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Avoidance of immune destruction is recognized as one of the hallmarks of cancer development. Although first predicted as a potential antitumor treatment modality more than 50 years ago, the widespread clinical use of cancer immunotherapies has only recently become a reality. Cancer immunotherapy works by reactivation of a stalled pre-existing immune response or by eliciting a de novo immune response, and its toolkit comprises antibodies, vaccines, cytokines, and cell-based therapies. The treatment paradigm in some malignancies has completely changed over the past 10 to 15 years. Massive efforts in preclinical development have led to a surge of clinical trials testing innovative therapeutic approaches as monotherapy and, increasingly, in combination. Here we provide an overview of approved and emerging antitumor immune therapies, focusing on the rich landscape of therapeutic approaches beyond those that block the canonical PD-1/PD-L1 and CTLA-4 axes and placing them in the context of the latest understanding of tumor immunology., Competing Interests: This work was supported by the Emerson Collective and a Conquer Cancer Foundation Young Investigator Award. Dr Gill is named as an inventor on multiple CAR T–related patents. Dr Welty has reported that he has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: The immune checkpoint receptor lymphocyte-activation gene 3 (LAG3) is a new target for immune checkpoint blockade (ICB), but the effects of LAG3 on atherosclerosis are not known., Objectives: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis., Methods: To study the role of LAG3 in atherosclerosis, we investigated both bone marrow chimeras lacking LAG3 in hematopoietic cells as well as global Lag3 -/- knockout mice. Effects of anti-LAG3 monoclonal antibody monotherapy and combination therapy with anti-programmed cell death protein 1 (PD-1) were tested in hypercholesterolemic low-density lipoprotein receptor knockout ( Ldlr -/- ) mice and evaluated by histology and flow cytometry., Results: LAG3-deficiency or treatment with blocking anti-LAG3 monoclonal antibodies led to increased levels of both interferon gamma-producing T helper 1 cells and effector/memory T cells, balanced by increased levels of regulatory T cells. Plaque size was affected by neither LAG3 deficiency nor LAG3 blockade, although density of T cells in plaques was 2-fold increased by loss of LAG3. Combination therapy of anti-PD-1 and anti-LAG3 had an additive effect on T cell activation and cytokine production and promoted plaque infiltration of T cells., Conclusions: Loss of LAG3 function promoted T cell activation and accumulation in plaques while not affecting plaque burden. Our report supports further clinical studies investigating cardiovascular risk in patients treated with anti-LAG3 ICB., Competing Interests: Dr Engelbertsen was supported by the Swedish Heart-Lung Foundation (#20200522, #20190449), Dr Rodriguez was supported by National Institutes of Health HL131862 and the Linda and David Roth Chair for Cardiovascular Research; is an inventor of issued patents related to LAG3; and is the founder of Lipid Genomics. Dr Lichtman was supported by National Institutes of Health HL131862. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

T-cell therapies, such as chimeric antigen receptor (CAR) T-cell, bispecific T-cell engager (BiTE) and tumor-infiltrating lymphocyte (TIL) therapies, fight cancer cells harboring specific tumor antigens. However, activation of the immune response by these therapies can lead to a systemic inflammatory response, termed cytokine release syndrome (CRS), that can result in adverse events, including cardiotoxicity. Retrospective studies have shown that cardiovascular complications occur in 10% to 20% of patients who develop high-grade CRS after CAR T-cell therapy and can include cardiomyopathy, heart failure, arrhythmias, and myocardial infarction. While cardiotoxicities have been less commonly reported with BiTE and TIL therapies, systematic surveillance for cardiotoxicity has not been performed. Patients undergoing T-cell therapies should be screened for cardiovascular conditions that may not be able to withstand the hemodynamic perturbations imposed by CRS. Generalized management of CRS, including the use of the interleukin-6 antagonist, tocilizumab, for high-grade CRS, is used to mitigate the risk of cardiotoxicity., Competing Interests: Dr Nohria is supported by the Catherine Fitch Fund and the Gelb Master Clinician Fund at Brigham and Women’s Hospital; and is a consultant for AstraZeneca, Boehringer Ingelheim, Bantam Pharmaceuticals, and Takeda Oncology. Dr Zaha has received support from the Cancer Prevention Research Institute of Texas (RP180404). Dr Yang has received research funding from CSL Behring, Boehringer Ingelheim, and Eli Lilly; and has received consulting fees from Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

As the clinical applications of immune checkpoint inhibitors (ICIs) expand, our knowledge of the potential adverse effects of these drugs continues to broaden. Emerging evidence supports the association between ICI therapy with accelerated atherosclerosis and atherosclerotic cardiovascular (CV) events. We discuss the biological plausibility and the clinical evidence supporting an effect of inhibition of these immune checkpoints on atherosclerotic CV disease. Further, we provide a perspective on potential diagnostic and pharmacological strategies to reduce atherosclerotic risk in ICI-treated patients. Our understanding of the pathophysiology of ICI-related atherosclerosis is in its early stages. Further research is needed to identify the mechanisms linking ICI therapy to atherosclerosis, leverage the insight that ICI therapy provides into CV biology, and develop robust approaches to manage the expanding cohort of patients who may be at risk for atherosclerotic CV disease., Competing Interests: Dr Neilan holds the Michael and Kathryn Park Endowed Chair in Cardiology and was also supported, in part, through a kind gift from A. Curtis Greer and Pamela Kohlberg and Christina and Paul Kazilionis, a Hassenfeld Scholar Award, and grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL130539, R01HL159187, R01HL137562, K24HL150238). Dr Zanni was supported, in part, through grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL146267 and R01HL137562) and from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (K24AI157882); and has served as the principal investigator on an investigator-initiated research grant from Gilead to her institution (Massachusetts General Hospital). Dr Neilan has served as a consultant for and received fees from Amgen, Genentech, Roche, BMS, Sanofi, CRC Oncology, and AbbVie outside of the current work; and received grant funding from AstraZeneca and Bristol Myers Squibb related to immune checkpoint inhibitors. Dr Suero-Abreu has reported that she has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Trametinib is a MEK1 (mitogen-activated extracellular signal-related kinase kinase 1) inhibitor used in the treatment of BRAF (rapid accelerated fibrosarcoma B-type)-mutated metastatic melanoma. Roughly 11% of patients develop cardiomyopathy following long-term trametinib exposure. Although described clinically, the molecular landscape of trametinib cardiotoxicity has not been characterized., Objectives: The aim of this study was to test the hypothesis that trametinib promotes widespread transcriptomic and cellular changes consistent with oxidative stress and impairs cardiac function., Methods: Mice were treated with trametinib (1 mg/kg/d). Echocardiography was performed pre- and post-treatment. Gross, histopathologic, and biochemical assessments were performed to probe for molecular and cellular changes. Human cardiac organoids were used as an in vitro measurement of cardiotoxicity and recovery., Results: Long-term administration of trametinib was associated with significant reductions in survival and left ventricular ejection fraction. Histologic analyses of the heart revealed myocardial vacuolization and calcification in 28% of animals. Bulk RNA sequencing identified 435 differentially expressed genes and 116 differential signaling pathways following trametinib treatment. Upstream gene analysis predicted interleukin-6 as a regulator of 17 relevant differentially expressed genes, suggestive of PI3K/AKT and JAK/STAT activation, which was subsequently validated. Trametinib hearts displayed elevated markers of oxidative stress, myofibrillar degeneration, an 11-fold down-regulation of the apelin receptor, and connexin-43 mislocalization. To confirm the direct cardiotoxic effects of trametinib, human cardiac organoids were treated for 6 days, followed by a 6-day media-only recovery. Trametinib-treated organoids exhibited reductions in diameter and contractility, followed by partial recovery with removal of treatment., Conclusions: These data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention., Competing Interests: Dr Norris was supported by grants from the National Institutes of Health (NIH) (R01-HL131546, R01-HL149696, R01-HL122906, R01-HL162913, and P30-1034444), the American Heart Association (19TPA34850095, 20SRG35540029, and 19TPA34900016), and the South Carolina Translational Research Institute (TD1612). Dr Mei was supported by grants from the NIH (R01HL133308), the National Science Foundation (EPS- 0903795), and the U.S. Department of Veterans Affairs Merit Review (I01 BX002327). Dr Beck was supported by training grants from the NIH (F31-HL158243 and T32-HL007260). Mr Arhontoulis and Mr Morningstar were supported by a training grant from the NIH (T32-HL007260). Dr Gensemer was supported by grants from the NIH (T32GM132055 and T32HL007260). The work at Medical University of South Carolina was performed in a facility constructed with support from NIH grant C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Additional funding support was provided by the Translational Sciences Lab in part by pilot research funding (Hollings Cancer Center’s Cancer Center Support Grant P30 CA138313 at the Medical University of South Carolina). The views expressed in this paper are those of the authors and do not necessarily represent the view of the National Heart, Lung, and Blood Institute, the NIH, or the American Heart Association. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Trametinib produces a cardiomyopathy characterized by elevated IL-6, increased oxidative stress, decreased cardiac contractility, loss of cell-to-cell communication, and myofibrillar breakdown. Our data support that these changes may be reversible over time. TRANSLATIONAL OUTLOOK: Elevations in IL-6 and oxidative stress, as well as transcriptomic changes associated with cardiac function, were observed. Future studies should examine the effects of tocilizumab on cardiotoxicity, drug resistance, and anticancer efficacy. Drug holidays may be used to prevent pathologic remodeling, as well as drug resistance. Last, the use of antioxidant drugs, including agents such as dexrazoxane, could be studied in the prevention of trametinib-induced cardiotoxicity., (© 2022 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Competing Interests: None disclosed.

Myeloproliferative neoplasms are associated with increased risk for thrombotic complications. These conditions most commonly involve somatic mutations in genes that lead to constitutive activation of the Janus-associated kinase signaling pathway (eg, Janus kinase 2, calreticulin, myeloproliferative leukemia protein). Acquired gain-of-function mutations in these genes, particularly Janus kinase 2, can cause a spectrum of disorders, ranging from clonal hematopoiesis of indeterminate potential, a recently recognized age-related promoter of cardiovascular disease, to frank hematologic malignancy. Beyond thrombosis, patients with myeloproliferative neoplasms can develop other cardiovascular conditions, including heart failure and pulmonary hypertension. The authors review the pathophysiologic mechanisms of cardiovascular complications of myeloproliferative neoplasms, which involve inflammation, prothrombotic and profibrotic factors (including transforming growth factor-beta and lysyl oxidase), and abnormal function of circulating clones of mutated leukocytes and platelets from affected individuals. Anti-inflammatory therapies may provide cardiovascular benefit in patients with myeloproliferative neoplasms, a hypothesis that requires rigorous evaluation in clinical trials., Competing Interests: Dr Ravid is supported by an American Heart Association Center Grant (857078) and by National Heart, Lung, and Blood Institute grants R01 HL136363 and R01HL158670. Dr Libby has received funding support from the National Heart, Lung, and Blood Institute (grants 1R01HL134892 and 1R01HL163099), the American Heart Association (grant 18CSA34080399), the RRM Charitable Fund, and the Simard Fund. Dr Hobbs is on the advisory boards of Incyte, Novartis, AbbVie, Constellation, and Blupring; has received research support from Incyte and Constellation; and has received grants from the American Society of Hematology/Harold Amos Medical Faculty Development Program and the K12 Paul Calabresi Career Development Award. Dr Ravid has received research support from Pharmaxis. Dr Libby is an unpaid consultant to or is involved in clinical trials for Amgen, AstraZeneca, the Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Norvo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron; is a member of the scientific advisory boards of Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, and XBiotech; has received research funding to his laboratory in the past 2 years from Novartis; is on the board of directors of XBiotech; has a financial interest in XBiotech, a company developing therapeutic human antibodies; and has a financial interest in TenSixteen Bio, a company targeting somatic mosaicism and CHIP to discover and develop novel therapeutics to treat age-related diseases. Dr Libby’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Dr Leiva has reported that he has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Objective: Mechanisms driving temporal fluctuations of inflammatory markers during pregnancy, and how these might differ between distinct perinatal depressive trajectories, are not well understood. The aim of this study was to investigate cytokines levels over the course of pregnancy in women with different trajectories of depressive symptoms peripartum, and relate the levels to levels of non-pregnant controls., Methods: Based on the Edinburgh Postnatal Depression Scale and/or selective serotonin reuptake inhibitors use, 131 women were categorized into: no (n = 65); antepartum (APD, n = 19), postpartum (PPD, n = 17) and persistent (n = 30) depressive symptoms. Plasma samples (n = 386) were analyzed for levels of interleukin (IL)-8, IL-18, Tumor necrosis factor-α, macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor A (VEGF-A) and fractalkine, at four different time-points (twice during pregnancy, during childbirth, and postpartum) using Bio-Plex Pro Human Cytokine Assays. Generalized linear mixed models were applied to analyze the associations between cytokine levels, time-point, perinatal depressive symptom trajectory group and their interaction., Results: For all markers but VEGF-A, pregnancy was associated with higher cytokine levels compared to the non-pregnant controls, with delivery being the most prominent time-point. For M-CSF, IL-18 and VEGF-A, levels were back to the non-pregnant status at postpartum week 8. An effect of perinatal depressive symptom trajectory groups on cytokine levels was found for VEGF-A. Women with PPD and women with APD had lower levels of VEGF-A throughout the study period compared to women with persistent depression, and women with PPD had lower levels compared to non-depressed women., Conclusions: Lower levels of VEGF-A were noted among women in some trajectories of depressive symptoms peripartum. The peripartum period is a time of tremendous immune system adaptations. Standardization of time-points for cytokine measurements in studies of perinatal depression are important in order to draw valid conclusions on the role of the immune system in perinatal depression., (© 2022 The Authors. Published by Elsevier Inc.)

Background: Since the introduction of imiquimod cream, patients have reported treatment-emergent symptoms that mimic influenza. However, clear relationships between the onset of symptoms from topical imiquimod and various variables (eg, patient's age) remain unclear., Objective: To evaluate potential relationships between the onset of visceral symptoms that mimic influenza and variables including patient age, the severity of local cutaneous reactions, the amount of surface area, areas of the body being treated, and serum levels of inflammatory cytokines present during 2 cycles of 14-day treatment of imiquimod 3.75% cream., Methods: In this single-center, open-label, investigator-initiated trial, 22 patients with 5-20 actinic keratosis were stratified into 1 of 2 age groups: ages 30-59 and ages 60-89., Results: Although the occurrence of systemic symptoms was infrequent during the treatment period, the majority of patients who reported local skin reactions preceding systemic symptoms developed them within 7-11 days of the treatment cycle. Levels of circulating cytokines had no predictive value., Limitations: This study was limited by its small sample size as well as the small number of cytokines evaluated. Chemokines and cytokines beyond those evaluated may contribute to influenza symptoms and/or systemic responses to imiquimod., Conclusion: The onset of local skin reactions may serve as a predictor for the potential onset of systemic symptoms that mimic those of influenza and could be used as a talking point for patients, though further research is needed., Competing Interests: Dr Bhatia is the Vice President of the American Academy of Dermatology, 2021-2022, and is an advisor, consultant, and investigator for Ortho Dermatologics., (© 2022 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Background: There is an incomplete understanding of the risk of COVID-19 infection in atopic dermatitis (AD) patients., Objective: To evaluate the risk of COVID-19 infection in AD patients in a large, diverse cohort., Methods: A case-control study of the All of Us cohort to analyze the association between AD and COVID-19. Comorbidities and risk factors were compared between cases and controls using multivariable analyses., Results: In a cohort of 11,752 AD cases with 47,008 matched controls, AD patients were more likely to have a COVID-19 diagnosis (4.2% vs 2.8%, P  < .001). AD remained significantly associated with COVID-19 in multivariable analysis (odds ratio, 1.29; P  < .001) after adjusting for demographic factors and comorbidities., Limitations: Ascertainment of AD and COVID-19 cases using electronic health records and lack of clinical data on AD severity or therapy and COVID-19 outcomes., Conclusion: AD is associated with increased odds of COVID-19 infection even after controlling for common comorbidities., Competing Interests: None disclosed., (© 2021 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Competing Interests: None disclosed.

Competing Interests: None disclosed.