Preclinical evaluation and first-in-dog clinical trials of PBMC-expanded natural killer cells for adoptive immunotherapy in dogs with cancer.

BACKGROUND: Natural killer (NK) cells are cytotoxic cells capable of recognizing heterogeneous cancer targets without prior sensitization, making them promising prospects for use in cellular immunotherapy. Companion dogs develop spontaneous cancers in the context of an intact immune system, representing a valid cancer immunotherapy model. Previously, CD5 depletion of peripheral blood mononuclear cells (PBMCs) was used in dogs to isolate a CD5dim-expressing NK subset prior to co-culture with an irradiated feeder line, but this can limit the yield of the final NK product. This study aimed to assess NK activation, expansion, and preliminary clinical activity in first-in-dog clinical trials using a novel system with unmanipulated PBMCs to generate our NK cell product. METHODS: Starting populations of CD5-depleted cells and PBMCs from healthy beagle donors were co-cultured for 14 days, phenotype, cytotoxicity, and cytokine secretion were measured, and samples were sequenced using the 3'-Tag-RNA-Seq protocol. Co-cultured human PBMCs and NK-isolated cells were also sequenced for comparative analysis. In addition, two first-in-dog clinical trials were performed in dogs with melanoma and osteosarcoma using autologous and allogeneic NK cells, respectively, to establish safety and proof-of-concept of this manufacturing approach. RESULTS: Calculated cell counts, viability, killing, and cytokine secretion were equivalent or higher in expanded NK cells from canine PBMCs versus CD5-depleted cells, and immune phenotyping confirmed a CD3-NKp46+ product from PBMC-expanded cells at day 14. Transcriptomic analysis of expanded cell populations confirmed upregulation of NK activation genes and related pathways, and human NK cells using well-characterized NK markers closely mirrored canine gene expression patterns. Autologous and allogeneic PBMC-derived NK cells were successfully expanded for use in first-in-dog clinical trials, resulting in no serious adverse events and preliminary efficacy data. RNA sequencing of PBMCs from dogs receiving allogeneic NK transfer showed patient-unique gene signatures with NK gene expression trends in response to treatment. CONCLUSIONS: Overall, the use of unmanipulated PBMCs appears safe and potentially effective for canine NK immunotherapy with equivalent to superior results to CD5 depletion in NK expansion, activation, and cytotoxicity. Our preclinical and clinical data support further evaluation of this technique as a novel platform for optimizing NK immunotherapy in dogs.

Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite: 2024 Update.

The Wilderness Medical Society convened an expert panel to develop a set of evidence-based guidelines for the prevention and treatment of frostbite. We present a review of pertinent pathophysiology. We then discuss primary and secondary prevention measures and therapeutic management. Recommendations are made regarding each treatment and its role in management. These recommendations are graded on the basis of the quality of supporting evidence and balance between the benefits and risks or burdens for each modality according to methodology stipulated by the American College of Chest Physicians. This is an updated version of the guidelines published in 2019.

Exposing omitted moderators: Explaining why effect sizes differ in the social sciences.

Policymakers increasingly rely on behavioral science in response to global challenges, such as climate change or global health crises. But applications of behavioral science face an important problem: Interventions often exert substantially different effects across contexts and individuals. We examine this heterogeneity for different paradigms that underlie many behavioral interventions. We study the paradigms in a series of five preregistered studies across one in-person and 10 online panels, with over 11,000 respondents in total. We find substantial heterogeneity across settings and paradigms, apply techniques for modeling the heterogeneity, and introduce a framework that measures typically omitted moderators. The framework's factors (Fluid Intelligence, Attentiveness, Crystallized Intelligence, and Experience) affect the effectiveness of many text-based interventions, producing different observed effect sizes and explaining variations across samples. Moderators are associated with effect sizes through two paths, with the intensity of the manipulation and with the effect of the manipulation directly. Our results motivate observing these moderators and provide a theoretical and empirical framework for understanding and predicting varying effect sizes in the social sciences.

Postoperative Care and Outcomes in Solid Organ Transplant Patients undergoing Lower Extremity Fracture Treatment.

OBJECTIVE: Determine the postoperative outcomes in solid-organ transplant (SOT) patients undergoing operative treatment of lower extremity fractures. METHODS: Design: Retrospective comparative study. SETTING: Academic Level 1 Trauma center. PATIENT SELECTION CRITERIA: Patients who underwent SOT and operative treatment for lower extremity fracture from 2013-2021 were identified, excluding pathologic fractures.Outcome Measures and Comparisons: postoperative complications, length of stay, time to death, 90-day and 1-year readmission rates, readmission causes, discharge location, and immunosuppressive regiments. RESULTS: 61 patients with an average age of 67 (range 29-88) were included. The mortality rate was 37.7%. The average follow-up was 15.2 months (range of 2 weeks to 10 years). The majority of patients (42.6%) had received a liver transplant, and femoral neck fractures constituted the largest fracture group (39.4%). The average length of stay was 10 days, with the shortest being one day and the longest being 126 days (SD 18). The majority of patients were not discharged home (56.6%). Only two suffered from a postoperative complication requiring another procedure: hardware removal and liner exchange for periprosthetic joint infection, respectively. There was a 27.9% 90-day readmission rate with two deaths within that period with the most common being altered mental status (29.4%), genitourinary infections (17.6%), repeat falls (11.8%), and low hemoglobin requiring transfusion (11.8%). The longest average time to death analyzed by transplant type was found among lung transplant patients (1076 days, 62.5% mortality), followed by liver transplant patients (949 days 35.0% mortality), then kidney transplant patients (834 days, 38.9% mortality). The shortest time to death was 71 days from index procedure. CONCLUSIONS: Family members of solid-organ transplant patients undergoing operative treatment of lower extremity fractures should be made aware of the high risk for 90-day readmission postoperatively (27.9%) and overall mortality (12.5%). Providers should be aware of the need for multidisciplinary involvement for inpatient care, monitoring postoperative complications and facilitating discharge planning. LEVEL OF EVIDENCE: Level IV. See Instructions for Authors for a complete description of levels of evidence.

Botulinum neurotoxin X lacks potency in mice and in human neurons.

Botulinum neurotoxins (BoNTs) are a class of toxins produced by Clostridium botulinum (C. botulinum) and other species of Clostridia. BoNT/X is a putative novel botulinum neurotoxin identified through genome sequencing and capable of SNARE cleavage, but its neurotoxic potential in humans and vertebrates remained unclear. The C. botulinum strain producing BoNT/X, Strain 111, encodes both a plasmid-borne bont/b2 as well as the chromosomal putative bont/x. This study utilized C. botulinum Strain 111 from Japan as well as recombinantly produced full-length BoNT/X to more fully analyze this putative pathogenic toxin. We confirmed production of full-length, catalytically active native BoNT/X by C. botulinum Strain 111, produced as a disulfide-bonded dichain polypeptide similar to other BoNTs. Both the purified native and the recombinant BoNT/X had high enzymatic activity in vitro but displayed very low potency in human-induced pluripotent stem cell-derived neuronal cells and in mice. Intraperitoneal injection of up to 50 µg of native BoNT/X in mice did not result in botulism; however, mild local paralysis was observed after injection of 2 µg into the gastrocnemius muscle. We further demonstrate that the lack of toxicity by BoNT/X is due to inefficient neuronal cell association and entry, which can be rescued by replacing the receptor binding domain of BoNT/X with that of BoNT/A. These data demonstrate that BoNT/X is not a potent vertebrate neurotoxin like the classical seven serotypes of BoNTs. IMPORTANCE: The family of botulinum neurotoxins comprises the most potent toxins known to humankind. New members of this family of protein toxins as well as more distantly related homologs are being identified. The discovery of BoNT/X via bioinformatic screen in 2017 as a putative new BoNT serotype raised concern about its potential as a pathogenic agent with no available countermeasures. This study for the first time assessed both recombinantly produced and native purified BoNT/X for its vertebrate neurotoxicity.

Making Sense of the Nonalcoholic Fatty Liver Disease Clinical Practice Guidelines: What Clinicians Need to Know.

Standards of care summarized in clinical practice guidelines for nonalcoholic fatty liver disease (NAFLD) offer clinicians a streamlined diagnostic and management approach based on the best available evidence. These recommendations have changed a great deal in recent years; today, there is a clear focus on screening for the early identification and risk stratification of patients at high risk of steatohepatitis and clinically significant fibrosis to promote timely referrals to specialty care when needed. This article reviews and provides the rationale for current guidelines for NAFLD screening, diagnosis, treatment, and monitoring and addresses barriers to providing evidence-based NAFLD care and how to overcome them. The current paradigm of care calls for primary care clinicians and specialists to work together, within a multidisciplinary care team familiar with obesity and diabetes care, to provide comprehensive management of these complex patients.

Expanding the ligandable proteome by paralog hopping with covalent probes.

More than half of the ~20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.

Identifying novel gene dysregulation associated with opioid overdose death: A meta-analysis of differential gene expression in human prefrontal cortex.

Only recently have human postmortem brain studies of differential gene expression (DGE) associated with opioid overdose death (OOD) been published; sample sizes from these studies have been modest (N = 40-153). To increase statistical power to identify OOD-associated genes, we leveraged human prefrontal cortex RNAseq data from four independent OOD studies and conducted a transcriptome-wide DGE meta-analysis (N = 285). Using a unified gene expression data processing and analysis framework across studies, we meta-analyzed 20 098 genes and found 335 significant differentially expressed genes (DEGs) by OOD status (false discovery rate < 0.05). Of these, 66 DEGs were among the list of 303 genes reported as OOD-associated in prior prefrontal cortex molecular studies, including genes/gene families (e.g., OPRK1, NPAS4, DUSP, EGR). The remaining 269 DEGs were not previously reported (e.g., NR4A2, SYT1, HCRTR2, BDNF). There was little evidence of genetic drivers for the observed differences in gene expression between opioid addiction cases and controls. Enrichment analyses for the DEGs across molecular pathway and biological process databases highlight an interconnected set of genes and pathways from orexin and tyrosine kinase receptors through MEK/ERK/MAPK signaling to affect neuronal plasticity.

Predicting suicide death after emergency department visits with mental health or self-harm diagnoses.

OBJECTIVE: Use health records data to predict suicide death following emergency department visits. METHODS: Electronic health records and insurance claims from seven health systems were used to: identify emergency department visits with mental health or self-harm diagnoses by members aged 11 or older; extract approximately 2500 potential predictors including demographic, historical, and baseline clinical characteristics; and ascertain subsequent deaths by self-harm. Logistic regression with lasso and random forest models predicted self-harm death over 90 days after each visit. RESULTS: Records identified 2,069,170 eligible visits, 899 followed by suicide death within 90 days. The best-fitting logistic regression with lasso model yielded an area under the receiver operating curve of 0.823 (95% CI 0.810-0.836). Visits above the 95th percentile of predicted risk included 34.8% (95% CI 31.1-38.7) of subsequent suicide deaths and had a 0.303% (95% CI 0.261-0.346) suicide death rate over the following 90 days. Model performance was similar across subgroups defined by age, sex, race, and ethnicity. CONCLUSIONS: Machine learning models using coded data from health records have moderate performance in predicting suicide death following emergency department visits for mental health or self-harm diagnosis and could be used to identify patients needing more systematic follow-up.

Alcohol Use Disorder-Associated DNA Methylation in the Nucleus Accumbens and Dorsolateral Prefrontal Cortex.

Background: Alcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms underlying the development and progression of AUD remain limited. Here, we interrogate AUD-associated DNA methylation (DNAm) changes within and across addiction-relevant brain regions: the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC). Methods: Illumina HumanMethylation EPIC array data from 119 decedents of European ancestry (61 cases, 58 controls) were analyzed using robust linear regression, with adjustment for technical and biological variables. Associations were characterized using integrative analyses of public gene regulatory data and published genetic and epigenetic studies. We additionally tested for brain region-shared and -specific associations using mixed effects modeling and assessed implications of these results using public gene expression data. Results: At a false discovery rate ≤ 0.05, we identified 53 CpGs significantly associated with AUD status for NAc and 31 CpGs for DLPFC. In a meta-analysis across the regions, we identified an additional 21 CpGs associated with AUD, for a total of 105 unique AUD-associated CpGs (120 genes). AUD-associated CpGs were enriched in histone marks that tag active promoters and our strongest signals were specific to a single brain region. Of the 120 genes, 23 overlapped with previous genetic associations for substance use behaviors; all others represent novel associations. Conclusions: Our findings identify AUD-associated methylation signals, the majority of which are specific within NAc or DLPFC. Some signals may constitute predisposing genetic and epigenetic variation, though more work is needed to further disentangle the neurobiological gene regulatory differences associated with AUD.

Development and validation of a novel fetal vesico-amniotic shunt, the vortex shunt.

Fetal lower urinary tract obstruction (LUTO) is a severe malformation associated with an up to 80% mortality risk as well as significant renal and pulmonary morbidity in survivors. Fetal vesico-amniotic shunts (VAS) bypass the bladder obstruction, improve amniotic fluid volume and enhance in-utero pulmonary development. VAS has been shown to reduce respiratory morbidity and mortality in the neonatal period without proven benefit on long-term renal and bladder function. Clinically available shunts are associated with an up to 80% dislodgement rate, leading to repeat invasive procedures which increase fetal and maternal risks. We developed a novel "Vortex" shunt, which incorporates enhanced fixation to reduce dislodgement, a one-way valve to optimize in-utero bladder function, and enhanced sonographic echogenicity that optimizes the accurate deployment. Following the validation of these characteristics in initial benchtop experiments we have moved to feasibility studies in the fetal lamb model. We hope that the Vortex shunt may ultimately facilitate shunt deployment, reduce dislodgement risk, improve neonatal morbidity and mortality, and decrease the significant healthcare expenditures associated with long-term morbidity in LUTO survivors. In this manuscript, we review the natural history of LUTO, the risks and benefits of clinically available fetal shunts, and our development and early validation experiments.

The recalibration and redevelopment of a model to calculate patients' probability of completing a colonoscopy following an abnormal fecal test.

OBJECTIVES: Fecal immunochemical testing (FIT) is an effective screening tool for colorectal cancer. If an FIT is abnormal, a follow-up colonoscopy is necessary to remove polyps or find cancers. We sought to develop a usable risk prediction model to identify patients unlikely to complete a colonoscopy following an abnormal FIT test. METHODS: We recalibrated and then redeveloped a prediction model in federally qualified health centers (FQHCs), using a retrospective cohort of patients aged 50-75 with an abnormal FIT test and clinical data. Logistic and Cox regressions were used to recalibrate and then redevelop the model. RESULTS: The initial risk model used data from eight FQHCs (26 clinics) including 1723 patients. When we applied the model to a single large FQHC (34 clinics, 884 eligible patients), the model did not recalibrate successfully (c-statistic dropped more than 0.05, from 0.66 to 0.61). The model was redeveloped in the same FQHC in a cohort of 1401 patients with a c-statistic of 0.65. CONCLUSIONS: The original model developed in a group of FQHCs did not adequately recalibrate in the single large FQHC. Health system, patient characteristics or data differences may have led to the inability to recalibrate the model. However, the redeveloped model provides an adequate model for the single FQHC.

Investigating the Relationship Between Smoking Behavior and Global Brain Volume.

Background: Previous studies have shown that brain volume is negatively associated with cigarette smoking, but there is an ongoing debate about whether smoking causes lowered brain volume or a lower brain volume is a risk factor for smoking. We address this debate through multiple methods that evaluate directionality: Bradford Hill's criteria, which are commonly used to understand a causal relationship in epidemiological studies, and mediation analysis. Methods: In 32,094 participants of European descent from the UK Biobank dataset, we examined the relationship between a history of daily smoking and brain volumes, as well as an association of genetic risk score to ever smoking with brain volume. Results: A history of daily smoking was strongly associated with decreased brain volume, and a history of heavier smoking was associated with a greater decrease in brain volume. The strongest association was between total gray matter volume and a history of daily smoking (effect size = -2964 mm3, p = 2.04 × 10-16), and there was a dose-response relationship with more pack years smoked associated with a greater decrease in brain volume. A polygenic risk score for smoking initiation was strongly associated with a history of daily smoking (effect size = 0.05, p = 4.20 × 10-84), but only modestly associated with total gray matter volume (effect size = -424 mm3, p = .01). Mediation analysis indicated that a history of daily smoking mediated the relationship between the smoking initiation polygenic risk score and total gray matter volume. Conclusions: A history of daily smoking is strongly associated with a decreased total brain volume.

Predicting risk of suicidal behavior from insurance claims data vs. linked data from insurance claims and electronic health records.

PURPOSE: Observational studies assessing effects of medical products on suicidal behavior often rely on health record data to account for pre-existing risk. We assess whether high-dimensional models predicting suicide risk using data derived from insurance claims and electronic health records (EHRs) are superior to models using data from insurance claims alone. METHODS: Data were from seven large health systems identified outpatient mental health visits by patients aged 11 or older between 1/1/2009 and 9/30/2017. Data for the 5 years prior to each visit identified potential predictors of suicidal behavior typically available from insurance claims (e.g., mental health diagnoses, procedure codes, medication dispensings) and additional potential predictors available from EHRs (self-reported race and ethnicity, responses to Patient Health Questionnaire or PHQ-9 depression questionnaires). Nonfatal self-harm events following each visit were identified from insurance claims data and fatal self-harm events were identified by linkage to state mortality records. Random forest models predicting nonfatal or fatal self-harm over 90 days following each visit were developed in a 70% random sample of visits and validated in a held-out sample of 30%. Performance of models using linked claims and EHR data was compared to models using claims data only. RESULTS: Among 15 845 047 encounters by 1 574 612 patients, 99 098 (0.6%) were followed by a self-harm event within 90 days. Overall classification performance did not differ between the best-fitting model using all data (area under the receiver operating curve or AUC = 0.846, 95% CI 0.839-0.854) and the best-fitting model limited to data available from insurance claims (AUC = 0.846, 95% CI 0.838-0.853). Competing models showed similar classification performance across a range of cut-points and similar calibration performance across a range of risk strata. Results were similar when the sample was limited to health systems and time periods where PHQ-9 depression questionnaires were recorded more frequently. CONCLUSION: Investigators using health record data to account for pre-existing risk in observational studies of suicidal behavior need not limit that research to databases including linked EHR data.

Critical Appraisal for Racial and Ethnic Equity in Clinical Prediction Models Extension: Development of a Critical Appraisal Tool Extension to Assess Racial and Ethnic Equity-Related Risk of Bias for Clinical Prediction Models.

Introduction: Despite mounting evidence that the inclusion of race and ethnicity in clinical prediction models may contribute to health disparities, existing critical appraisal tools do not directly address such equity considerations. Objective: This study developed a critical appraisal tool extension to assess algorithmic bias in clinical prediction models. Methods: A modified e-Delphi approach was utilized to develop and obtain expert consensus on a set of racial and ethnic equity-based signaling questions for appraisal of risk of bias in clinical prediction models. Through a series of virtual meetings, initial pilot application, and an online survey, individuals with expertise in clinical prediction model development, systematic review methodology, and health equity developed and refined this tool. Results: Consensus was reached for ten equity-based signaling questions, which led to the development of the Critical Appraisal for Racial and Ethnic Equity in Clinical Prediction Models (CARE-CPM) extension. This extension is intended for use along with existing critical appraisal tools for clinical prediction models. Conclusion: CARE-CPM provides a valuable risk-of-bias assessment tool extension for clinical prediction models to identify potential algorithmic bias and health equity concerns. Further research is needed to test usability, interrater reliability, and application to decision-makers.

Evaluating 17 methods incorporating biological function with GWAS summary statistics to accelerate discovery demonstrates a tradeoff between high sensitivity and high positive predictive value.

Where sufficiently large genome-wide association study (GWAS) samples are not currently available or feasible, methods that leverage increasing knowledge of the biological function of variants may illuminate discoveries without increasing sample size. We comprehensively evaluated 17 functional weighting methods for identifying novel associations. We assessed the performance of these methods using published results from multiple GWAS waves across each of five complex traits. Although no method achieved both high sensitivity and positive predictive value (PPV) for any trait, a subset of methods utilizing pleiotropy and expression quantitative trait loci nominated variants with high PPV (>75%) for multiple traits. Application of functionally weighting methods to enhance GWAS power for locus discovery is unlikely to circumvent the need for larger sample sizes in truly underpowered GWAS, but these results suggest that applying functional weighting to GWAS can accurately nominate additional novel loci from available samples for follow-up studies.

Trans-ancestry epigenome-wide association meta-analysis of DNA methylation with lifetime cannabis use.

Cannabis is widely used worldwide, yet its links to health outcomes are not fully understood. DNA methylation can serve as a mediator to link environmental exposures to health outcomes. We conducted an epigenome-wide association study (EWAS) of peripheral blood-based DNA methylation and lifetime cannabis use (ever vs. never) in a meta-analysis including 9436 participants (7795 European and 1641 African ancestry) from seven cohorts. Accounting for effects of cigarette smoking, our trans-ancestry EWAS meta-analysis revealed four CpG sites significantly associated with lifetime cannabis use at a false discovery rate of 0.05 [Formula: see text]: cg22572071 near gene ADGRF1, cg15280358 in ADAM12, cg00813162 in ACTN1, and cg01101459 near LINC01132. Additionally, our EWAS analysis in participants who never smoked cigarettes identified another epigenome-wide significant CpG site, cg14237301 annotated to APOBR. We used a leave-one-out approach to evaluate methylation scores constructed as a weighted sum of the significant CpGs. The best model can explain 3.79% of the variance in lifetime cannabis use. These findings unravel the DNA methylation changes associated with lifetime cannabis use that are independent of cigarette smoking and may serve as a starting point for further research on the mechanisms through which cannabis exposure impacts health outcomes.

Redox Hopping in Metal-Organic Frameworks through the Lens of the Scholz Model.

Initially proposed by Lovric and Scholz to explain redox reactions in solid-phase voltammetry, the Scholz model's applications have expanded to redox reactions in various materials. As an extension of the Cottrell equation, the Scholz model enabled the quantification of electron hopping and ion diffusion with coefficients, De and Di, respectively. Research utilizing the Scholz model indicated that, in most cases, a huge bottleneck results from the ion diffusion which is slower than electron hopping by orders of magnitude. Therefore, electron and ion motion can be tuned and optimized to increase the charge transport and conductivity through systematic investigations guided by the Scholz model. The strategy may be extended to other solid-state materials in the future, e.g., battery anodes/cathodes. In this Perspective, the applications of the Scholz model in different materials will be discussed. Moreover, the limitations of the Scholz model will also be introduced, and viable solutions to those limitations discussed.

High data-rate communication link supported through the exploitation of optical channels in a characterized turbulent underwater environment.

Underwater turbulence presents a myriad of challenges for underwater optical systems through wavefront distortion and beam deflection. In this work, an underwater turbulence emulator is developed and thoroughly characterized to experimentally test the proposed underwater turbulence mitigation technique. This technique applies a modified HOBBIT system introduced in atmospheric turbulence to the relatively unknown underwater turbulence domain. By varying a beam's spatial position and relative phase gradient, a volume of turbulence is rapidly probed to determine the beam state for optimal propagation. This probe and control method is applied in multiple facets, including improved optical power transmission as well as supporting a 25-Gbps communication link through a dynamic environment.

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients.

BACKGROUND: MCL-1 is a prosurvival B-cell lymphoma 2 family protein that plays a critical role in tumor maintenance and survival and can act as a resistance factor to multiple anticancer therapies. Herein, we describe the generation and characterization of the highly potent and selective MCL-1 inhibitor ABBV-467 and present findings from a first-in-human trial that included patients with relapsed/refractory multiple myeloma (NCT04178902). METHODS: Binding of ABBV-467 to human MCL-1 was assessed in multiple cell lines. The ability of ABBV-467 to induce tumor growth inhibition was investigated in xenograft models of human multiple myeloma and acute myelogenous leukemia. The first-in-human study was a multicenter, open-label, dose-escalation study assessing safety, pharmacokinetics, and efficacy of ABBV-467 monotherapy. RESULTS: Here we show that administration of ABBV-467 to MCL-1-dependent tumor cell lines triggers rapid and mechanism-based apoptosis. In vivo, intermittent dosing of ABBV-467 as monotherapy or in combination with venetoclax inhibits the growth of xenografts from human hematologic cancers. Results from a clinical trial evaluating ABBV-467 in patients with multiple myeloma based on these preclinical data indicate that treatment with ABBV-467 can result in disease control (seen in 1 patient), but may also cause increases in cardiac troponin levels in the plasma in some patients (seen in 4 of 8 patients), without other corresponding cardiac findings. CONCLUSIONS: The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients.

Apoptosis is a type of cell death that removes abnormal cells from the body. Cancer cells can have increased levels of MCL-1, a protein that helps cells survive and prevents apoptosis. ABBV-467 is a new drug that blocks the action of MCL-1 (an MCL-1 inhibitor) and could promote apoptosis. In animal models, ABBV-467 led to cancer cell death and delayed tumor growth. ABBV-467 was also studied in a clinical trial in 8 patients with multiple myeloma, a blood cancer. In 1 patient, ABBV-467 treatment prevented the cancer from getting any worse for 8 months. However, in 4 out of 8 patients ABBV-467 increased the levels of troponin, a protein associated with damage to the heart. This concerning side effect may impact the future development of MCL-1 inhibitors as anticancer drugs.