38 results on '"John H. Baird"'
Search Results
2. PB2346: ZUMA-24: A PHASE 2, OPEN-LABEL, MULTICENTER STUDY OF AXICABTAGENE CILOLEUCEL IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B-CELL LYMPHOMA GIVEN WITH CORTICOSTEROIDS IN THE OUTPATIENT SETTING
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Lori Leslie, Michael Tees, Ian W. Flinn, Tulio Rodriguez, John H. Baird, Abhinav Deol, Monica Mead, Carlos Bachier, Aaron P. Rapoport, Brian Mcclune, Daanish Hoda, Miguel-Angel Perales, Yan Zheng, Simone Filosto, Madison Davis, Harry Miao, Jenny J. Kim, and Olalekan O. Oluwole
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. Long-Term Follow-Up of Bridging Therapies Prior to CAR T-Cell Therapy for Relapsed/Refractory Large B Cell Lymphoma
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Colton Ladbury, Savita Dandapani, Claire Hao, Mildred Fabros, Arya Amini, Sagus Sampath, Scott Glaser, Karen Sokolov, Jekwon Yeh, John H. Baird, Swetha Kambhampati, Alex Herrera, Matthew Mei, Liana Nikolaenko, Geoffrey Shouse, and Lihua E. Budde
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bridging therapy ,bridging radiation ,large B-cell lymphoma (LBCL) ,chimeric antigen receptor T-cell (CAR T) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Bridging therapy (BT) with systemic therapy (ST), radiation therapy (RT), or combined-modality therapy (CMT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). We report the long-term outcomes of the patients who received commercial CAR T-cell therapy with or without BT. Methods: The patients with LBCL who underwent infusion of a commercial CD19 CAR T product were eligible. The radiation was stratified as comprehensive or focal. The efficacy outcomes and toxicity were analyzed. Results: In total, 156 patients were included and, of them, 52.5% of the patients received BT. The median progression-free survival (PFS) was 0.65 years in the BT cohort compared to 1.45 years in the non-BT cohort. The median overall survival (OS) was 3.16 years in the BT cohort and was not reached in the non-BT cohort. The patients who received comprehensive radiation (versus focal) had significantly improved PFS and OS, achieving a 1-year PFS of 100% vs. 9.1% and 1-year OS of 100% vs. 45.5%. There was no difference in the severe toxicity between any of the nonbridging or BT cohorts. Conclusions: BT did not appear to compromise outcomes with respect to response rates, disease control, survival, and toxicity. The patients with limited disease treated with RT had favorable outcomes.
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- 2023
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4. A phase 2 study of brentuximab vedotin in patients with CD30-positive advanced systemic mastocytosis
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Jason Gotlib, John H. Baird, Tracy I. George, Cheryl Langford, Isabel Reyes, Justin Abuel, Cecelia Perkins, Kurt Schroeder, Prithviraj Bose, and Srdan Verstovsek
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: There is an unmet need for effective therapies for advanced systemic mastocytosis (advSM). CD30 is expressed on the surface of neoplastic mast cells (MC) in more than 50% of patients with advSM. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate with preclinical evidence supporting both an antineoplastic effect and an attenuation of immunoglobulin E-associated mediator release. These observations are the basis for this phase 2 trial of BV monotherapy (1.8 mg/kg IV every 3 weeks up to 8 cycles) in patients with CD30-positive advSM. The primary objective was to determine the efficacy of BV according to International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria. Secondary objectives included evaluation of safety, changes in bone marrow (BM) MC burden, serum tryptase level, flow cytometric quantification of MC surface expression of CD30, and self-reported symptom burden. The trial enrolled 10 patients with a diagnosis of CD30+ advSM (aggressive SM, SM with an associated hematologic neoplasm [SM-AHN], or mast cell leukemia [MCL]) with 1 or more signs of SM-related organ damage. According to IWG-MRT-ECNM criteria, none of the patients demonstrated better than stable disease with BV. In addition, there were no significant reductions in BM MC burden, serum tryptase levels, or MC surface expression of CD30. Self-reported symptom scores showed no durable improvement with BV treatment. We conclude that BV is not active as a single agent in CD30+ advSM. This trial was registered at www.clinicaltrials.gov as #NCT01807598.
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- 2019
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5. An Unusual Cause of Epistaxis: Paranasal Sinus Myeloid Sarcoma
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Karuna Dewan, John H. Baird, and Courtney B. Shires
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We report a case of a 65-year-old female who presented with right-sided headaches, blurring of vision in the right eye, cold-induced epistaxis, and facial numbness in the trigeminal nerve distribution. Laboratory studies revealed a significant number of myeloblasts on peripheral smear with granulated cytoplasm, irregular nuclei, and prominent vacuoles. Magnetic resonance imaging (MRI) of the brain demonstrated a T1-enhancing 1.5 cm right-sided dural-based lesion involving the medial sphenoid wing, cavernous sinus, infratemporal fossa, and sphenoid sinus region. An endoscopic biopsy of the lesion within the sphenoid sinus confirmed the diagnosis of myeloid sarcoma, with myeloblasts comprising 30% of cellularity by flow cytometry. A subsequent bone marrow biopsy revealed a hypercellular marrow with 23% blasts by flow cytometry that demonstrated a similar immunophenotypic pattern to those seen in the sinus mass. Fluorescence in situ hybridization (FISH) testing revealed the balanced translocation t(8;21)(q22;q22.1), consistent with a diagnosis of acute myeloid leukemia with RUNX1-RUNX1T1-balanced translocation by WHO 2016 criteria. Myeloid sarcoma represents a rare extramedullary presentation of acute myeloid leukemia (AML), either alone or in conjunction with blood or bone marrow involvement. This case emphasizes the need for a broad differential diagnosis and an aggressive work-up for any unusual paranasal sinus mass.
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- 2019
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6. Interferon-γ blockade in CAR T-cell therapy–associated macrophage activation syndrome/hemophagocytic lymphohistiocytosis
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Michael Rainone, Dat Ngo, John H. Baird, L. Elizabeth Budde, Myo Htut, Ibrahim Aldoss, and Vinod Pullarkat
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Hematology - Published
- 2023
7. Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy
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Zinaida Good, Jay Y. Spiegel, Bita Sahaf, Meena B. Malipatlolla, Zach J. Ehlinger, Sreevidya Kurra, Moksha H. Desai, Warren D. Reynolds, Anita Wong Lin, Panayiotis Vandris, Fang Wu, Snehit Prabhu, Mark P. Hamilton, John S. Tamaresis, Paul J. Hanson, Shabnum Patel, Steven A. Feldman, Matthew J. Frank, John H. Baird, Lori Muffly, Gursharan K. Claire, Juliana Craig, Katherine A. Kong, Dhananjay Wagh, John Coller, Sean C. Bendall, Robert J. Tibshirani, Sylvia K. Plevritis, David B. Miklos, and Crystal L. Mackall
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General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2022
8. COVID-19 and Other Viral Infections in Patients With Hematologic Malignancies
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Courtney E. Harris, Abi Vijenthira, Shin Yeu Ong, Lindsey Robert Baden, Lisa K. Hicks, and John H. Baird
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General Medicine - Abstract
COVID-19 and our armamentarium of strategies to combat it have evolved dramatically since the virus first emerged in late 2019. Vaccination remains the primary strategy to prevent severe illness, although the protective effect can vary in patients with hematologic malignancy. Strategies such as additional vaccine doses and now bivalent boosters can contribute to increased immune response, especially in the face of evolving viral variants. Because of these new variants, no approved monoclonal antibodies are available for pre-exposure or postexposure prophylaxis. Patients with symptomatic, mild-to-moderate COVID-19 and risk features for developing severe COVID-19, who present within 5-7 days of symptom onset, should be offered outpatient therapy with nirmatrelvir/ritonavir (NR) or in some cases with intravenous (IV) remdesivir. NR interacts with many blood cancer treatments, and reviewing drug interactions is essential. Patients with severe COVID-19 should be managed with IV remdesivir, tocilizumab (or an alternate interleukin-6 receptor blocker), or baricitinib, as indicated based on the severity of illness. Dexamethasone can be considered on an individual basis, weighing oxygen requirements and patients' underlying disease and their perceived ability to clear infection. Finally, as CD19-targeted and B-cell maturation (BCMA)–targeted chimeric antigen receptor (CAR) T-cell therapies become more heavily used for relapsed/refractory hematologic malignancies, viral infections including COVID-19 are increasingly recognized as common complications, but data on risk factors and prophylaxis in this patient population are scarce. We summarize the available evidence regarding viral infections after CAR T-cell therapy.
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- 2023
9. Nivolumab Plus ICE As First Salvage Therapy in High-Risk Relapsed/Refractory Hodgkin Lymphoma
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Matthew Mei, Joycelynne Palmer, Ni-Chun Tsai, Hun Ju Lee, Iris Isufi, Leslie L. Popplewell, Lynne Smith, Lacolle Peters, Lara Rodriguez, James Godfrey, John H. Baird, Joo Y. Song, Steven T. Rosen, Larry W. Kwak, Stephen J Forman, and Alex F. Herrera
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. Real-World Outcomes of CD19 CAR T Cell Therapy in Adult Patients with Relapsed Refractory Transformed Diffuse Large B-Cell Lymphoma
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Swetha Kambhampati, Leslie Popplewell, Yan Wang, Matthew Mei, Liana Nikolaenko, Geoffrey Shouse, Alex F. Herrera, Jasmine Zain, Tanya Siddiqi, James Godfrey, Dr. John H Baird, Steven Rosen, Alexey V. Danilov, Ji-Lian Cai, Ricardo Spielberger, Joycelynne Palmer, Annette Brown, Larry W. Kwak, Eileen Smith, Stephen J. Forman, and L. Elizabeth E. Budde
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Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2023
11. Lactate dehydrogenase to carboxyhemoglobin ratio as a biomarker of heme release to heme processing is associated with higher tricuspid regurgitant jet velocity and early death in sickle cell disease
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Caterina P. Minniti, Annelies J. Van Vuren, Eduard J. van Beers, Gregory J. Kato, John H. Baird, and Laurel Mendelsohn
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Adult ,Cell ,Early death ,Disease ,Anemia, Sickle Cell ,Heme ,Correspondences ,Hemolysis ,chemistry.chemical_compound ,Jet velocity ,Lactate dehydrogenase ,Correspondence ,medicine ,Humans ,Carbon Monoxide ,L-Lactate Dehydrogenase ,business.industry ,Hematology ,Tricuspid Valve Insufficiency ,medicine.anatomical_structure ,chemistry ,Carboxyhemoglobin ,Cancer research ,Biomarker (medicine) ,business ,Biomarkers - Published
- 2021
12. CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR–refractory large B-cell lymphoma
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Warren D. Reynolds, Bita Sahaf, Zachary Ehlinger, Steven A. Feldman, Matthew J. Frank, Andrew R. Rezvani, Surbhi Sidana, Jay Y. Spiegel, Allison P. Jacob, Lori Muffly, Kara L. Davis, Shabnum Patel, Jean Oak, Eric H. Yang, Ilan R. Kirsch, Robert Lowsky, Laura Johnston, Juliana Craig, John S. Tamaresis, Michael G. Ozawa, John H. Baird, Sheren F. Younes, David B. Miklos, Parveen Shiraz, Chelsea D. Mullins, Crystal L. Mackall, Robert S. Negrin, Liora M. Schultz, Wen-Kai Weng, Everett Meyer, Sally Arai, Yasodha Natkunam, and Sneha Ramakrishna
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Oncology ,medicine.medical_specialty ,Clinical Trials and Observations ,Sialic Acid Binding Ig-like Lectin 2 ,Antigens, CD19 ,Immunology ,Immunotherapy, Adoptive ,Biochemistry ,CD19 ,Refractory ,Internal medicine ,medicine ,Humans ,Adverse effect ,B-cell lymphoma ,Clinical Trials, Phase I as Topic ,biology ,business.industry ,Remission Induction ,CD22 ,Cell Biology ,Hematology ,Prognosis ,medicine.disease ,Chimeric antigen receptor ,Lymphoma ,biology.protein ,Chimeric Antigen Receptor T-Cell Therapy ,Lymphoma, Large B-Cell, Diffuse ,business - Abstract
The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.
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- 2021
13. Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma
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Zachary Ehlinger, Everett Meyer, David B. Miklos, Matthew J. Frank, John S. Tamaresis, Laura Johnston, Janice W Brown, Surbhi Sidana, Robert S. Negrin, David J Epstein, John H. Baird, Theresa Latchford, Andrew R. Rezvani, Robert Lowsky, Juliana Craig, Lori Muffly, Sally Arai, Gursharan K. Claire, Wen-Kai Weng, Bita Sahaf, Parveen Shiraz, Crystal L. Mackall, and Jay Y. Spiegel
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medicine.medical_specialty ,Clinical Trials and Observations ,medicine.medical_treatment ,Antigens, CD19 ,Single Center ,Immunotherapy, Adoptive ,Gastroenterology ,Immune Reconstitution ,Internal medicine ,medicine ,Humans ,Pneumocystis jirovecii ,B-cell lymphoma ,Biological Products ,biology ,business.industry ,Hazard ratio ,Hematology ,Immunotherapy ,medicine.disease ,biology.organism_classification ,Lymphoma ,Platelet transfusion ,biology.protein ,Lymphoma, Large B-Cell, Diffuse ,Antibody ,business - Abstract
Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count
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- 2021
14. Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas
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Brian J. Sworder, David M. Kurtz, Stefan K. Alig, Matthew J. Frank, Navika Shukla, Andrea Garofalo, Charles W. Macaulay, Mohammad Shahrokh Esfahani, Mari N. Olsen, James Hamilton, Hitomi Hosoya, Mark Hamilton, Jay Y. Spiegel, John H. Baird, Takeshi Sugio, Mia Carleton, Alexander F.M. Craig, Sheren F. Younes, Bita Sahaf, Natasha D. Sheybani, Joseph G. Schroers-Martin, Chih Long Liu, Jean S. Oak, Michael C. Jin, Sara Beygi, Andreas Hüttmann, Christine Hanoun, Ulrich Dührsen, Jason R. Westin, Michael S. Khodadoust, Yasodha Natkunam, Robbie G. Majzner, Crystal L. Mackall, Maximilian Diehn, David B. Miklos, and Ash A. Alizadeh
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Cancer Research ,Oncology ,Medizin - Abstract
Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.
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- 2021
15. Abstract 3603: Reverse fate mapping of CD19-targeted CAR T cells in patients with large B-cell lymphoma
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Zinaida Good, Mark P. Hamilton, Jay Y. Spiegel, Sreevidya Kurra, Moksha Desai, Snehit Prabhu, Eric Yang, Michael G. Ozawa, Paul J. Hanson, Fang Wu, Matthew J. Frank, John H. Baird, Lori Muffly, Gursharan K. Claire, Juliana Craig, Katherine A. Kong, Dhananjay Wagh, John Coller, Sylvia K. Plevritis, Bita Sahaf, David B. Miklos, and Crystal L. Mackall
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Cancer Research ,Oncology - Abstract
Autologous T cells genetically engineered to express a chimeric antigen receptor targeting CD19 (CD19-CAR) have achieved high complete response rates in patients with hematologic malignancies, but >50% of patients progress following therapy. Here, we sought to understand key T-cell intrinsic factors impacting efficacy, namely CAR T-cell expansion, persistence, and homing to the tumor. Using an approach called reverse fate mapping, we followed individual T-cell clones at the single-cell level from pre-manufacture apheresis to the infusion product, tumor-involved lymph node, and blood at peak and late expansion in 12 adult patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel, an FDA-approved CD19-CAR T-cell immunotherapy. The resulting CAR T-cell atlas comprises matched transcriptome (scRNA-seq) and surface protein expression (CITE-seq) for 322,028 cells from 44 samples, with 119,397 unique T-cell receptor (TCR) clonotypes identified. This atlas enabled us to ask questions like: “What were the phenotypes of the most successful CAR T-cell clones at the time of infusion or pre-manufacture apheresis?” We found that T-cell clonotypes with juvenile features at apheresis, including IL7R expression, were the most successful at expansion to higher frequencies in the infusion product, while clones with effector gene expression programs, such as those encoding perforin and granzymes, contracted between apheresis and product. Conversely, it was GZMK-expressing T cells in pre-manufacture apheresis that were dominant in the tumor early following CAR T-cell infusion. Further, T-cell clonotypes with active effector programs at infusion dominated at peak expansion. Finally, we defined active expression modules and pathways in the infusion product for CAR T-cell clones that homed to the tumor or became dominant at late expansion. These analyses pinpoint the molecular mechanisms that could be modulated to rationally steer CAR T-cell differentiation trajectories at the genetic or pharmacological level. This work was supported in part by the Parker Institute for Cancer Immunotherapy, California Institute for Regenerative Medicine, Kite Pharma, and Stanford Cancer Institute. Citation Format: Zinaida Good, Mark P. Hamilton, Jay Y. Spiegel, Sreevidya Kurra, Moksha Desai, Snehit Prabhu, Eric Yang, Michael G. Ozawa, Paul J. Hanson, Fang Wu, Matthew J. Frank, John H. Baird, Lori Muffly, Gursharan K. Claire, Juliana Craig, Katherine A. Kong, Dhananjay Wagh, John Coller, Sylvia K. Plevritis, Bita Sahaf, David B. Miklos, Crystal L. Mackall. Reverse fate mapping of CD19-targeted CAR T cells in patients with large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3603.
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- 2022
16. Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy
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Judith A. Shizuru, Jay Y. Spiegel, Lori Muffly, Matthew J. Frank, Surbhi Sidana, Wen-Kai Weng, John S. Tamaresis, Robert S. Negrin, Sally Arai, Andrew Johnsrud, Juliana Craig, James L. Zehnder, Robert Lowsky, Andrew R. Rezvani, David B. Miklos, Theresa Latchford, John H. Baird, Laura Johnston, Everett Meyer, Parveen Shiraz, and Crystal L. Mackall
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medicine.medical_specialty ,Clinical Trials and Observations ,Cell- and Tissue-Based Therapy ,Fibrinogen ,Gastroenterology ,Risk Factors ,Internal medicine ,medicine ,Humans ,Platelet ,Retrospective Studies ,Univariate analysis ,Receptors, Chimeric Antigen ,business.industry ,Genitourinary system ,Incidence (epidemiology) ,Incidence ,Thrombosis ,Hematology ,medicine.disease ,Lymphoma ,Chimeric Antigen Receptor T-Cell Therapy ,business ,medicine.drug - Abstract
Key Points Clinically significant bleeding occurred in 9% of patients after CAR T therapy and was associated with features of systemic coagulopathy.Low baseline platelets and possibly high-grade ICANS are risk factors for bleeding and require close monitoring for bleeding up to 1 month., Visual Abstract, Bleeding and thrombotic events are an emerging toxicity associated with chimeric antigen receptor (CAR) therapies. To determine their incidence, we retrospectively analyzed consecutive adult patients (N = 127) with large B-cell lymphoma (LBCL) or B-cell acute lymphoblastic leukemia (B-ALL) treated from 2017 through 2020 with axicabtagene ciloleucel (axi-cel; n = 89) or a bispecific CD19/CD22 CAR (n = 38). Twelve (9.4%) and 8 (6.3%) patients developed bleeding and thrombosis within the first 3 months, respectively. In the axi-cel subgroup, these occurred in 11.2% and 6.7%, respectively. Bleeding occurred between days 8 and 30 (median, 17.5) and thrombosis between days 2 and 91 (median, 29). Bleeding sites included genitourinary, soft tissue, intracranial, gastrointestinal, and pulmonary and were associated with features of consumptive coagulopathy. On univariate analysis, patients with bleeding were older, had lower baseline platelets (86 × 103/μL vs 178 × 103/μL; P < .01), lower platelet and fibrinogen nadirs , and elevated lactate dehydrogenase. Immune effector cell (IEC)–associated neurotoxicity syndrome (ICANS) grade ≥3 was associated with increased bleeding (50% vs 15%; P = .01), thrombosis (50% vs 16%; P = .04), prothrombin time prolongation, hypofibrinogenemia, and elevated D-dimer. Low pretreatment platelet counts were associated with bleeding in a multivariate logistic regression model. Patients with thrombocytopenia or severe ICANS are at increased risk of bleeding and should be closely monitored, particularly within the first month after CAR therapy. Future studies in larger cohorts should assess risk factors for systemic coagulopathies in CAR T therapy, including their association with neurotoxicity.
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- 2021
17. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial
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Steven A. Feldman, Kara L. Davis, John H. Baird, Robert Lowsky, Rachel C. Lynn, Magali Bazzano, Judith A. Shizuru, Matthew J. Frank, Surbhi Sidana, Maria Caterina Rotiroti, Maria Iglesias, Sean Mackay, Sally Arai, Bita Sahaf, Shabnum Patel, Nirali N. Shah, Laura Johnston, Jay Y. Spiegel, Jing Zhou, Juliana Craig, Robert S. Negrin, Robbie G. Majzner, Andrew R. Rezvani, Zach Ehlinger, Ilan R. Kirsch, Parveen Shiraz, Chelsea D. Mullins, Michael G. Ozawa, Nikolaos Gkitsas, Crystal L. Mackall, Terry J. Fry, Warren D. Reynolds, Yasodha Natkunam, Sneha Ramakrishna, Scott J. Bornheimer, Allison P. Jacob, Lori Muffly, Jean Oak, Haiying Qin, Katherine A. Kong, Wen-Kai Weng, Everett Meyer, Nasheed Hossain, John S. Tamaresis, Sheren F. Younes, David B. Miklos, Liora M. Schultz, Eric J Yang, and Harshini Chinnasamy
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0301 basic medicine ,Oncology ,Adult ,medicine.medical_specialty ,Lymphoma, B-Cell ,Lymphoma ,medicine.medical_treatment ,Sialic Acid Binding Ig-like Lectin 2 ,Antigens, CD19 ,Cancer immunotherapy ,Immunotherapy, Adoptive ,General Biochemistry, Genetics and Molecular Biology ,CD19 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,immune system diseases ,Recurrence ,Phase I trials ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,B-cell lymphoma ,B cell ,Aged ,Acute lymphocytic leukaemia ,biology ,business.industry ,General Medicine ,Immunotherapy ,Middle Aged ,medicine.disease ,Chimeric antigen receptor ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Disease Progression ,business ,Progressive disease - Abstract
Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19− or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial (NCT03233854) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19−/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22−/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency., Bispecific CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in patients with large B cell lymphoma and B cell acute lymphoblastic leukemia, with relapses associated with loss of CD19 but not CD22.
- Published
- 2020
18. Clinical Validation of KIT Inhibition in Advanced Systemic Mastocytosis
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Jason Gotlib and John H. Baird
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Mutation, Missense ,Receptor tyrosine kinase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mastocytosis, Systemic ,Internal medicine ,medicine ,Humans ,Midostaurin ,Systemic mastocytosis ,Clinical Trials as Topic ,Hematology ,biology ,business.industry ,Imatinib ,Staurosporine ,medicine.disease ,Mast cell ,Clinical trial ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,medicine.anatomical_structure ,Amino Acid Substitution ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Bone marrow ,business ,medicine.drug - Abstract
We discuss recent developments in the treatment of advanced systemic mastocytosis (advSM) with inhibitors of the KIT receptor tyrosine kinase. advSM is a heterogeneous group of neoplasms of poor prognosis characterized by the accumulation of neoplastic mast cells. The canonical KIT D816V mutation is present in approximately 90% of SM patients, and its detection is critical for both diagnosis and therapeutic decision-making. The multikinase/KIT inhibitor midostaurin was recently approved for advSM. This agent can reverse SM-related organ damage and disease symptoms, and decrease the bone marrow mast cell burden and splenomegaly. However, complete remissions are rare and durability of responses is variable. Potent and selective KIT D816V inhibitors including avapritinib (BLU-285) and DCC-2618 have entered clinical trials, and rational combination strategies are under development. The clinical efficacy of KIT inhibitors validate KIT as a key oncogenic driver in mast cell neoplasms. An improved understanding of the genetic heterogeneity beyond KIT will help inform the dynamics of response and relapse.
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- 2018
19. CD22-CAR T-Cell Therapy Mediates High Durable Remission Rates in Adults with Large B-Cell Lymphoma Who Have Relapsed after CD19-CAR T-Cell Therapy
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Robert S. Negrin, Jean Oak, Kara L. Davis, Lori Muffly, Sheren F. Younes, Bita Sahaf, Juliana Craig, Maria Iglesias, Yasodha Natkunam, David B. Miklos, Shabnum Patel, Robert Lowsky, Sneha Ramakrishna, Surbhi Sidana, Wen-Kai Weng, Jay Y. Spiegel, Andrew R. Rezvani, Laura Johnston, Parveen Shiraz, Sally Arai, Emma Crawford, Zachary Ehlinger, Crystal L. Mackall, Steven A. Feldman, Emily Egeler, John H. Baird, Matthew J. Frank, Warren D. Reynolds, Liora M. Schultz, Harshini Chinnasamy, and Hrishikesh K. Srinagesh
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biology ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,CD19 ,Cell therapy ,Cancer research ,medicine ,biology.protein ,CAR T-cell therapy ,B-cell lymphoma ,business ,CD22 CAR-T - Abstract
BACKGROUND: Patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after failure of CD19-directed CAR T-cell therapy (CAR19) have a dire prognosis, with an overall response rate (ORR) of 29% to conventional salvage therapies, and a median overall survival (OS) of 6 months. CD22 is expressed on the majority of B-cell malignancies. Autologous CAR T-cells targeting CD22 (CAR22) have yielded an ORR of 70-90% in pediatric patients with R/R B-cell acute lymphoblastic leukemia (B-ALL), including those who had previously failed CAR19 therapy. Based on these encouraging results, we evaluated CAR22 in adult patients with R/R LBCL, focusing on those with CAR19-refractory disease. METHODS: This ongoing single-institution phase I dose escalation clinical trial (NCT04088890) is evaluating a CAR construct incorporating the m971 CD22 single chain variable fragments and 41BB/CD3z endodomains integrated within autologous T-cells via lentiviral transduction. After lymphodepletion (LD) with fludarabine and cyclophosphamide, patients are infused with cryopreserved CAR T-cells after a 7- to 11-day closed manufacturing process utilizing the CliniMACS Prodigy device (Miltenyi). Primary objectives assess the ability to successfully manufacture CAR22 and safety. Secondary objectives include efficacy and durability of responses. RESULTS: Twenty-one patients with LBCL [n=12 at dose level 1 (DL1), 1x10 6 CAR+ cells/kg; n=9 at dose level 2 (DL2), 3x10 6 CAR+ cells/kg] have been enrolled with a median age of 64 years (range, 36-79) and a median of 4 (range, 3-8) prior lines of therapy. All patients had at least one high risk feature, including failure of prior CAR19 therapy (n=20); refractory disease to second-line or later therapy (n=17); elevated lactate dehydrogenase (LDH) pre-LD (n=17); high tumor burden (n=9); a history of primary refractory disease (n=7); failure of prior autologous hematopoietic stem cell transplantation (HSCT) (n=6); never achieving CR to any therapy (n=5); or LBCL with MYC gene rearrangements (n=5). Successful manufacturing of cells was achieved in all patients. All patients reached day 28 post-infusion and are included in the safety and efficacy analysis presented here; updated results will be presented at the meeting. Every patient experienced cytokine release syndrome (CRS); 20/21 (95%) were Grade 1-2, 1/21 (5%) were Grade 3. Four patients (19%) experienced immune effector cell-associated neurotoxicity syndrome (ICANS); all cases were Grade 1-2 and resolved within 2 days. Five patients (24%) experienced a hyperinflammatory macrophage activation syndrome (MAS), manifested in all cases by pancytopenia and consumptive coagulopathy (DIC) requiring transfusion and/or growth factor support. One patient who received DL2 had a Grade 5 infectious event in the setting of ongoing MAS and pancytopenia. Relative to DL1, higher prevalence of Grade ≥3 cytopenias beyond D28 (89% vs. 50%) and MAS (33% vs. 17%) were observed at DL2; thus, DL1 was selected as the maximally tolerated dose (MTD). ORR at D28 was 86% (CR, n=11; PR, n=7), and was similar between DL1 and DL2 (92% vs. 78%; p=ns). 3/7 (43%) initial PR improved to CR at a median of 3 months post-infusion. All 14 patients (67% of cohort) who achieved CR remain in remission, with a mean follow-up of 7.3 months (range, 1.2-21.3); median progression free survival (PFS) and OS have not yet been reached. Five patients died from disease progression, and one patient died from septic shock in CR. CD22 expression by flow was downregulated or absent in 1/3 (33%) patients evaluated after relapse. Peak CAR-T expansion as detected by peripheral blood flow cytometry occurred at a median of 14 days, with a trend towards earlier and higher peak levels in DL2 patients. Significantly higher mean CAR-T levels occurred at peak expansion in patients who developed MAS (1070±915 vs. 196±209 CAR+ cells/μL; p=0.001). CONCLUSIONS: Infusion of CAR22 in R/R LBCL is safe and well tolerated at DL1. Manufacturing of CAR22 was uniformly successful. With a mean follow-up of 7.3 months, the ORR and CR rates are 18/21 (86%) and 14/21 (67%), respectively. These data demonstrate CAR22 to be an effective salvage therapy for CAR19-refractory or CD19-negative LBCL. Figure 1 Figure 1. Disclosures Frank: Allogene Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees. Oak: Kite Pharma-Gilead: Research Funding. Arai: Magenta Therapeutics: Research Funding. Rezvani: Kaleido: Other: One-time scientific advisory board; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding; US Department of Justice: Consultancy. Shiraz: Kite Pharma-Gilead: Research Funding. Sidana: Janssen: Consultancy, Research Funding; Allogene: Research Funding; Magenta Therapeutics: Consultancy, Research Funding; BMS: Consultancy. Weng: Kite Pharma: Research Funding. Davis: Novartis Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Research Funding. Feldman: Samsara Biocapital: Consultancy; Obsidian: Consultancy; Lonza PerMed: Consultancy; Gradalis: Consultancy. Mackall: Lyell: Consultancy, Current equity holder in publicly-traded company, Other: Founder; Syncopation Life Sciences: Consultancy, Current holder of individual stocks in a privately-held company, Other: Founder; Apricity: Consultancy, Current equity holder in publicly-traded company; Neoimmune Tech: Consultancy; Nektar: Consultancy, Research Funding. Miklos: Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics: Patents & Royalties; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees. Muffly: Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding; Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy. OffLabel Disclosure: CD22-directed CAR-T therapy for the treatment of adults with relapsed/refractory large B-cell lymphoma
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- 2021
20. Bleeding and Thrombosis Are Associated with Endothelial Dysfunction in CAR-T Cell Therapy and Are Increased in Patients Experiencing Neurologic Toxicity
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Matthew J. Frank, Andrew R. Rezvani, Robert Lowsky, Surbhi Sidana, Andrew Johnsrud, Laura Johnston, Sally Arai, Robert S. Negrin, David B. Miklos, Parveen Shiraz, Juliana Craig, Crystal L. Mackall, Wen-Kai Weng, James L. Zehnder, John H. Baird, Judith A. Shizuru, Everett Meyer, Theresa Latchford, Jay Y. Spiegel, and Lori Muffly
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Transplantation ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,Thrombin time ,medicine.disease ,Biochemistry ,Thrombosis ,Lymphoma ,Cytokine release syndrome ,Internal medicine ,Cohort ,medicine ,Coagulopathy ,Molecular Medicine ,Immunology and Allergy ,Platelet ,business - Abstract
Background Treatment with chimeric antigen receptor (CAR) T cell therapies have shown dramatic, often durable responses for relapsed/refractory B-cell malignancies. However, it can be associated with significant side effects such as cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS) and life-threatening consumptive coagulopathies. The underlying pathobiology of such hemostatic defects and their distinct clinical sequelae remains obscure. This retrospective study aims at quantifying CAR T therapy associated bleeding and thrombotic complications and their association with CRS, ICANS, and laboratory derangements. Methods 130 adult patients with DLBCL or B-ALL treated between 2017-2020 with CD19 CAR-T therapy axicabtagene ciloleucel (N=90) or a bispecific CD 19/22 CAR construct utilizing 4-1BB costimulatory domains (N=40) were analyzed to determine dynamics of coagulation parameters and platelet counts as well as incidences of bleeding or thrombosis in the first three months after CAR T infusion. Events were included if graded ≥ 2 or if intervention was required. Platelet counts and coagulation parameters were collected prior to lymphodepletion (pre-LD), day 0, 3, 7, 14, 21, 28, 60 and 90. Results 12 (9.2%) and 8 (6.2%) patients developed bleeding and thrombotic complications in the first three months after CAR-T infusion, respectively. Events are characterized in Figure 1. All bleeding events occurred between days 0-30 (median 17.5, range 8-30), while thrombotic events occurred between days 2-91 (median day 29, range, 2-91). Two (1.5%) patients experienced both bleeding and thrombosis. Bleeding events coincided with the onset of thrombocytopenia and hypofibrinogenemia, and patients who bled had lower platelet (median 22.5 vs. 47 K/uL; p=0.03) and fibrinogen (median 151 vs. 351 ug/mL; p=0.007) nadirs in the first 30 days compared to those without bleeding. Temporally, the lowest median platelet nadir occurred at day 7 in patients with bleeding events vs. day 21 in patients without bleeding, while timing of fibrinogen nadirs were at day 21 in both. Patients with bleeding episodes were more likely to be older (median age: 70 vs. 60 yrs, p=0.03), have thrombocytopenia prior to lymphodepletion therapy (median 117.5 vs. 174.5 K/uL, p=0.01), and have elevated LDH (lymphoma subgroup; p=0.07). Other lab derangements in the first 30 days seen more frequently in patients with bleeding included prolonged thrombin time (TT) (21% vs. 6%; p=0.02), PT (16% vs. 5%; p=0.06), and elevated d-dimer (16% vs. 3%; p=0.01) indicative of a consumptive process. Thrombotic events were not significantly associated with elevated or peak d-dimer values (median 4.97 vs. 2.37 ug/mL, p=0.20). Interestingly, occurrence or severity of CRS was not associated with bleeding or thrombotic events, nor was it associated with marked derangements in coagulation abnormalities. However, higher grade ICANS (grade > 3) was associated with bleeding (42% vs. 15%; p=0.038), thrombosis (50% vs. 16%; p=0.03), and evidence of endothelial activation including PT prolongation (78% vs. 35%; p 13 (10%) patients received anticoagulation for prophylaxis or therapeutic indications that predated CAR T infusion. Four started anticoagulation secondarily for thrombotic events after CAR-T infusion, and one received tissue plasminogen activator (tPA) for an acute stroke. In this group, no patients developed bleeding complications from anticoagulation. Conclusion Both bleeding (9.2%), and thrombotic (6.2%) events are observed after CAR T cell therapy, with bleeding limited to the first month in our cohort. Notably, ICANS was uniquely associated with PT prolongation, hypofibrinogenemia, and increased fibrin degradation, in addition to both bleeding and thrombosis. These results suggest that a systemic coagulopathy coincides with high grade ICANS and whether these neurologic events truly represent sequelae of widespread vascular dysfunction warrants further investigation. Anticoagulation was safe in the patients whom it was indicated. Risk factors for bleeding and thrombotic complications should be studied prospectively to develop risk-assessment models and clinical guidelines for management of bleeding and thrombosis (including prophylaxis) during CAR T therapy. Disclosures Muffly: Adaptive: Research Funding; Servier: Research Funding; Amgen: Consultancy. Negrin:BioEclipse Therapeutics: Current equity holder in private company; Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; KUUR Therapeutics: Consultancy; Biosource: Current equity holder in private company; Amgen: Consultancy; UpToDate: Honoraria. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Meyer:Orca Bio: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Rezvani:Pharmacyclics: Research Funding. Mackall:Apricity Health: Consultancy, Current equity holder in private company; NeoImmune Tech: Consultancy; Nektar Therapeutics: Consultancy; Allogene: Current equity holder in publicly-traded company; BMS: Consultancy; Lyell Immunopharma: Consultancy, Current equity holder in private company. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Sidana:Janssen: Consultancy.
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- 2021
21. CD22-Directed CAR T-Cell Therapy Mediates Durable Complete Responses in Adults with Relapsed or Refractory Large B-Cell Lymphoma after Failure of CD19-Directed CAR T-Cell Therapy and High Response Rates in Adults with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia
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Shabnum Patel, Andrew R. Rezvani, Warren D. Reynolds, Kara L. Davis, Sally Arai, Matthew J. Frank, Robert S. Negrin, Bita Sahaf, Jay Y. Spiegel, Robert Lowsky, Zachary Ehlinger, Juliana Craig, Lori Muffly, Steven A. Feldman, Wen-Kai Weng, Surbhi Sidana, John H. Baird, Jean Oak, Laura Johnston, Liora M. Schultz, Yasodha Natkunam, Sneha Ramakrishna, Sheren F. Younes, David B. Miklos, Parveen Shiraz, and Crystal L. Mackall
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Oncology ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Lymphoma ,Fludarabine ,Clinical trial ,Cytokine release syndrome ,Refractory ,Median follow-up ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
BACKGROUND: CD22 is expressed on the majority of B-cell malignancies. Autologous CAR T-cells targeting CD22 (CAR22) have yielded objective response rates (ORR) of 70-90% in pediatric patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL), including those who had previously failed CD19-directed CAR T-cell (CAR19) therapy. Based on these encouraging results, we evaluated CAR22 in adult patients with R/R ALL and for the first time in patients with R/R large B-cell lymphoma (LBCL), including those who had failed prior autologous CAR19 therapy. METHODS: This single-institution phase I dose escalation clinical trial (NCT04088890) is evaluating a CAR construct incorporating the m971 CD22 single chain variable fragments and 41BB/CD3z endodomains integrated within autologous T-cells via lentiviral transduction. After lymphodepletion with fludarabine and cyclophosphamide, patients were infused with fresh or cryopreserved CAR T-cells after a 7- to 11-day closed manufacturing process utilizing the CliniMACS Prodigy device (Miltenyi). The current cohort includes patients treated at dose level 1 (DL1), which was 1x106 CAR+ cells/kg. Primary objectives assessed the ability to successfully manufacture CAR22 and safety. Overall response rate (ORR) at 28 days post-infusion (D28) was a secondary objective. RESULTS: Three patients with LBCL have been enrolled with a median age of 53 years (range, 51-57) and a median of 6 (range, 5-8) prior lines of therapy. All three patients received prior CAR19 and had refractory disease to second-line or later therapy (n=3); had not undergone autologous hematopoietic stem cell transplantation (HSCT) (n=3); had MYC and BCL2 gene rearrangements (double-hit lymphoma; n=2); had high tumor burden (SPD >50 cm2; n=2); had a history of primary refractory disease (n=1); or had never achieved CR to any therapy (n=1). Six patients with ALL have been enrolled with a median age of 43.5 years (range, 23-62) and a median of 6 (range, 4-8) prior lines of therapy. All six patients received prior allogeneic HSCT and had Ph-positive disease (n=3); had central nervous system (CNS) involvement (n=3); had extramedullary disease (n=2); had high disease burden (BM blasts >5%; n=2); had received prior CD19-directed therapy (n=5); or had received prior CD22-directed therapy (n=3). Successful manufacturing of cells at DL1 was achieved in all patients. All patients (LBCL n=3, ALL n=6) reached day 28 and are included in the safety and response analysis presented here; updated results will be presented at the meeting. Eight patients (88.9%) experienced cytokine release syndrome (CRS); all were Grade 1-2. There were no cases of immune effector cell-associated neurotoxicity syndrome (ICANS). No differences in toxicities were seen across the patient age spectrum and no Grade 5 toxicities occurred following CAR22 infusion. In LBCL, all patients achieved a response at D28 (ORR=100%; CR, n=1, PR, n=2). Both patients with a D28 PR improved to CR by day 90 and 180. All patients remain in CR, with a median follow-up of 8.4 months (range, 6-9.3). In ALL, all patients achieved a CR at D28 (ORR=100%; MRD-, n=5, MRD+, n=1). After a median follow up of 5.1 months (range, 1-8.2), three patients relapsed at 2.5, 4, and 5.5 months after infusion; one patient died while undergoing subsequent therapy 7.3 months post-infusion. CD22 expression by flow cytometry was downregulated or absent in two patients after relapse. Peak CAR expansion as detected by peripheral blood flow cytometry reached a median level of 90.1 (LBCL; range, 85.4-350) and 43.4 (ALL; range, 0.9-399.6) CAR+ cells/µL between D14 and D21. In two LBCL patients with progression following CAR19, CAR22 levels were 11.7 and 55.9 fold higher than prior CAR19 levels at peak expansion. CONCLUSIONS: Infusion of CD22-targeting CAR T-cells in R/R LBCL and ALL is safe and well tolerated. Manufacturing of CAR22 was uniformly successful. To date, 3 of 3 heavily treated adult patients with LBCL whose disease relapsed after prior CAR19 have each achieved CR durable to at least 6 months. All adult ALL patients have achieved CR following CAR22, with some early relapses observed. Accrual is ongoing. Disclosures Negrin: Amgen: Consultancy; Biosource: Current equity holder in private company; UpToDate: Honoraria; KUUR Therapeutics: Consultancy; Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; BioEclipse Therapeutics: Current equity holder in private company. Rezvani:Pharmacyclics: Research Funding. Shiraz:ORCA BioSystems: Research Funding; Kite, a Gilead Company: Research Funding. Sidana:Janssen: Consultancy. Mackall:BMS: Consultancy; Allogene: Current equity holder in publicly-traded company; Apricity Health: Consultancy, Current equity holder in private company; Nektar Therapeutics: Consultancy; NeoImmune Tech: Consultancy; Lyell Immunopharma: Consultancy, Current equity holder in private company. Miklos:Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Muffly:Amgen: Consultancy; Adaptive: Research Funding; Servier: Research Funding. OffLabel Disclosure: CD22-directed CAR T-cell Therapy for the treatment of adults with relapsed/refractory LBCL and B-ALL
- Published
- 2020
22. An Unusual Cause of Epistaxis: Paranasal Sinus Myeloid Sarcoma
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John H. Baird, Courtney Shires, and Karuna Dewan
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Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,lcsh:RC633-647.5 ,business.industry ,Infratemporal fossa ,Myeloid leukemia ,Case Report ,lcsh:Diseases of the blood and blood-forming organs ,General Medicine ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cavernous sinus ,Biopsy ,medicine ,Myeloid sarcoma ,Bone marrow ,Differential diagnosis ,business ,Sinus (anatomy) ,030215 immunology - Abstract
We report a case of a 65-year-old female who presented with right-sided headaches, blurring of vision in the right eye, cold-induced epistaxis, and facial numbness in the trigeminal nerve distribution. Laboratory studies revealed a significant number of myeloblasts on peripheral smear with granulated cytoplasm, irregular nuclei, and prominent vacuoles. Magnetic resonance imaging (MRI) of the brain demonstrated a T1-enhancing 1.5 cm right-sided dural-based lesion involving the medial sphenoid wing, cavernous sinus, infratemporal fossa, and sphenoid sinus region. An endoscopic biopsy of the lesion within the sphenoid sinus confirmed the diagnosis of myeloid sarcoma, with myeloblasts comprising 30% of cellularity by flow cytometry. A subsequent bone marrow biopsy revealed a hypercellular marrow with 23% blasts by flow cytometry that demonstrated a similar immunophenotypic pattern to those seen in the sinus mass. Fluorescence in situ hybridization (FISH) testing revealed the balanced translocation t(8;21)(q22;q22.1), consistent with a diagnosis of acute myeloid leukemia with RUNX1-RUNX1T1-balanced translocation by WHO 2016 criteria. Myeloid sarcoma represents a rare extramedullary presentation of acute myeloid leukemia (AML), either alone or in conjunction with blood or bone marrow involvement. This case emphasizes the need for a broad differential diagnosis and an aggressive work-up for any unusual paranasal sinus mass.
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- 2019
23. Anti-CD22 CAR T-Cell Therapy Mediates Durable Complete Responses in Adults with Relapsed or Refractory Large B-Cell Lymphoma after Failure of Anti-CD19 CAR T-Cell Therapy and High Response Rates in Adults with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia
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Steven R. Feldman, Juliana Craig, Kara L. Davis, Robert Lowsky, Zachary Ehlinger, Sheren F. Younes, Robert S. Negrin, David B. Miklos, Sally Arai, Parveen Shiraz, Crystal L. Mackall, Liora M. Schultz, Bita Sahaf, Yasodha Natkunam, John H. Baird, Wen-Kai Weng, Surbhi Sidana, Sneha Ramakrishna, Lori Muffly, Laura Johnston, Jean Oak, Shabnum Patel, Warren D. Reynolds, Matthew J. Frank, Andrew R. Rezvani, and Jay Y. Spiegel
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Transplantation ,business.industry ,Anti cd19 ,Cell Biology ,Hematology ,B-cell acute lymphoblastic leukemia ,medicine.disease ,Cell therapy ,Refractory ,Cancer research ,Molecular Medicine ,Immunology and Allergy ,CAR T-cell therapy ,Medicine ,business ,CD22 CAR-T ,B-cell lymphoma - Published
- 2021
24. Lactate Dehydrogenase to Carboxyhemoglobin Ratio As a Biomarker of Heme Release to Heme Processing Is Associated with Higher Tricuspid Regurgitant Jet Velocity and Early Death in Sickle Cell Disease
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Eduard J. van Beers, Laurel Mendelsohn, Gregory J. Kato, Richard van Wijk, Caterina P. Minniti, Annelies J. Van Vuren, and John H. Baird
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medicine.medical_specialty ,biology ,Bilirubin ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Pulmonary hypertension ,Sickle cell anemia ,Ferritin ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Lactate dehydrogenase ,Carboxyhemoglobin ,medicine ,Cardiology ,biology.protein ,Hemoglobin ,Heme - Abstract
Background Chronic hemolysis is a hallmark of sickle cell disease (SCD). Intravascular hemolysis in particular is associated with severe vasculopathic complications including pulmonary hypertension (PH) and early mortality. Free heme causes oxidative damage and recently was identified as erythrocyte-derived Danger Associated Molecular Pattern (e-DAMP), associated with endothelial activation and vaso-occlusion in SCD (Belcher et al., Blood. 2014; Ghosh et al., J. Clin. Invest. 2013). Intravascular hemolysis is associated with elevated levels of serum lactate dehydrogenase (LDH). Heme catabolism leads to endogenous carbon monoxide (CO) production by heme oxygenase-1 (HO1), and CO is eliminated in exhaled breath. CO is transported primarily as the conjugate carboxyhemoglobin (HbCO), and end-alveolar CO (EACO) is an accepted proxy marker for its concentration in blood. We evaluated several lab values and ratios that might reflect the relative contribution of intravascular heme release and overall heme processing. Methods We investigated the relationship between EACO, HbCO (NCT01547793, cohort A) and other biomarkers of hemolysis in adults with SCD at steady state as part of the clinical cohort at the National Institutes of Health Clinical Center, Bethesda, Maryland, USA (NCT00011648, cohort B). Of the patients included in the cohort B, all routine samples with results on HbCO were included in the analyses. In a subgroup of the cohort B with data available on HbCO, echocardiography and/or mortality, we evaluated the correlation between LDH/HbCO ratio and echocardiographic markers of PH and all-cause mortality (cohort C). Combining all recognized available markers for hemolysis (total bilirubin, AST, absolute reticulocyte count, hemoglobin, median LDH, median HbCO and LDH/HbCO ratio) in a multivariate Cox proportional hazards model for survival led to selection of a predictive model encompassing three biomarkers: LD/HbCO ratio, AST and hemoglobin. Of these three markers, the LD/HbCO ratio was the most predictive factor. We also conducted univariate correlations with clinical outcome indicators. Main findings Erythropoietic and hemolytic laboratory parameters of the cohorts are provided in Table 1. HbCO concentrations and EACO were strongly correlated (Pearson's correlation r=0.66, p The patients of cohort C were divided into low (peak TRV =3.0m/s, N=13) categories, based upon prior cut-points determined by risk of development of PH and early mortality (Mehari A. et al. JAMA. 2012) (Figure 1, panel A). LDH/HbCO ratios were positively correlated with TRV (r=0.38, p=3.0m/s (Mann-Whitey U test; p=0.02). In contrast, LDH values alone were not discriminative. All patients (25/25) with a LDH/HbCO ratio 1,200. In the intermediate risk subgroup, PH was only diagnosed in individuals with LDH/HbCO ratios exceeding 1,200. Median follow-up was 12.1 years (IQR 10.3; 16.3), 25% (23/91) of the patients died during follow-up. Five-year, 10-year and 15-year overall survival in the group with LDH/HbCO ratio >1,200 were respectively 92.1%, 76.0% and 69.1%, whereas 5-year, 10-year and 15-year overall survival in the group with LDH/HbCO ratio Main conclusions A ratio of two readily available clinical laboratory markers, LDH and HbCO, is promising as a potential biomarker in SCD. Increased LDH/HbCO ratios are strongly associated with elevated TRV and all-cause mortality, and thereby might improve the individual risk prediction in SCD patients. These markers deserve additional validation in future prospective trials. Disclosures van Wijk: Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. Minniti:Doris Duke Foundation: Research Funding. Kato:Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding. van Beers:Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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- 2019
25. Identification of Two CAR T-Cell Populations Associated with Complete Response or Progressive Disease in Adult Lymphoma Patients Treated with Axi-Cel
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Zinaida Good, Bita Sahaf, Sean C. Bendall, Gursharan K. Claire, Jay Y. Spiegel, Katherine A. Kong, Lori Muffly, Crystal L. Mackall, Meena Malipatlolla, David B. Miklos, Matthew J. Frank, Juliana Craig, and John H. Baird
- Subjects
education.field_of_study ,medicine.medical_specialty ,Immunology ,Population ,Becton dickinson ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Clinical trial ,Identification (information) ,Family medicine ,medicine ,Car t cells ,education ,Diffuse large B-cell lymphoma ,health care economics and organizations ,Progressive disease ,Complete response - Abstract
Axicabtagene ciloleucel (Axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Long-term analysis of the ZUMA-1 phase 1-2 clinical trial showed that ~40% of Axi-cel patients remained progression-free at 2 years (Locke et al., Lancet Oncology 2019). Those patients who achieved a complete response (CR) at 6 months generally remained progression-free long-term. The biological basis for achieving a durable CR in patients receiving Axi-cel remains poorly understood. Here, we sought to identify CAR T-cell intrinsic features associated with CR at 6 months in DLBCL patients receiving commercial Axi-cel at our institution. Using mass cytometry, we assessed expression of 33 surface or intracellular proteins relevant to T-cell function on blood collected before CAR T cell infusion, on day 7 (peak expansion), and on day 21 (late expansion) post-infusion. To identify cell features that distinguish patients with durable CR (n = 11) from those who developed progressive disease (PD, n = 14) by 6 months following Axi-cel infusion, we performed differential abundance analysis of multiparametric protein expression on CAR T cells. This unsupervised analysis identified populations on day 7 associated with persistent CR or PD at 6 months. Using 10-fold cross-validation, we next fitted a least absolute shrinkage and selection operator (lasso) model that identified two clusters of CD4+ CAR T cells on day 7 as potentially predictive of clinical outcome. The first cluster identified by our model was associated with CR at 6 months and had high expression of CD45RO, CD57, PD1, and T-bet transcription factor. Analysis of protein co-expression in this cluster enabled us to define a simple gating scheme based on high expression of CD57 and T-bet, which captured a population of CD4+ CAR T cells on day 7 with greater expansion in patients experiencing a durable CR (mean±s.e.m. CR: 26.13%±2.59%, PD: 10.99%±2.53%, P = 0.0014). In contrast, the second cluster was associated with PD at 6 months and had high expression of CD25, TIGIT, and Helios transcription factor with no CD57. A CD57-negative Helios-positive gate captured a population of CD4+ CAR T cells was enriched on day 7 in patients who experienced progression (CR: 9.75%±2.70%, PD: 20.93%±3.70%, P = 0.016). Co-expression of CD4, CD25, and Helios on these CAR T cells highlights their similarity to regulatory T cells, which could provide a basis for their detrimental effects. In this exploratory analysis of 25 patients treated with Axi-cel, we identified two populations of CD4+ CAR T cells on day 7 that were highly associated with clinical outcome at 6 months. Ongoing analyses are underway to fully characterize this dataset, to explore the biological activity of the populations identified, and to assess the presence of other populations that may be associated with CAR-T expansion or neurotoxicity. This work demonstrates how multidimensional correlative studies can enhance our understanding of CAR T-cell biology and uncover populations associated with clinical outcome in CAR T cell therapies. This work was supported by the Parker Institute for Cancer Immunotherapy. Figure Disclosures Muffly: Pfizer: Consultancy; Adaptive: Research Funding; KITE: Consultancy. Miklos:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees. Mackall:Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board.
- Published
- 2019
26. Blasts of a Different Sort
- Author
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John H. Baird, Jenny Hoffman, and Jason Gotlib
- Subjects
Computer science ,sort ,Arithmetic - Published
- 2017
27. Letter to the Editor: On the November December 2016 Image Challenge
- Author
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Jason Gotlib and John H. Baird
- Subjects
Letter to the editor ,business.industry ,Art history ,Medicine ,business - Published
- 2017
28. A Stimulating Case of Leukocytosis
- Author
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John H. Baird and Jason Gotlib
- Subjects
medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Leukocytosis ,medicine.symptom ,business ,Gastroenterology - Published
- 2016
29. Inhibiting Adipose Tissue Lipogenesis Reprograms Thermogenesis and PPARγ Activation to Decrease Diet-Induced Obesity
- Author
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Fong Fu-Hsu, Babak Razani, Clay F. Semenkovich, Haowei Song, Anne P.L. Jensen-Urstad, Katsuhiko Funai, Meral K. El Ramahi, Trey Coleman, Li Yin, John H. Baird, John Turk, and Irfan J. Lodhi
- Subjects
medicine.medical_specialty ,Physiology ,Blotting, Western ,Adipose tissue ,Peroxisome proliferator-activated receptor ,Biology ,Article ,Mass Spectrometry ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Internal medicine ,Adipocyte ,medicine ,Animals ,Immunoprecipitation ,Obesity ,Cloning, Molecular ,Molecular Biology ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Lipogenesis ,Lipid metabolism ,Thermogenesis ,3T3 Cells ,Cell Biology ,Enzyme Activation ,PPAR gamma ,Fatty acid synthase ,Endocrinology ,chemistry ,Adipose Tissue ,Adipogenesis ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,biology.protein ,Body Composition ,Fatty Acid Synthases ,Energy Metabolism ,Sugar Alcohol Dehydrogenases - Abstract
SummaryDe novo lipogenesis in adipocytes, especially with high fat feeding, is poorly understood. We demonstrate that an adipocyte lipogenic pathway encompassing fatty acid synthase (FAS) and PexRAP (peroxisomal reductase activating PPARγ) modulates endogenous PPARγ activation and adiposity. Mice lacking FAS in adult adipose tissue manifested increased energy expenditure, increased brown fat-like adipocytes in subcutaneous adipose tissue, and resistance to diet-induced obesity. FAS knockdown in embryonic fibroblasts decreased PPARγ transcriptional activity and adipogenesis. FAS-dependent alkyl ether phosphatidylcholine species were associated with PPARγ and treatment of 3T3-L1 cells with one such ether lipid increased PPARγ transcriptional activity. PexRAP, a protein required for alkyl ether lipid synthesis, was associated with peroxisomes and induced during adipogenesis. PexRAP knockdown in cells decreased PPARγ transcriptional activity and adipogenesis. PexRAP knockdown in mice decreased expression of PPARγ-dependent genes and reduced diet-induced adiposity. These findings suggest that inhibiting PexRAP or related lipogenic enzymes could treat obesity and diabetes.
- Published
- 2012
- Full Text
- View/download PDF
30. Voriconazole-induced periostitis after allogeneic stem cell transplantation
- Author
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John H, Baird, Belinda K, Birnbaum, David L, Porter, and Noelle V, Frey
- Subjects
Leukemia, Myeloid, Acute ,Periostitis ,14-alpha Demethylase Inhibitors ,Humans ,Neoplasms, Second Primary ,Voriconazole ,Middle Aged ,Allografts ,Radionuclide Imaging ,Carcinoma, Renal Cell ,Kidney Neoplasms ,Stem Cell Transplantation - Published
- 2015
31. Voriconazole-induced periostitis after allogeneic stem cell transplantation
- Author
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David L. Porter, Noelle V. Frey, Belinda K. Birnbaum, and John H. Baird
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Voriconazole ,Pathology ,medicine.medical_specialty ,Myeloid ,business.industry ,Hematology ,medicine.disease ,Periostitis ,Transplantation ,Leukemia ,medicine.anatomical_structure ,medicine ,Carcinoma ,Radionuclide imaging ,Stem cell ,business ,medicine.drug - Published
- 2015
32. A Novel Synthetic Route to 1,3-Disubstituted Naphthalenes
- Author
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James M. Coxon, Lucjan Strekowski, John H. Baird, Andrew Burritt, Alexander S. Kiselyov, and Roman L. Wydra
- Subjects
chemistry.chemical_compound ,Trifluoromethyl ,chemistry ,Group (periodic table) ,Organic Chemistry ,Organic chemistry ,chemistry.chemical_element ,Lithium - Abstract
1-(2-Substituted 1-propenyl)-2-(trifluoromethyl)benzenes are cyclized to 3-substituted 1-(4-methylpiperazino)naphthalenes in a lithium 4-methylpiperazide-mediated reaction that involves the trifluoromethyl group.
- Published
- 1994
33. ChemInform Abstract: A Novel Synthetic Route to 1,3-Disubstituted Naphthalenes
- Author
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Andrew Burritt, Alexander S. Kiselyov, John H. Baird, James M. Coxon, Lucjan Strekowski, and Roman L. Wydra
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chemistry.chemical_compound ,Trifluoromethyl ,chemistry ,Group (periodic table) ,Carbonyl derivatives ,chemistry.chemical_element ,Lithium ,General Medicine ,Medicinal chemistry - Abstract
1-(2-Substituted 1-propenyl)-2-(trifluoromethyl)benzenes are cyclized to 3-substituted 1-(4-methylpiperazino)naphthalenes in a lithium 4-methylpiperazide-mediated reaction that involves the trifluoromethyl group.
- Published
- 2010
34. The neuropsychiatric program of the Veterans Administration
- Author
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Daniel Blain and John H. Baird
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Psychiatry ,medicine.medical_specialty ,business.industry ,Neuropsychiatry ,United States ,Psychiatry and Mental health ,United States Department of Veterans Affairs ,medicine ,Humans ,business ,Administration (government) ,Veterans - Published
- 2010
35. Renal risks of cardiac catheterization in the elderly
- Author
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John H. Baird, Michael W. Rich, Charles A. Crecelius, and Marcos Rothstein
- Subjects
Nephrology ,medicine.medical_specialty ,Kidney ,business.industry ,Urology ,medicine.medical_treatment ,Geriatric nephrology ,Renal function ,medicine.disease ,Nephrotoxicity ,Nephropathy ,medicine.anatomical_structure ,Internal medicine ,medicine ,Geriatrics and Gerontology ,Intensive care medicine ,business ,Contraindication ,Cardiac catheterization - Abstract
Age-related changes in renal structure and function and an increased prevalence of comorbid illnesses predispose the elderly patient to increase risk of contrast-induced nephropathy following cardiac catheterization and other procedures. This article briefly reviews the effects of aging on the kidney, then summarizes current literature on the risks of nephrotoxicity following cardiac catheterization in elderly patients. Finally, a series of therapeutic guidelines are proposed which should serve to minimize the risk of contrast nephropathy in elderly patients requiring cardiac catheterization. Based on available evidence, it is concluded that the risk of serious deterioration in renal function following contrast exposure is acceptably low and should not be considered a strong contraindication to performing cardiac catheterization in appropriately selected elderly patients.
- Published
- 1992
36. End-Alveolar Carbon Monoxide As a Measure of Erythrocyte Survival and Hemolytic Severity in Sickle Cell Disease
- Author
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Yang Xia, Laurel Mendelsohn, Dihua Xu, John H. Baird, Mary Jackson, Gregory J. Kato, James S. Nichols, Caterina P. Minniti, Daniel B. Kim-Shapiro, and Rehan Saiyed
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medicine.medical_specialty ,Pathology ,Red Cell ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease_cause ,medicine.disease ,Biochemistry ,Gastroenterology ,Hemolysis ,Nitric oxide ,chemistry.chemical_compound ,Red blood cell ,medicine.anatomical_structure ,chemistry ,Internal medicine ,medicine ,Prospective cohort study ,business ,Oxidative stress ,Blood sampling ,Blood drawing - Abstract
Introduction: In sickle cell disease, polymerization of sickle hemoglobin gives rise to changes in the integrity and viability of the erythrocyte, leading to both extravascular and intravascular hemolysis and shortened life-span. Current gold standard techniques to estimate RBC survival require that a label be placed on the cells that can be followed while the RBCs age in the circulation. These studies are infrequently employed in practice, due to the need for multiple blood draws and an extended period of observation (6 weeks) in order to obtain the necessary time points. Endogenous CO is a technique that has been used in multiple studies to assess RBC survival, based upon the principal that virtually all CO produced in human beings results from cleavage of the α-methene bond of heme and is completely excreted via the lungs. Because RBC destruction accounts for approximately 80% of heme turnover in the body, endogenous CO production can be used as a quantitative indicator of RBC life span. Furne has reported on the development of a simple, rapid, and noninvasive method for determining RBC life span based on gas chromatography measurement of exhaled alveolar CO (EACO) concentration immediately upon awakening corrected for atmospheric CO, as determined with a device that simulates the body's equilibration with CO. We set up to investigate the use of early morning end-alveolar CO (EACO) concentration as a quantitative measure of RBC life span and correlate it to indirect measurements of hemolytic rate in subjects with sickle cell disease. Material and methods: EACO was measured within 24 hours of breath collection in 67 SCD adult patients (67 HbSS, 4 HbSC and 1 HbSb-Thalassemia) and 14 HbAA race matched controls on an Ametrek TA 7000 Gas Purity Monitor. Subjects were at steady state, at least 30 days from transfusion or acute exacerbations. Breath samples were collected immediately upon awakening the same day as blood sampling for additional tests. EACO groups were compared using the Mann-Whitney test. EACO values were used to calculate the red blood cell lifespan by the method of Furne (PMID 12878986), using the calculation: RBC survival (days) = 1,380 · [Hb]/EACO. Correlation analyses are reported using Pearson's correlation coefficient. The statistical significance was set at a two-side p < .05. Analyses were performed with R version 2.13.1 (2011-07-08). Results: EACO was nearly four-fold higher in patients than controls (median 2.25 vs. 0.58 ppm, p Conclusions: Our results confirm the usefulness of exhaled CO measurement as a marker of hemolysis and red cell survival and in substantial, prospective cohort of adult patients with SCD, confirming and considerably extending results of other investigators. EACO-derived RBC survival can be used to update estimates from Crosby in 1955 regarding the proportion of overall hemolysis falling into the extravascular and intravascular categories, the latter related to oxidative stress and scavenging of nitric oxide. This assay may be a useful biomarker in clinical trials of therapeutic interventions aimed at improving red cell life-span in SCD and other hemolytic anemias. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
37. Some Aspects of Dietetics in The Veterans Administration1
- Author
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Col. John H. Baird
- Subjects
Nutrition and Dietetics ,Food Science - Published
- 1945
38. The Value of an Intrahospital Staff Postgraduate Course of Study in Neuropsychiatry
- Author
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John H. Baird
- Subjects
Psychiatry and Mental health ,Medical education ,business.industry ,Medicine ,Neuropsychiatry ,business ,Value (mathematics) ,Course (navigation) - Published
- 1932
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