartum. The postpartum period is a critical period for addressing maternal mortality and SMM and this has been endorsed by professional organizations emphasizing the importance of postpartum care being an ongoing process rather than a single encounter. However, use of postpartum care is deficient even for high-risk patients. As a result, maternal outcomes are suboptimal and result in excess harm. One reason for this inadequate use of recommended care is typical coverage limits on Medicaid insurance for pregnancy. Traditionally, Medicaid provides pregnancy related coverage for eligible recipients through 60 days postpartum. After that, many beneficiaries lose coverage restricting access to postpartum care. During the COVID-19 pandemic, the Families First Coronavirus Response Act halted Medicaid disenrollments since March 2020 resulting in continuous coverage for pregnant women beyond 60 days postpartum, but this expired on March 31, 2023. Meanwhile, the American Rescue Plan Act of March 2021 provided states with federal funding to extend postpartum coverage up to one year. This extended postpartum coverage created a unique opportunity to examine the impact of postpartum insurance coverage continuity. Thus, we propose to make use of a natural experiment comparing women on Medicaid (treatment group) to women on commercial (control group) insurance during their delivery hospitalization within 15 states before and after state policy adoption of postpartum Medicaid coverage extensions. We will build upon unique population-based datasets that we have amassed and combine over 25 years (2008-2026) of vital statistics birth and death records linked with maternal and newborn hospital discharge data across 15 U.S. states. Using a difference-in-differences methodology, we will examine the effect of 1-year postpartum Medicaid coverage extensions on: 1) short interpregnancy interval and preterm birth and low birth weight outcomes, 2) infant hospitalizations and ED use, 3) postpartum maternal hospitalizations, ED use, and SMM, and 4) disparities in the above outcomes by race/ethnicity, rural/urban residence, state Medicaid expansion versus non-expansion status, and state income eligibility limits for pregnant women. At the completion of this project, we will have rigorous evidence on whether continuous postpartum insurance coverage is improving maternal and newborn outcomes and mitigating disparities.

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Analysis of clinical trial data to better understand Long Covid

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National Center for Advancing Translational Sciences (NCATS)

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Long COVID is a new chronic illness that represents an emerging public health crisis about which the medical community needs more information. The COVID-OUT trial was a phase 3, randomized, placebo-controlled clinical trial of early outpatient treatment of COVID-19 using a 2x3 factorial design to efficiently test 3 district treatments: metformin, ivermectin, and fluvoxamine. COVID-OUT continued follow-up assessments through 10 months after randomization. This unique long-term follow-up included monthly surveys to assess whether participants had been diagnosed with long COVID, had persistent or new symptoms, had new diagnoses, new medications, and repeat infections and vaccinations. The COVID-OUT trial also collected and quantified viral load from nasal swab samples at baseline, Days 5 and 10. This proposal seeks funding to conduct secondary analyses of already-collected data from the COVID-OUT trial to improve knowledge and understanding about long COVID. The COVID-OUT dataset is uniquely comprehensive with viral load samples and information on chronic disease development and progression, and it has less than 2% missingness for clinical outcomes during acute infection, and less than 5% missing long-term data through 9 months. Dr. Bramante started the COVID-OUT trial as a KL2 scholar, and the proposed R03 would support Dr. Bramante’s development into a fully independent translational researcher and conducting the proposed analyses will also give Dr. Bramante important insights into how to balance feasibility of clinical trial conduct and depth of data collected, which will inform future clinical trials. Aim 1 will replicate two newly emergent symptom-based definitions of long COVID, from ACTIV-6 and the RECOVER prospective cohort, in the COVID-Out monthly follow-up data. This will serve to understand whether the comparisons of medications versus placebo in the trial are supported across new definitions of long Covid. These are post-hoc, therefore hypothesis-generating analyses. Aim 1a will assess the specific symptom phenotypes identified in the RECOVER prospective cohort, and present descriptive analyses of symptoms at each month after randomization. Aim 2 will create a predictive model of Long COVID using this comprehensive dataset that includes: baseline demographic data, home medications and comorbidities, viral load data, outcomes and treatments received during initial acute COVID infection and subsequent infections, and vaccinations and boosters received before and after enrollment. This model can be repeated for the long COVID outcomes replicated in Aim 1, and will be important for adding information to the medical literature to better understand risks associated with developing long Covid. Aim 3 will assess whether changes in sleep, physical activity, and weight effect outcomes during acute COVID-19 infect or during long-term follow-up, as sleep, adiposity, and physical activity influence the immune system. The use of existing data for analyses proposed in this R03 would address communication and logistical roadblocks that exist when trying to define and efficiently research new diseases that arise in pandemic proportions.

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Centers for Disease Control and Prevention (U.S.)

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Post-Acute Sequelae of SARS-CoV-2 Infection

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Virtual World-based Cardiac Rehabilitation to Promote Data-Powered Cardiovascular Health Among Cardiac Patients: A Multicenter Randomized Clinical Trial

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Despite well-established benefits of reduced mortality and improved quality of life, <25% of eligible patients participate in cardiac rehabilitation (CR). Disparities in CR participation are particularly worse among patients most affected by cardiovascular (CV) disease including those of lower socioeconomic status and those living in rural and dense urban areas. Participation barriers include inflexible CR hours and considerable distances to CR centers. In the post-COVID-19 pandemic era, novel CR delivery methods to mitigate barriers to care are crucial. Data-driven telehealth models using virtual technologies have emerged to expand CR access through home-based delivery. One such modality, virtual worlds (VWs), are 3-D, immersive computer-based environments allowing users to interact via online personas (avatars), simulate in-person experiences, and social network. VWs are applied for physical rehabilitation, health education, and chronic disease management and could address CR participation barriers. Our major project goal is to use a Hybrid Type 1 implementation trial design to rigorously test the efficacy of a behavioral theory-informed, 12-week, VW-based CR (VWCR) intervention compared to center-based CR (CBCR) for improving CV health and CR participation among cardiac patients. CV health will be measured by the American Heart Association Life’s Essential 8 (LE8) composite score, an evidence-based metric of 8 health-promoting behaviors/clinical factors (e.g., diet, blood pressure) that improves CV outcomes. We will conduct a multiphase, multicenter, 2-arm, randomized controlled non-inferiority trial with 150 adult cardiac patients. We hypothesize that patients randomized to our patient-centric VWCR intervention will have noninferior CV health profiles and higher adherence rates than those randomized to CBCR. This R01 proposal aligns with the NLM’s focus on next-generation technologies to “reach more people in more ways through enhanced dissemination and engagement.” Building on our patient informed VWCR preliminary work, we propose 2 aims. Aim 1 will determine the effect of VWCR on CV health among cardiac patients compared to CBCR. Primary outcome is the LE8 score. Aim 2 will determine whether patients randomized to VWCR will have improved participation in and adherence to CR compared to those in CBCR. Primary outcome is adherence (attendance of ≥70% of sessions prescribed). We will use mixed methods to assess adherence and sustainability/scalability potential. Secondary outcomes include major adverse CV events, psychosocial measures (quality of life, self-efficacy, self-regulation, social support), cost effectiveness and implementation outcomes according to the RE-AIM framework. A Patient/Community/Stakeholder Advisory Board will provide input for all activities. Our innovative, reproducible VWCR intervention integrates theory-informed and empirically supported components to influence the LE8. If successful, our results can pave the way for scalable, broad implementation of VWCR to increase CR accessibility and improve CV health outcomes among cardiac patients.

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Reach  Effectiveness  Adoption  Implementation  and Maintenance

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United States National Library of Medicine

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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

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7. ABSTRACT – PROJECT 3 (TELEHEALTH VS VIRTUAL VISITS IN ORGANIC ACIDEMIAS) In a recent survey from the National Organization for Rare Disorders (NORD), nearly 40% of patients/caregivers with rare disorders reported traveling more than 60 miles for medical care. The same survey also found that 70% of respondents would like the option of telehealth for medical appointments and that during the SARS-CoV-2 pandemic, 88% of those offered a video appointment accepted. Of those accepting a video visit, 92% said it was a positive experience. In addition to the access to care issues, the NORD survey also found that 62% of patients with rare diseases were not able to attend work due to their appointments, and that 26% of children missed school regularly for appointments. Consequently, NORD is strongly advocating robust access to telehealth services for patients with rare diseases. Access to care for rare organic acidemias is an even greater challenge. In a recent survey by the Organic Acidemia Association and Propionic Acidemia Foundation, access to care was a top concern for individuals and families. According to the American Board of Medical Genetics and Genomics website, ten US states have no provider certified in either clinical or medical biochemical genetics demonstrating a significant gap in access to local specialists with expertise in organic acidemias. Although telemedicine has been shown to be effective for genetic counseling and genetic patient evaluations, care for individuals with organic acidemias involves more than counseling and diagnosis. Treatment for organic acidemias is complex requiring a combination of low protein diets, medications/supplements, strict adherence to treatment regimens, and the implementation of sick-day protocols in collaboration with the healthcare team. Frequent monitoring of growth, nutrition, and laboratory values and ongoing education are critical to successfully managing organic acidemias. We hypothesize that telehealth is one strategy for increasing access to high-quality care for organic acidemias. To test this hypothesis, we will perform the first large, multi-center study evaluating the efficacy of telehealth for organic acidemias with the following aims: 1) Assess whether virtual clinic visits are equivalent to in-person visits at achieving treatment goals, 2) Compare attendance at clinic visits and knowledge of treatment regimens for those receiving care at virtual and in-person visits, and 3) Assess patient and parent satisfaction and patient-care team relationships with virtual clinic visits compared to in-person visits. Overall, this multi-center, longitudinal study of virtual vs. in-person medical visits will demonstrate whether virtual visits are effective at providing high quality care for individuals with these disorders. As virtual visits may be a strategy for increasing access to clinical trials and meeting enrollment goals in trials for organic acidemias, the results of this study are important for both clinical trial readiness and improving patient access to quality care.

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A Pilot Study to Correlate 4-[18F]fluoro-1-naphthol PET/CT Imaging with Chronic Graft Versus Host Disease Manifestations

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/ PROJECT SUMMARY Allogeneic hematopoietic cell transplant (alloHCT) is a curative therapy for many life-threatening hematologic malignancies but its full therapeutic potential is undermined by complications such as chronic graft-versus-host disease (GVHD). Chronic GVHD is the greatest cause of non- relapse mortality and develops in 25-50% of long-term survivors of alloHCT. Novel approaches are needed to diagnose and treat chronic GVHD after alloHCT. 4-[18F]fluoro-1-naphthol ([18F]4FN) is a novel radiotracer that is specific to high energy reactive oxygen and nitrogen species produced during the respiratory burst in the active innate immune system. The proposed pilot study will apply [18F]4FN PET/CT to 16 patients with joint and other manifestations of chronic GVHD to obtain preliminary estimates of the anatomic and temporal correlations between [18F]4FN PET/CT signal intensity / location and chronic GVHD manifestations. Although PET, CT, and MRI have previously been used to image chronic GVHD, our approach differs by the use of [18F]4FN which reflects the functional activity of the innate immunity as indicated by respiratory burst intensity in contrast to glucose uptake as in [18F]fluoro-2-deoxyglucose (FDG) PET or anatomical changes as in CT and MRI. Patients will receive one to three [18F]4FN PET/CT scans and six to twelve Chronic GVHD Assessments. Data from these endpoints will be used to calculate preliminary estimates of the utility of [18F]4FN PET/CT as a predictive and prognostic / pharmacodynamic biomarker. We will test the following hypotheses with our specific aims: 1) [18F]4FN PET/CT images correlate anatomically with chronic GVHD manifestations and selected [18F]4FN PET/CT images will precede chronic GVHD manifestation changes. 2) [18F]4FN PET/CT images will provide pharmacodynamic metrics for treatment of chronic GVHD. Information gained from this pilot study will form the scientific basis for a subsequent larger phase II imaging trial to evaluate [18F]4FN PET/CT as a quantitative, predictive, and prognostic / pharmacodynamic biomarker for chronic GVHD. [18F]4FN PET/CT could be applied to other inflammatory conditions such as acute GVHD and cytokine release syndrome / immune effector cell associated neurotoxicity syndrome after CAR T cell infusion, and rheumatologic diseases. This multiple principal investigator project combines the unique, complementary expertise of Drs. Chen (alloHCT, chronic GVHD) and Piwnica-Worms (molecular imaging, radiopharmaceuticals). In 2022-2023, MD Anderson Cancer Center performed 416 adult alloHCTs of which 13.5% developed chronic GVHD within 1 year.

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United States National Institutes of Health