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David L. Porter - One of the best experts on this subject based on the ideXlab platform.

  • Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2018
    Co-Authors: Noelle V Frey, David L. Porter
    Abstract:

    Abstract Chimeric Antigen Receptor (CAR)-modified T cells (CAR-Ts) targeting CD19 have resulted in unprecedented durable remissions for patients with relapsed and refractory B cell malignancies. Cytokine release syndrome (CRS), resulting from rapid immune activation induced by CAR-Ts, is the most significant treatment-related toxicity. CRS initially manifests with fever and can progress to life-threatening capillary leak with hypoxia and hypotension. The clinical signs of CRS correlate with T cell activation and high levels of cytokines including IL-6. Tocilizumab, an anti-IL-6 Receptor antagonist, is the standard for CRS management, but optimal timing of administration is unclear. The development of a supportive infrastructure by treatment centers is important to maintain safe administration as access expands. Collaborative efforts are underway to harmonize the definition and grading of CRS to allow for better interpretation of toxicities across CAR-T products and clinical trials and allow for informed management algorithms.

  • Chimeric Antigen Receptor car t therapies for the treatment of hematologic malignancies clinical perspective and significance
    Journal for ImmunoTherapy of Cancer, 2018
    Co-Authors: Michael Boyiadzis, David L. Porter, Marcela V. Maus, James N. Kochenderfer, Renier J Brentjens, Stephan A Grupp, David G Maloney, Madhav V Dhodapkar, Sattva S Neelapu
    Abstract:

    Chimeric Antigen Receptor (CAR) T cell therapies – adoptive T cell therapies that have been genetically engineered for a new Antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.

  • Cytokine release syndrome associated with Chimeric-Antigen Receptor T-cell therapy: clinicopathological insights
    Blood, 2017
    Co-Authors: Amrom E. Obstfeld, David L. Porter, Carl H June, Noelle V Frey, Simon F Lacey, Joseph J Melenhorst, Keith Mansfield, Mariusz A Wasik
    Abstract:

    To the editor: Chimeric-Antigen Receptor T-cell (CART-cell) immunotherapy has proven clinical efficacy,[1][1] particularly in B-cell leukemia and lymphoma.[2][2][⇓][3]-[4][4] However, it causes a unique set of toxicities, the foremost of which is cytokine release syndrome (CRS).[5][5],[6][6] The

  • Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia
    Critical care medicine, 2017
    Co-Authors: Julie C. Fitzgerald, Carl H June, Shannon L Maude, Pamela A Shaw, David M Barrett, Simon F Lacey, Joseph J Melenhorst, Scott L. Weiss, Robert A. Berg, David L. Porter
    Abstract:

    Objective Initial success with Chimeric Antigen Receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after Chimeric Antigen Receptor-modified T cell therapy. Design Retrospective cohort study. Setting Academic children's hospital. Patients Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with Chimeric Antigen Receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495). Interventions All subjects received Chimeric Antigen Receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 Receptor antibody tocilizumab. Measurements and main results Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement. Conclusions Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.

  • Chimeric Antigen Receptor T cell therapy: 25years in the making
    Blood Rev, 2016
    Co-Authors: S. Gill, Marcela V. Maus, David L. Porter
    Abstract:

    Chimeric Antigen Receptor (CAR) T cell therapy of cancer is generating enormous enthusiasm. Twenty-five years after the concept was first proposed, major advances in molecular biology, virology, and good manufacturing practices (GMP)-grade cell production have transformed antibody-T cell chimeras from a scientific curiosity to a fact of life for academic cellular immunotherapy researchers and, increasingly, for patients. In this review, we explain the preclinical concept, outline how it has been translated to the clinic, and draw lessons from the first years of CAR T cell therapy for the practicing clinician.

David G Maloney - One of the best experts on this subject based on the ideXlab platform.

Stephan A Grupp - One of the best experts on this subject based on the ideXlab platform.

  • tisagenlecleucel model based cellular kinetic analysis of Chimeric Antigen Receptor t cells
    CPT: Pharmacometrics & Systems Pharmacology, 2019
    Co-Authors: Andrew M Stein, Stephan A Grupp, John E Levine, Theodore W Laetsch, Michael A Pulsipher, Michael Boyer, Keith J August, Bruce L Levine
    Abstract:

    Tisagenlecleucel is a Chimeric Antigen Receptor-T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half-life, and terminal half-life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or corticosteroids on the expansion rate was observed. This work represents the first mixed-effect model-based analysis of Chimeric Antigen Receptor-T cell therapy and may be clinically impactful as future studies examine prophylactic interventions in patients at risk of higher grade cytokine release syndrome and the effects of these interventions on Chimeric Antigen Receptor-T cell expansion.

  • Chimeric Antigen Receptor car t therapies for the treatment of hematologic malignancies clinical perspective and significance
    Journal for ImmunoTherapy of Cancer, 2018
    Co-Authors: Michael Boyiadzis, David L. Porter, Marcela V. Maus, James N. Kochenderfer, Renier J Brentjens, Stephan A Grupp, David G Maloney, Madhav V Dhodapkar, Sattva S Neelapu
    Abstract:

    Chimeric Antigen Receptor (CAR) T cell therapies – adoptive T cell therapies that have been genetically engineered for a new Antigen-specificity - have displayed significant success in treating patients with hematologic malignancies, leading to three recent US Food and Drug Administration approvals. Based on the promise generated from these successes, the field is rapidly evolving to include new disease indications and CAR designs, while simultaneously reviewing and optimizing toxicity and management protocols. As such, this review provides expert perspective on the significance and clinical considerations of CAR T cell therapies in order to provide timely information to clinicians about this revolutionary new therapeutic class.

  • toxicity management after Chimeric Antigen Receptor t cell therapy one size does not fit all
    Nature Reviews Clinical Oncology, 2018
    Co-Authors: David T Teachey, Michael R Bishop, David G Maloney, Stephan A Grupp
    Abstract:

    Toxicity management after Chimeric Antigen Receptor T cell therapy: one size does not fit 'ALL'

  • cd19 targeted Chimeric Antigen Receptor t cell therapy for acute lymphoblastic leukemia
    Blood, 2015
    Co-Authors: Shannon L Maude, David L. Porter, Stephan A Grupp, David T Teachey
    Abstract:

    Relapsed and refractory acute lymphoblastic leukemia (ALL) remains difficult to treat, with minimal improvement in outcomes seen in more than 2 decades despite advances in upfront therapy and improved survival for de novo ALL. Adoptive transfer of T cells engineered to express a Chimeric Antigen Receptor (CAR) has emerged as a powerful targeted immunotherapy, showing striking responses in highly refractory populations. Complete remission (CR) rates as high as 90% have been reported in children and adults with relapsed and refractory ALL treated with CAR-modified T cells targeting the B-cell–specific Antigen CD19. Distinct CAR designs across several studies have produced similar promising CR rates, an encouraging finding. Even more encouraging are durable remissions observed in some patients without additional therapy. Duration of remission and CAR-modified T-cell persistence require further study and more mature follow-up, but emerging data suggest these factors may distinguish CAR designs. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. This review will discuss the current landscape of CD19 CAR clinical trials, CRS pathophysiology and management, and remaining challenges.

  • Chimeric Antigen Receptor therapy for cancer
    Annual Review of Medicine, 2014
    Co-Authors: David M Barrett, David L. Porter, Stephan A Grupp, Nathan Singh, Carl H June
    Abstract:

    Improved outcomes for patients with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, synthetic biology, and cell-processing technologies has paved the way for clinical applications of Chimeric Antigen Receptor– based therapies. This new form of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and on elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. The potential to target essentially any tumor-associated cell-surface Antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer.

Carl H June - One of the best experts on this subject based on the ideXlab platform.

  • Chimeric Antigen Receptor therapy
    The New England Journal of Medicine, 2018
    Co-Authors: Carl H June, Michel Sadelain
    Abstract:

    Chimeric Antigen Receptor T Cells This review addresses T-cell engineering and synthetic immunity, with a focus on producing durable remissions in patients with treatment-refractory tumors. Toxic e...

  • Cytokine release syndrome associated with Chimeric-Antigen Receptor T-cell therapy: clinicopathological insights
    Blood, 2017
    Co-Authors: Amrom E. Obstfeld, David L. Porter, Carl H June, Noelle V Frey, Simon F Lacey, Joseph J Melenhorst, Keith Mansfield, Mariusz A Wasik
    Abstract:

    To the editor: Chimeric-Antigen Receptor T-cell (CART-cell) immunotherapy has proven clinical efficacy,[1][1] particularly in B-cell leukemia and lymphoma.[2][2][⇓][3]-[4][4] However, it causes a unique set of toxicities, the foremost of which is cytokine release syndrome (CRS).[5][5],[6][6] The

  • kinase inhibitor ibrutinib to prevent cytokine release syndrome after anti cd19 Chimeric Antigen Receptor t cells for b cell neoplasms
    Leukemia, 2017
    Co-Authors: Marco Ruella, Carl H June, Simon F Lacey, Saad S Kenderian, Olga Shestova, Michael Klichinsky, Joseph J Melenhorst, Mariusz A Wasik, Saar Gill
    Abstract:

    Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 Chimeric Antigen Receptor T cells for B-cell neoplasms

  • Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia
    Critical care medicine, 2017
    Co-Authors: Julie C. Fitzgerald, Carl H June, Shannon L Maude, Pamela A Shaw, David M Barrett, Simon F Lacey, Joseph J Melenhorst, Scott L. Weiss, Robert A. Berg, David L. Porter
    Abstract:

    Objective Initial success with Chimeric Antigen Receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after Chimeric Antigen Receptor-modified T cell therapy. Design Retrospective cohort study. Setting Academic children's hospital. Patients Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with Chimeric Antigen Receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495). Interventions All subjects received Chimeric Antigen Receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 Receptor antibody tocilizumab. Measurements and main results Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement. Conclusions Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.

  • Going viral: Chimeric Antigen Receptor T-cell therapy for hematological malignancies
    Immunological Reviews, 2015
    Co-Authors: Saar Gill, Carl H June
    Abstract:

    On July 1, 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to CTL019, the anti-CD19 Chimeric Antigen Receptor T-cell therapy developed at the University of Pennsylvania. This is the first personalized cellular therapy for cancer to be so designated and occurred 25 years after the first publication describing genetic redirection of T cells to a surface Antigen of choice. The peer-reviewed literature currently contains the outcomes of more than 100 patients treated on clinical trials of anti-CD19 redirected T cells, and preliminary results on many more patients have been presented. At last count almost 30 clinical trials targeting CD19 were actively recruiting patients in North America, Europe, and Asia. Patients with high-risk B-cell malignancies therefore represent the first beneficiaries of an exciting and potent new treatment modality that harnesses the power of the immune system as never before. A handful of trials are targeting non-CD19 hematological and solid malignancies and represent the vanguard of enormous preclinical efforts to develop CAR T-cell therapy beyond B-cell malignancies. In this review, we explain the concept of Chimeric Antigen Receptor gene-modified T cells, describe the extant results in hematologic malignancies, and share our outlook on where this modality is likely to head in the near future.

Simon F Lacey - One of the best experts on this subject based on the ideXlab platform.

  • Cytokine release syndrome associated with Chimeric-Antigen Receptor T-cell therapy: clinicopathological insights
    Blood, 2017
    Co-Authors: Amrom E. Obstfeld, David L. Porter, Carl H June, Noelle V Frey, Simon F Lacey, Joseph J Melenhorst, Keith Mansfield, Mariusz A Wasik
    Abstract:

    To the editor: Chimeric-Antigen Receptor T-cell (CART-cell) immunotherapy has proven clinical efficacy,[1][1] particularly in B-cell leukemia and lymphoma.[2][2][⇓][3]-[4][4] However, it causes a unique set of toxicities, the foremost of which is cytokine release syndrome (CRS).[5][5],[6][6] The

  • kinase inhibitor ibrutinib to prevent cytokine release syndrome after anti cd19 Chimeric Antigen Receptor t cells for b cell neoplasms
    Leukemia, 2017
    Co-Authors: Marco Ruella, Carl H June, Simon F Lacey, Saad S Kenderian, Olga Shestova, Michael Klichinsky, Joseph J Melenhorst, Mariusz A Wasik, Saar Gill
    Abstract:

    Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 Chimeric Antigen Receptor T cells for B-cell neoplasms

  • Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia
    Critical care medicine, 2017
    Co-Authors: Julie C. Fitzgerald, Carl H June, Shannon L Maude, Pamela A Shaw, David M Barrett, Simon F Lacey, Joseph J Melenhorst, Scott L. Weiss, Robert A. Berg, David L. Porter
    Abstract:

    Objective Initial success with Chimeric Antigen Receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after Chimeric Antigen Receptor-modified T cell therapy. Design Retrospective cohort study. Setting Academic children's hospital. Patients Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with Chimeric Antigen Receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495). Interventions All subjects received Chimeric Antigen Receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 Receptor antibody tocilizumab. Measurements and main results Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement. Conclusions Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.

  • Chimeric Antigen Receptor t cells against cd19 for multiple myeloma
    The New England Journal of Medicine, 2015
    Co-Authors: Alfred L Garfall, Marcela V. Maus, Zhaohui Zheng, Simon F Lacey, Joseph J Melenhorst, Weiting Hwang, Yolanda D Mahnke, Dan T Vogl, Adam D Cohen, Brendan M Weiss
    Abstract:

    A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 Chimeric Antigen Receptor, after myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation. Four years earlier, autologous transplantation with a higher melphalan dose (200 mg per square meter) had induced only a partial, transient response. Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment. This response was achieved despite the absence of CD19 expression in 99.95% of the patient’s neoplastic plasma cells. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02135406.)

  • phase iia trial of Chimeric Antigen Receptor modified t cells directed against cd19 ctl019 in patients with relapsed or refractory cd19 lymphomas
    Journal of Clinical Oncology, 2015
    Co-Authors: Stephen J Schuster, David L. Porter, Simon F Lacey, Jakub Svoboda, Daniel J Landsburg, Anthony R Mato, Sunita D Nasta, Gaurav Shah, Elise A Chong, Joseph J Melenhorst
    Abstract:

    8516 Background: Autologous T cells expressing a Chimeric Antigen Receptor with an external anti-CD19 single chain antibody domain and CD3ζ and 4-1BB signaling domains (CTL019 cells) mediate anti-t...