Clinical Assistant Professor, Anesthesiology, Perioperative and Pain Medicine
Fellowship, Massachusetts General Hospital, Adult cardiothoracic anesthesiology (2019)
Board Certification, American Board of Anesthesiology, Anesthesiology (2018)
Residency, Massachusetts General Hospital, Anesthesiology (2017)
Medical Education, Harvard Medical School (2013)
Matthew Meyer, Rahul Bhattacharya, Wilton Levine, Sai Kantareddy, Dustin Long, Sanjay Sarma, David Bartels, Devan Bartles, Matthew Vanneman. "United States Patent WO2019/222139A1 Wireless-enabled suture needle", Massachusetts General Hospital and the Massachusetts Institute of Technology, Nov 21, 2019
Glenn Dranoff, Ryan Sullivan, Matthew Vanneman. "United States Patent US20180355013 An NKG2D-Fc fusion protein for immunotherapy", Dana-Farber Cancer Insitute, Nov 11, 2016
Glenn Dranoff, Matthew Vanneman, Gordon Freeman. "United States Patent US20110311535A1 NKG2D-Fc for immunotherapy", Dana-Farber Cancer Institute, Dec 18, 2009
Variability and relative contribution of surgeon and anesthesia specific time components to total procedural time in cardiac surgery.
The Journal of thoracic and cardiovascular surgery
OBJECTIVES: Decreasing variability in time intensive tasks during cardiac surgery may reduce total procedural time, lower costs, reduce clinician burnout, and improve patient access. The relative contribution and variability of surgeon and anesthesia control times to total procedural time is unknown.METHODS: 669 patients undergoing coronary artery bypass graft surgery were enrolled. Using linear regression, we estimated adjusted surgeon and anesthesia control times controlling for patient and procedural covariates. The primary end point compared overall surgeon and anesthesia control times. The secondary end point compared the variability in adjusted surgeon and anesthesiologist control times. Sensitivity analyses quantified the relative importance of the specific surgeon and anesthesiologist in the adjusted linear models.RESULTS: The median surgeon control time was 4.1 hours (interquartile range: 3.4 to 4.9 hours) compared to a median anesthesia control time of 1.0 hours (interquartile range: 0.8 to 1.2 hours, p < 0.001). Using linear regression, the variability in adjusted surgeon control time amongst surgeons (range: 1.8 hours) was 3.5-fold greater than the variability in adjusted anesthesia control time amongst anesthesiologists (range: 0.5 hours, p < 0.001). The specific surgeon and anesthesiologist accounted for 50% of the explanatory power of the predictive model (p < 0.001).CONCLUSIONS: Surgeon control time variability is significantly greater than anesthesia control time variability and strongly associated with the surgeon performing the procedure. While these results suggest surgeon control time variability is an attractive operational target, further studies are needed to determine practitioner specific and modifiable attributes to reduce variability and improve efficiency.
View details for DOI 10.1016/j.jtcvs.2023.08.011
View details for PubMedID 37574007
- Disparities in the Timing of Preoperative Hemodialysis Among Patients With End-Stage Kidney Disease. JAMA network open 2023; 6 (7): e2326326
Infectious Risk of Arterial Lines: A Narrative Review.
Journal of cardiothoracic and vascular anesthesia
Arterial catheter-related bloodstream infections have been identified as a significant healthcare burden. However, the incidence of arterial catheter-related infections is commonly underestimated in clinical practice, and adherence to CDC-recommended practices is inconsistent. Several categories of interventions have been studied to prevent arterial catheter-related bloodstream infections, which include barrier precautions, cutaneous antisepsis, insertion site selection, dressings, chlorhexidine-impregnated sponges, and the duration of catheter placement with or without catheter replacement. The majority of these studies are limited by small sample sizes and single-center designs, and further randomized trials are needed to update current clinical practice guidelines to reduce the risk of arterial catheter-related infections.
View details for DOI 10.1053/j.jvca.2023.06.037
View details for PubMedID 37500369
ABO Blood Group and Bleeding and Survival in VA-ECMO Patients.
Journal of intensive care medicine
ABO blood group has been shown to be a major determinant of plasma von Willebrand factor (vWF) levels. O blood group is associated with the lowest vWF levels and confers an increased risk of hemorrhagic events, while AB blood group has the highest levels and is associated with thromboembolic events. We hypothesized in extracorporeal membrane oxygenation (ECMO) patients that O blood type would have the highest and AB blood type would have the lowest transfusions, with an inverse relationship to survival. A retrospective analysis of 307 VA-ECMO patients at a major quaternary referral hospital was performed. The distribution of blood groups included 124 group O (40%), 122 group A (40%), 44 group B (14%), and 17 group AB (6%) patients. Regarding usage of packed red blood cells, fresh frozen plasma, and platelets, there was a non-statistically significant difference in transfusions, with group O having the least and group AB having the most requirements. However, there was a statistically significant difference in cryoprecipitate usage when comparing to group O: group A (1.77, 95% CI: 1.05-2.97, P<.05), group B (2.05, 95% CI: 1.16-3.63, P<.05), and group AB (3.43, 95% CI: 1.71-6.90, P<.001). Furthermore, a 20% increase in length of days on ECMO was associated with a 2-12% increase in blood product usage. The cumulative 30-day mortality rate for groups O and A was 60%, group B was 50%, and group AB was 40%; the 1-year mortality rate for groups O and A was 65%, group B was 57%, and group AB was 41%; however, the mortality differences were not statistically significant.
View details for DOI 10.1177/08850666231178759
View details for PubMedID 37291851
The Year in Electrophysiology: Selected Highlights From 2022.
Journal of cardiothoracic and vascular anesthesia
This special article is the fifth in an annual series for the Journal of Cardiothoracic and Vascular Anesthesia. The authors would like to thank the Editor-in-Chief, Dr Kaplan, the Associate Editor-in-Chief, Dr Augoustides, and the editorial board for the opportunity to author this series, which summarizes the key research papers in the electrophysiology (EP) field relevant to cardiothoracic and vascular anesthesiologists. These articles are shaping perioperative EP procedures and practices, such as pulsed-field ablation, cryoablation for first-line treatment for atrial fibrillation, advancements in conduction system pacing, safety issues related to smartphones and cardiac implantable electronic devices, and alterations in EP workflow as the world emerges from the COVID-19 pandemic. Special emphasis is placed on the implications of these advancements for the anesthetic care of patients undergoing EP procedures.
View details for DOI 10.1053/j.jvca.2023.03.025
View details for PubMedID 37080842
- Preoperative Hemodialysis Timing and Postoperative Mortality in Patients With End-stage Kidney Disease-Reply. JAMA 2023; 329 (11): 939-940
- 2022 Clinical Updates in Liver Transplantation. Journal of cardiothoracic and vascular anesthesia 2023
- The Art of the Null Hypothesis-Considerations for Study Design and Scientific Reporting. Journal of cardiothoracic and vascular anesthesia 2023
Association Between Preoperative Hemodialysis Timing and Postoperative Mortality in Patients With End-stage Kidney Disease.
For patients with end-stage kidney disease treated with hemodialysis, the optimal timing of hemodialysis prior to elective surgical procedures is unknown.To assess whether a longer interval between hemodialysis and subsequent surgery is associated with higher postoperative mortality in patients with end-stage kidney disease treated with hemodialysis.Retrospective cohort study of 1 147 846 procedures among 346 828 Medicare beneficiaries with end-stage kidney disease treated with hemodialysis who underwent surgical procedures between January 1, 2011, and September 30, 2018. Follow-up ended on December 31, 2018.One-, two-, or three-day intervals between the most recent hemodialysis treatment and the surgical procedure. Hemodialysis on the day of the surgical procedure vs no hemodialysis on the day of the surgical procedure.The primary outcome was 90-day postoperative mortality. The relationship between the dialysis-to-procedure interval and the primary outcome was modeled using a Cox proportional hazards model.Of the 1 147 846 surgical procedures among 346 828 patients (median age, 65 years [IQR, 56-73 years]; 495 126 procedures [43.1%] in female patients), 750 163 (65.4%) were performed when the last hemodialysis session occurred 1 day prior to surgery, 285 939 (24.9%) when the last hemodialysis session occurred 2 days prior to surgery, and 111 744 (9.7%) when the last hemodialysis session occurred 3 days prior to surgery. Hemodialysis was also performed on the day of surgery for 193 277 procedures (16.8%). Ninety-day postoperative mortality occurred after 34 944 procedures (3.0%). Longer intervals between the last hemodialysis session and surgery were significantly associated with higher risk of 90-day mortality in a dose-dependent manner (2 days vs 1 day: absolute risk, 4.7% vs 4.2%, absolute risk difference, 0.6% [95% CI, 0.4% to 0.8%], adjusted hazard ratio [HR], 1.14 [95% CI, 1.10 to 1.18]; 3 days vs 1 day: absolute risk, 5.2% vs 4.2%, absolute risk difference, 1.0% [95% CI, 0.8% to 1.2%], adjusted HR, 1.25 [95% CI, 1.19 to 1.31]; and 3 days vs 2 days: absolute risk, 5.2% vs 4.7%, absolute risk difference, 0.4% [95% CI, 0.2% to 0.6%], adjusted HR, 1.09 [95% CI, 1.04 to 1.13]). Undergoing hemodialysis on the same day as surgery was associated with a significantly lower hazard of mortality vs no same-day hemodialysis (absolute risk, 4.0% for same-day hemodialysis vs 4.5% for no same-day hemodialysis; absolute risk difference, -0.5% [95% CI, -0.7% to -0.3%]; adjusted HR, 0.88 [95% CI, 0.84-0.91]). In the analyses that evaluated the interaction between the hemodialysis-to-procedure interval and same-day hemodialysis, undergoing hemodialysis on the day of the procedure significantly attenuated the risk associated with a longer hemodialysis-to-procedure interval (P<.001 for interaction).Among Medicare beneficiaries with end-stage kidney disease, longer intervals between hemodialysis and surgery were significantly associated with higher risk of postoperative mortality, mainly among those who did not receive hemodialysis on the day of surgery. However, the magnitude of the absolute risk differences was small, and the findings are susceptible to residual confounding.
View details for DOI 10.1001/jama.2022.19626
View details for PubMedID 36326747
Trends in Cardiac Anesthesiologist Compensation, Work Patterns, and Training From 2010 to 2020: A Longitudinal Analysis of the Society of Cardiovascular Anesthesiologists Salary Survey.
Anesthesia and analgesia
Increasing cardiac procedural volume, a shortage of practicing cardiac anesthesiologists, and growth in specialist physician compensation would be expected to increase cardiac anesthesiologist compensation and work load. Additionally, more cardiac anesthesiologists are graduating from accredited fellowships and completing echocardiography certification. The Society of Cardiovascular Anesthesiologists (SCA) biannual salary survey longitudinally measures these data; we analyzed these data from 2010 to 2020 and hypothesized survey respondent inflation-adjusted total compensation, work load, and training would increase. For the primary outcome, we adjusted the median reported annual gross taxable income for inflation using the Consumer Price Index and then used linear regression to assess changes in inflation-adjusted median compensation. For the secondary outcomes, we analyzed the number of cardiac anesthetics managed annually and the most common care delivery staffing ratios. For the tertiary outcomes, we assessed changes in the proportion of respondents reporting transesophageal echocardiography (TEE) certification and completion of a 12-month cardiac anesthesia fellowship. We performed sensitivity analyses adjusting for yearly proportions of academic and private practice respondents. Annual survey response rates ranged from 8% to 17%. From 2010 to 2020, respondents reported a continuously compounded inflation-adjusted compensation decrease of 1.1% (95% confidence interval [CI], -1.6% to -0.6%; P = .003), equivalent to a total inflation-adjusted salary reduction of 10%. In sensitivity analysis, private practice respondents reported a continuously compounded compensation loss of -0.8% (95% CI, -1.4% to -0.2%; P = .022), while academic respondents reported no significant change (continuously compounded change, 0.4%; 95% CI, -0.4% to 1.1%; P = .23). The percentage of respondents managing more than 150 cardiac anesthetics per year increased from 26% in 2010 to 43% in 2020 (adjusted odds ratio [aOR], 1.03 per year; 95% CI, 1.03-1.04; P < .001). The proportion of respondents reporting high-ratio care models increased from 31% to 41% (aOR, 1.01 per year; 95% CI, 1.01-1.02; P < .001). Reported TEE certification increased from 69% to 90% (aOR, 1.10 per year; 95% CI, 1.10-1.11; P < .001); reported fellowship training increased from 63% to 82% (aOR, 1.15 per year; 95% CI, 1.14-1.16; P < .001). After adjusting for the proportion of academic or private practice survey respondents, SCA salary survey respondents reported decreasing inflation-adjusted compensation, rising volumes of cardiac anesthetics, and increasing levels of formal training in the 2010 to 2020 period. Future surveys measuring burnout and job satisfaction are needed to assess the association of increasing work and lower compensation with attrition in cardiac anesthesiologists.
View details for DOI 10.1213/ANE.0000000000006191
View details for PubMedID 36136075
ABO Blood Group and Bleeding in VA-ECMO Patients
LIPPINCOTT WILLIAMS & WILKINS. 2022: 149-153
View details for Web of Science ID 000840283000056
- Intraoperative Considerations in a Patient on Intravenous Epoprostenol Undergoing Minimally Invasive Cardiac Surgery. Journal of cardiothoracic and vascular anesthesia 2022
- SGLT-2 Inhibitors: Proliferating Indications and Perioperative Pitfalls. Journal of cardiothoracic and vascular anesthesia 2022
- The Year in Electrophysiology: Selected Highlights from 2021. Journal of cardiothoracic and vascular anesthesia 2022
- Transcatheter Aortic Valve Dissemination: The More the Merrier or Too Much of a Good Thing? Journal of cardiothoracic and vascular anesthesia 1800
- Focusing on the Long Game: Updates on Aortic Valve Research From the Valve Academic Research Consortium. Journal of cardiothoracic and vascular anesthesia 2021
Anesthetic Considerations for Percutaneous Coronary Intervention for Chronic Total Occlusions-A Narrative Review.
Journal of cardiothoracic and vascular anesthesia
Advancing stent technology has enabled interventional cardiologists to perform percutaneous coronary intervention (PCI) to open chronic total occlusions (CTOs). Because PCI for CTOs improve patient anginal symptoms and quality of life, these procedures have been increasing over the past decade. Compared to standard PCI, these procedures are technically more difficult, with prolonged procedure time and increased risk of complications. Accordingly, anesthesiologists are increasingly being asked to provide sedation for these patients in the cardiac catheterization suite. In CTO PCI, anesthesiologists are more likely to encounter complications such as coronary artery perforation, malignant arrhythmias, non-target vessel ischemia, bleeding and shock. Additionally, CTO PCI may be supported by mechanical circulatory support devices. Understanding the procedural techniques of these complex PCI procedures is important to enable optimal anesthetic care in these patients. This narrative review discusses the pathophysiology, risks, benefits, procedural steps, and main anesthetic considerations for patients undergoing CTO PCI. Despite a growing body of literature, future research is still required to elucidate optimal anesthetic and mechanical support strategies in patients undergoing CTO PCI.
View details for DOI 10.1053/j.jvca.2021.08.001
View details for PubMedID 34493436
Perioperative Implications of the 2020 American Heart Association Scientific Statement on Drug-Induced Arrhythmias-A Focused Review.
Journal of cardiothoracic and vascular anesthesia
The recently released American Heart Association (AHA) scientific statement on drug-induced arrhythmias discussed medications commonly associated with bradycardia, supraventricular tachycardias, and ventricular arrhythmias. The foundational data for this statement were collected from general outpatient and inpatient populations. Patients undergoing surgical and minimally invasive treatments are a unique subgroup, because they may experience hemodynamic changes associated with anesthesia and their procedure, receive multiple drug combinations not given in either inpatient or outpatient settings, or experience postprocedural inflammatory syndromes. Accordingly, the generalizability of the AHA scientific statement to this perioperative population is unclear. This focused review highlights important aspects of the new AHA scientific statement and their application to the perioperative setting. The authors review medications frequently encountered and given by anesthesiologists and their risk of drug-induced arrhythmias and discuss common anesthetic and adjunctive medications and their associated risks of bradycardia, atrial fibrillation, torsades de pointes, and drug-induced Brugada syndrome. In many instances, the risk of arrhythmia reported by the AHA scientific statement in the general population appeared to be higher than found in perioperative arenas. Furthermore, the authors discuss the arrhythmia risk of additional medications commonly ordered or administered by anesthesiologists that are not included in the AHA scientific statement. As patient and procedural complexity increases and novel anesthetic combinations propagate, further research and observational studies will be required to delineate further perioperative risks for drug-induced arrhythmia.
View details for DOI 10.1053/j.jvca.2021.05.008
View details for PubMedID 34144871
- Predicting Post-Liver Transplant Outcomes-Rise of the Machines or a Foggy Crystal Ball? Journal of cardiothoracic and vascular anesthesia 2021
A Focused Transesophageal Echocardiography Protocol for Intraoperative Management During Orthotopic Liver Transplantation
JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA
2020; 34 (7): 1824–32
The value of a simplified, focused intraoperative transesophageal echocardiography (TEE) protocol in patients undergoing liver transplantation (LT) is unknown. We sought to create and assess a 5-view LT TEE examination focused on 5 prespecified common causes of hypotension during LT.Retrospective cohort study.Single-center tertiary academic hospital.All patients undergoing LT with TEE from January 2010 through May 2019.None.A 5-view LT TEE protocol adapted from a published rescue TEE protocol was assessed retrospectively in a cohort of 106 patients. The primary outcome was the frequency with which the protocol would have detected a composite of 5 prespecified causes of hypotension if the TEE exam had been limited to those views. To assess potential influence on intraoperative care, management changes associated with TEE images were extracted from the medical record. The prespecified diagnoses occurred 24 times; the LT TEE protocol would have detected 22 of 24 of these (92%, 95% confidence interval [CI]: 74%-98%). Intraoperative management changes occurred in 15 of 16 patients (94%) with 1 of the prespecified TEE findings, compared with 1 of 27 patients (3.7%) with TEE findings outside those diagnoses (p < 0.0001).In a retrospective cohort study, a simplified LT TEE protocol would have detected 92% of prespecified TEE findings. Management changes occurred in 94% of those patients, while changes rarely occurred in patients with other TEE findings. A focused LT TEE protocol may diagnose critical pathology adequately and guide management during LT when standard monitors are insufficient.
View details for DOI 10.1053/j.jvca.2020.01.028
View details for Web of Science ID 000538116100022
View details for PubMedID 32144070
- Positioning for Perioperative Success: Insights from the European Society of Cardiology Statement on Atrial Fibrillation and Acute Heart Failure. Journal of cardiothoracic and vascular anesthesia 2020
- Perioperative and Echocardiographic Considerations for the Inspiris Resilia Aortic Valve--Current and Future. Journal of cardiothoracic and vascular anesthesia 2020
Anesthesiologists Guide to the 2019 AHA/ACC/HRS Focused Update for the Management of Patients With Atrial Fibrillation.
Journal of cardiothoracic and vascular anesthesia
2020; 34 (7): 1925–32
Perioperative physicians should be well versed in atrial fibrillation (AF) management because it is the most common sustained arrythmia in the United States. In this narrative review of the 2019 American Heart Association/American College of Cardiologists/Heart Rhythm Society Focused Update on Atrial Fibrillation, the authors detail the emergence of new evidence from completed studies that may affect the management of patients with AF presenting for surgery. Updates regarding non-vitamin K oral anticoagulants (NOACs) comprise the bulk of the update with newer evidence emerging regarding their equivalence and/or superiority compared to Coumadin. Apixaban is now the preferred drug of choice for first line stroke prevention in nonvalvular AF over Coumadin. Renal dysfunction and the management of patients with AF on hemodialysis is examined; in patients on hemodialysis with AF, the focused update recommends administration of either warfarin or dose-reduced apixaban. Evidence from new trials addressing the appropriate bridging of NOACs before surgery is discussed. Patients with nonvalvular AF may not exhibit an added benefit from bridging of anticoagulation, and perioperative physicians should balance the risks of stroke and major bleeding before surgery. Advances in nonpharmacologic treatment and management of AF are outlined, including left atrial appendage occlusion devices, catheter ablations, and electrical cardioversion. Anesthesiologists' understanding of these 2019 updated guidelines will allow for more adept optimization of patients with AF presenting for surgery.
View details for DOI 10.1053/j.jvca.2019.08.046
View details for PubMedID 31561986
Improving Transfusion Safety in the Operating Room With a Barcode Scanning System Designed Specifically for the Surgical Environment and Existing Electronic Medical Record Systems: An Interrupted Time Series Analysis.
Anesthesia and analgesia
Manual processes for verifying patient identification before blood transfusion and documenting this pretransfusion safety check are prone to errors, and compliance with manual systems is especially poor in urgent operating room settings. An automated, electronic barcode scanner system would be expected to improve pretransfusion verification and documentation.Audits were conducted of blood transfusion documentation under a manual paper system from January to October 2014. An electronic barcode scanning system was developed to streamline transfusion safety checking and automate documentation. This system was implemented in 58 operating rooms between October and December 2014, with follow-up compliance audits through December 2015. The association of barcode scanner implementation with transfusion documentation compliance was assessed using an interrupted time series analysis. Anesthesia providers were surveyed regarding their opinions on the electronic system. In mid-2016, the scanning system was modified to transfer from the Metavision medical record system to Epic OpTime. Follow-up analysis assessed performance of this system within Epic during 2017.In an interrupted time series analysis, the proportion of units with compliant documentation was estimated to be 19.6% (95% confidence interval [CI], 10.7-25.6) the week before scanner implementation, and 74.4% (95% CI, 59.4-87.4) the week after implementation. There was a significant postintervention level change (odds ratio 10.80, 95% CI, 6.31-18.70; P < .001) and increase in slope (odds ratio 1.14 per 1-week increase, 95% CI, 1.11-1.17; P < .001). After implementation, providers chose to use the new electronic system for 98% of transfusions. Across the 2 years analyzed (15,997 transfusions), the electronic system detected 45 potential transfusion errors in 27 unique patients, and averted transfusion of 36 mismatched blood products into 20 unique patients. A total of 69%, 86%, and 88% of providers reported the electronic system improved patient safety, blood transfusion workflow, and transfusion documentation, respectively. When providers used the barcode scanner, no transfusion errors or reactions were reported. The scanner system was successfully transferred from Metavision to Epic without retraining staff or changing workflows.A barcode-based system designed for easy integration to different commonly used anesthesia information management systems was implemented in a large urban academic hospital. The system allows a single user with the assistance of a software system to perform and document pretransfusion safety verification. The system improved transfusion documentation compliance, averted potential transfusion errors, and became the preferred method of blood transfusion safety checking.
View details for DOI 10.1213/ANE.0000000000005084
View details for PubMedID 32769384
- TRACKing Down Perioperative Transfusion in Cardiac Surgery JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA 2019; 33 (10): 2676–78
Vasoplegia During Cardiopulmonary Bypass: Current Literature and Rescue Therapy Options.
Journal of cardiothoracic and vascular anesthesia
Vasoplegia syndrome in the cardiac surgical intensive care unit and postoperative period has been an area of interest to clinicians because of its prevalence and effects on morbidity and mortality. However, there is a paucity of evidence regarding the treatment of vasoplegia syndrome during cardiopulmonary bypass (on-CPB VS). This review aims to detail the incidence, outcomes, and possible treatment options for patients who develop vasoplegia during bypass. The pharmacologic rescue agents discussed are used in cases in which vasoplegia during CPB is refractory to standard catecholamine agents, such as norepinephrine, epinephrine, and phenylephrine. Methods to improve vasoplegia during CPB can be both pharmacologic and nonpharmacologic. In particular, optimization of CPB parameters plays an important nonpharmacologic role in vasoplegia during CPB. Pharmacologic agents that have been demonstrated as being effective in vasoplegia include vasopressin, terlipressin, methylene blue, hydroxocobalamin, angiotensin II (Giapreza), vitamin C, flurbiprofen (Ropion), and hydrocortisone. Although these agents have not been specifically evaluated for vasoplegia during CPB, they have shown signs of effectiveness for vasoplegia postoperatively to varying degrees. Understanding the evidence for, dosing, and side effects of these agents is crucial for cardiac anesthesiologists when treating vasoplegia during CPB bypass.
View details for DOI 10.1053/j.jvca.2019.12.013
View details for PubMedID 31917073
- Studies on the effectiveness of flipped classrooms: are we comparing apples to apples? Medical education 2017; 51 (12): 1293–94
- A Young Man with a Mediastinal Mass and Sudden Cardiac Arrest. Annals of the American Thoracic Society 2015; 12 (8): 1235–39
Compartment-specific bioluminescence imaging platform for the high-throughput evaluation of antitumor immune function
2012; 119 (15): E131–E138
Conventional assays evaluating antitumor activity of immune effector cells have limitations that preclude their high-throughput application. We adapted the recently developed Compartment-Specific Bioluminescence Imaging (CS-BLI) technique to perform high-throughput quantification of innate antitumor activity and to show how pharmacologic agents (eg, lenalidomide, pomalidomide, bortezomib, and dexamethasone) and autologous BM stromal cells modulate that activity. CS-BLI-based screening allowed us to identify agents that enhance or inhibit innate antitumor cytotoxicity. Specifically, we identified compounds that stimulate immune effector cells against some tumor targets but suppressed their activity against other tumor cells. CS-BLI offers rapid, simplified, and specific evaluation of multiple conditions, including drug treatments and/or cocultures with stromal cells and highlights that immunomodulatory pharmacologic responses can be heterogeneous across different types of tumor cells. This study provides a framework to identify novel immunomodulatory agents and to prioritize compounds for clinical development on the basis of their effect on antitumor immunity.
View details for DOI 10.1182/blood-2011-04-348490
View details for Web of Science ID 000302917200001
View details for PubMedID 22289890
View details for PubMedCentralID PMC3325048
Combining immunotherapy and targeted therapies in cancer treatment
NATURE REVIEWS CANCER
2012; 12 (4): 237–51
During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.
View details for DOI 10.1038/nrc3237
View details for Web of Science ID 000302134900009
View details for PubMedID 22437869
View details for PubMedCentralID PMC3967236
Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr Virus Protein LMP1 in a Mouse Model
2012; 148 (4): 739–51
B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach.
View details for DOI 10.1016/j.cell.2011.12.031
View details for Web of Science ID 000300622400015
View details for PubMedID 22341446
View details for PubMedCentralID PMC3313622
Compartment-Specific Bioluminescence Imaging Platform for the Open-Ended Identification of Novel Immunomodulatory Agents and High-Throughput Evaluation of Anti-Tumor Immune Function
AMER SOC HEMATOLOGY. 2010: 202
View details for Web of Science ID 000289662200452
IAP inhibitors enhance co-stimulation to promote tumor immunity
JOURNAL OF EXPERIMENTAL MEDICINE
2010; 207 (10): 2195–2206
The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor κB (NF-κB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-κB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell-dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer.
View details for DOI 10.1084/jem.20101123
View details for Web of Science ID 000282649800015
View details for PubMedID 20837698
View details for PubMedCentralID PMC2947073
Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2009; 106 (37): 15825–30
Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12-43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial immunotherapy might potentiate graft-versus-leukemia in patients.
View details for DOI 10.1073/pnas.0908358106
View details for Web of Science ID 000269806600058
View details for PubMedID 19717467
View details for PubMedCentralID PMC2747203
Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction
2009; 113 (8): 1681–88
The identification of cancer antigens that contribute to transformation and are linked with immune-mediated tumor destruction is an important goal for immunotherapy. Toward this end, we screened a murine renal cell carcinoma cDNA expression library with sera from mice vaccinated with irradiated tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF). Multiple nonmutated, overexpressed proteins that function in tumor cell migration, protein/nucleic acid homeostasis, metabolism, and stress responses were detected. Among these, the most frequently recognized clone was protein disulfide isomerase (PDI). High titer antibodies to human PDI were similarly induced in an acute myeloid leukemia patient who achieved a complete response after vaccination with irradiated, autologous GM-CSF-secreting tumor cells in the setting of nonmyeloablative allogeneic bone marrow transplantation. Moreover, ERp5, a closely related disulfide isomerase involved in major histocompatibility complex (MHC) class I chain-related protein A (MICA) shedding, also evoked potent humoral reactions in diverse solid and hematologic malignancy patients who responded to GM-CSF-secreting tumor cell vaccines or antibody blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Together, these findings reveal the unexpected immunogenicity of PDIs and raise the possibility that these gene products might serve as targets for therapeutic monoclonal antibodies.
View details for DOI 10.1182/blood-2007-09-114157
View details for Web of Science ID 000263566100010
View details for PubMedID 19008459
View details for PubMedCentralID PMC2647666
GM-CSF Secreting Leukemia Cell Vaccination after Allogeneic Reduced Intensity Hematopoietic Stem Cell Transplantation for Advanced Myeloid Malignancies
AMER SOC HEMATOLOGY. 2008: 306
View details for Web of Science ID 000262104701049
GM-CSF secreting leukaemia cell vaccinations after allogeneic reduced-intensity peripheral blood stem cell transplantation for advanced myeloid malignancies
NATURE PUBLISHING GROUP. 2008: S408
View details for Web of Science ID 000254359201032
MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2008; 105 (4): 1285–90
Monoclonal gammopathy of undetermined significance (MGUS) is a common disorder of aging and a precursor lesion to full-blown multiple myeloma (MM). The mechanisms underlying the progression from MGUS to MM are incompletely understood but include the suppression of innate and adaptive antitumor immunity. Here, we demonstrate that NKG2D, an activating receptor on natural killer (NK) cells, CD8(+) T lymphocytes, and MHC class I chain-related protein A (MICA), an NKG2D ligand induced in malignant plasma cells through DNA damage, contribute to the pathogenesis of MGUS and MM. MICA expression is increased on plasma cells from MGUS patients compared with normal donors, whereas MM patients display intermediate MICA levels and a high expression of ERp5, a protein disulfide isomerase linked to MICA shedding (sMICA). MM, but not MGUS, patients harbor circulating sMICA, which triggers the down-regulation of NKG2D and impaired lymphocyte cytotoxicity. In contrast, MGUS, but not MM, patients generate high-titer anti-MICA antibodies that antagonize the suppressive effects of sMICA and stimulate dendritic cell cross-presentation of malignant plasma cells. Bortezomib, a proteasome inhibitor with anti-MM clinical efficacy, activates the DNA damage response to augment MICA expression in some MM cells, thereby enhancing their opsonization by anti-MICA antibodies. Together, these findings reveal that the alterations in the NKG2D pathway are associated with the progression from MGUS to MM and raise the possibility that anti-MICA monoclonal antibodies might prove therapeutic for these disorders.
View details for DOI 10.1073/pnas.0711293105
View details for Web of Science ID 000252873900037
View details for PubMedID 18202175
View details for PubMedCentralID PMC2234130