The Experts below are selected from a list of 564933 Experts worldwide ranked by ideXlab platform
Sakthivel Sadayappan - One of the best experts on this subject based on the ideXlab platform.
-
an acute immune response underlies the benefit of cardiac stem Cell Therapy
Nature, 2020Co-Authors: Ronald J Vagnozzi, Marjorie Maillet, Michelle A Sargent, Hadi Khalil, Anne Katrine Z Johansen, Jennifer A Schwanekamp, Allen J York, Vincent Huang, Matthias Nahrendorf, Sakthivel SadayappanAbstract:Clinical trials using adult stem Cells to regenerate damaged heart tissue continue to this day1,2, despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect3. The rationale for these Cell Therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury4,5. Here we examine the mechanistic basis for Cell Therapy in mice after ischaemia–reperfusion injury, and find that—although heart function is enhanced—it is not associated with the production of new cardiomyocytes. Cell Therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+ and CX3CR1+ macrophages. Intracardiac injection of two distinct types of adult stem Cells, Cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2+ and CX3CR1+ macrophages, and provided functional rejuvenation to the heart after ischaemia–reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extraCellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac Cell Therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart. Cardiac stem Cell Therapy in mouse models of ischaemia–reperfusion injury demonstrates that improvement in heart function is linked to an immune response characterized by the induction of CCR2+ and CX3CR1+ macrophages.
-
an acute immune response underlies the benefit of cardiac stem Cell Therapy
Nature, 2020Co-Authors: Ronald J Vagnozzi, Marjorie Maillet, Michelle A Sargent, Hadi Khalil, Anne Katrine Z Johansen, Jennifer A Schwanekamp, Allen J York, Vincent Huang, Matthias Nahrendorf, Sakthivel SadayappanAbstract:Clinical trials using adult stem Cells to regenerate damaged heart tissue continue to this day1,2, despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect3. The rationale for these Cell Therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury4,5. Here we examine the mechanistic basis for Cell Therapy in mice after ischaemia-reperfusion injury, and find that-although heart function is enhanced-it is not associated with the production of new cardiomyocytes. Cell Therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+ and CX3CR1+ macrophages. Intracardiac injection of two distinct types of adult stem Cells, Cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2+ and CX3CR1+ macrophages, and provided functional rejuvenation to the heart after ischaemia-reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extraCellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac Cell Therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart.
-
an acute immune response underlies the benefit of cardiac adult stem Cell Therapy
bioRxiv, 2018Co-Authors: Ronald J Vagnozzi, Marjorie Maillet, Michelle A Sargent, Hadi Khalil, Anne Katrine Z Johansen, Jennifer A Schwanekamp, Allen J York, Vincent Huang, Matthias Nahrendorf, Sakthivel SadayappanAbstract:Clinical trials using adult stem Cells to regenerate damaged heart tissue continue to this day despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biologic effect. The rationale for these Cell Therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischemic injury. Here we examined the mechanistic basis for Cell Therapy in mice after ischemia/reperfusion (I/R) injury, and while heart function was enhanced, it was not associated with new cardiomyocyte production. Cell Therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+ and CX3CR1+ macrophages. Here we observed that intra-cardiac injection of 2 distinct types of progenitor Cells, freeze/thaw-killed Cells or a chemical inducer of the innate immune response similarly induced regional CCR2+ and CX3CR1+ macrophage accumulation and provided functional rejuvenation to the I/R-injured heart. Mechanistically, this selective macrophage response altered cardiac fibroblast activity and reduced border zone extraCellular matrix (ECM) content and enhanced the mechanical properties of the injured area. The functional benefit of cardiac Cell Therapy is thus due to an acute inflammatory-based wound healing response that rejuvenates the mechanical properties of the infarcted area of the heart. Such results suggest a re-evaluation of strategies underlying cardiac Cell Therapy in current and planned human clinical trials.
Satoshi Sobajima - One of the best experts on this subject based on the ideXlab platform.
-
feasibility of a stem Cell Therapy for intervertebral disc degeneration
The Spine Journal, 2008Co-Authors: Satoshi Sobajima, Adam L. Shimer, Lars G Gilbertson, Gianluca Vadala, James D KangAbstract:BACKGROUND CONTEXT: Different strategies to supplement/replenish the disc Cell population have been proposed. Recently, adult stem Cells have shown promise as a Cell source for a variety of tissue engineering and Cell Therapy applications. A stem Cell can renew itself through Cell division and can be induced to develop into many different specialized Cell types. Moreover, stem Cells have shown ability to migrate and engraft within various tissues, as well as to exert stimulatory effects on other Cell types through various mechanisms (eg, paracrine effects, Cell-Cell interactions). These characteristics make stem Cells worthy of investigation as a source of Cells for intervertebral disc (IVD) tissue engineering and Cell Therapy. PURPOSE: To determine feasibility of a stem Cell Therapy of IVD degeneration. STUDY DESIGN: In vitro studies of adult human Cells to examine interactions between nucleus pulposus Cells (NPCs) and mesenchymal stem Cells (MSCs) at different ratios in 3-D pellet culture. In vivo studies of healthy adult rabbit discs injected with allogenic adult rabbit MSCs to examine stem Cell survival and engraftment in living disc tissue. METHODS: In vitro study: Human NPCs were cocultured with human MSCs in different ratios (75:25, 50:50, 25:75) for 2 weeks in pellet culture, for comparison with pure NPC (100:0) and pure MSC (0:100) pellet cultures. Proteoglycan synthesis rate and glycosaminoglycan (GAG) content were measured by radioactive sulfate incorporation and dimethylmethylene blue assay, respectively. In vivo study: MSCs were isolated from the bone marrow of a New Zealand White (NZW) rabbit, retrovirally transduced with the lacZ marker gene, and injected into the nucleus pulposi of the L2-3, L3-4, and L4-5 lumbar discs of 12 other NZW rabbits. Three rabbits each were sacrificed at 3, 6, 12, or 24 weeks after Cell implantation, and X-Gal staining was done to assess survival and localization of MSCs in the disc tissues. RESULTS: In vitro study: the 75:25 and 50:50 NPC:MSC cocultures yielded the greatest increases in extraCellular matrix (ECM) production. In vivo study: MSCs were detected in histological sections of rabbit discs up to 24 weeks after allogenic stem Cell implantation, without evidence of systemic illness in the recipient rabbits. The 24-week results in particular suggested the possibility of stem Cell migration and engraftment into the inner annulus fibrosus. CONCLUSIONS: These encouraging results support feasibility of a stem Cell Therapy approach toward supplementation/replenishment of IVD Cells and synthesis/maintenance of a more functional ECM in a degenerated disc. Moreover, the in vivo results demonstrate that transplanted MSCs survive and successfully engraft into the IVD tissue, and are effective vehicles for exogenous gene delivery to the IVD--thus there appear to be multiple mechanisms whereby stem Cells might able to confer therapeutic effects in a stem Cell Therapy of IVD degeneration.
-
feasibility of a stem Cell Therapy for intervertebral disc degeneration
The Spine Journal, 2008Co-Authors: Satoshi Sobajima, Adam L. Shimer, Lars G Gilbertson, Gianluca Vadala, Joseph S Kim, James D KangAbstract:Abstract: Editor's preface Background context Different strategies to supplement/replenish the disc Cell population have been proposed. Recently, adult stem Cells have shown promise as a Cell source for a variety of tissue engineering and Cell Therapy applications. A stem Cell can renew itself through Cell division and can be induced to develop into many different specialized Cell types. Moreover, stem Cells have shown ability to migrate and engraft within various tissues, as well as to exert stimulatory effects on other Cell types through various mechanisms (eg, paracrine effects, Cell-Cell interactions). These characteristics make stem Cells worthy of investigation as a source of Cells for intervertebral disc (IVD) tissue engineering and Cell Therapy. Purpose To determine feasibility of a stem Cell Therapy of IVD degeneration. Study design In vitro studies of adult human Cells to examine interactions between nucleus pulposus Cells (NPCs) and mesenchymal stem Cells (MSCs) at different ratios in 3-D pellet culture. In vivo studies of healthy adult rabbit discs injected with allogenic adult rabbit MSCs to examine stem Cell survival and engraftment in living disc tissue. Methods In vitro study: Human NPCs were cocultured with human MSCs in different ratios (75:25, 50:50, 25:75) for 2 weeks in pellet culture, for comparison with pure NPC (100:0) and pure MSC (0:100) pellet cultures. Proteoglycan synthesis rate and glycosaminoglycan (GAG) content were measured by radioactive sulfate incorporation and dimethylmethylene blue assay, respectively. In vivo study: MSCs were isolated from the bone marrow of a New Zealand White (NZW) rabbit, retrovirally transduced with the lacZ marker gene, and injected into the nucleus pulposi of the L2–3, L3–4, and L4–5 lumbar discs of 12 other NZW rabbits. Three rabbits each were sacrificed at 3, 6, 12, or 24 weeks after Cell implantation, and X-Gal staining was done to assess survival and localization of MSCs in the disc tissues. Results In vitro study: the 75:25 and 50:50 NPC:MSC cocultures yielded the greatest increases in extraCellular matrix (ECM) production. In vivo study: MSCs were detected in histological sections of rabbit discs up to 24 weeks after allogenic stem Cell implantation, without evidence of systemic illness in the recipient rabbits. The 24-week results in particular suggested the possibility of stem Cell migration and engraftment into the inner annulus fibrosus. Conclusions These encouraging results support feasibility of a stem Cell Therapy approach toward supplementation/replenishment of IVD Cells and synthesis/maintenance of a more functional ECM in a degenerated disc. Moreover, the in vivo results demonstrate that transplanted MSCs survive and successfully engraft into the IVD tissue, and are effective vehicles for exogenous gene delivery to the IVD—thus there appear to be multiple mechanisms whereby stem Cells might able to confer therapeutic effects in a stem Cell Therapy of IVD degeneration.
James D Kang - One of the best experts on this subject based on the ideXlab platform.
-
feasibility of a stem Cell Therapy for intervertebral disc degeneration
The Spine Journal, 2008Co-Authors: Satoshi Sobajima, Adam L. Shimer, Lars G Gilbertson, Gianluca Vadala, James D KangAbstract:BACKGROUND CONTEXT: Different strategies to supplement/replenish the disc Cell population have been proposed. Recently, adult stem Cells have shown promise as a Cell source for a variety of tissue engineering and Cell Therapy applications. A stem Cell can renew itself through Cell division and can be induced to develop into many different specialized Cell types. Moreover, stem Cells have shown ability to migrate and engraft within various tissues, as well as to exert stimulatory effects on other Cell types through various mechanisms (eg, paracrine effects, Cell-Cell interactions). These characteristics make stem Cells worthy of investigation as a source of Cells for intervertebral disc (IVD) tissue engineering and Cell Therapy. PURPOSE: To determine feasibility of a stem Cell Therapy of IVD degeneration. STUDY DESIGN: In vitro studies of adult human Cells to examine interactions between nucleus pulposus Cells (NPCs) and mesenchymal stem Cells (MSCs) at different ratios in 3-D pellet culture. In vivo studies of healthy adult rabbit discs injected with allogenic adult rabbit MSCs to examine stem Cell survival and engraftment in living disc tissue. METHODS: In vitro study: Human NPCs were cocultured with human MSCs in different ratios (75:25, 50:50, 25:75) for 2 weeks in pellet culture, for comparison with pure NPC (100:0) and pure MSC (0:100) pellet cultures. Proteoglycan synthesis rate and glycosaminoglycan (GAG) content were measured by radioactive sulfate incorporation and dimethylmethylene blue assay, respectively. In vivo study: MSCs were isolated from the bone marrow of a New Zealand White (NZW) rabbit, retrovirally transduced with the lacZ marker gene, and injected into the nucleus pulposi of the L2-3, L3-4, and L4-5 lumbar discs of 12 other NZW rabbits. Three rabbits each were sacrificed at 3, 6, 12, or 24 weeks after Cell implantation, and X-Gal staining was done to assess survival and localization of MSCs in the disc tissues. RESULTS: In vitro study: the 75:25 and 50:50 NPC:MSC cocultures yielded the greatest increases in extraCellular matrix (ECM) production. In vivo study: MSCs were detected in histological sections of rabbit discs up to 24 weeks after allogenic stem Cell implantation, without evidence of systemic illness in the recipient rabbits. The 24-week results in particular suggested the possibility of stem Cell migration and engraftment into the inner annulus fibrosus. CONCLUSIONS: These encouraging results support feasibility of a stem Cell Therapy approach toward supplementation/replenishment of IVD Cells and synthesis/maintenance of a more functional ECM in a degenerated disc. Moreover, the in vivo results demonstrate that transplanted MSCs survive and successfully engraft into the IVD tissue, and are effective vehicles for exogenous gene delivery to the IVD--thus there appear to be multiple mechanisms whereby stem Cells might able to confer therapeutic effects in a stem Cell Therapy of IVD degeneration.
-
feasibility of a stem Cell Therapy for intervertebral disc degeneration
The Spine Journal, 2008Co-Authors: Satoshi Sobajima, Adam L. Shimer, Lars G Gilbertson, Gianluca Vadala, Joseph S Kim, James D KangAbstract:Abstract: Editor's preface Background context Different strategies to supplement/replenish the disc Cell population have been proposed. Recently, adult stem Cells have shown promise as a Cell source for a variety of tissue engineering and Cell Therapy applications. A stem Cell can renew itself through Cell division and can be induced to develop into many different specialized Cell types. Moreover, stem Cells have shown ability to migrate and engraft within various tissues, as well as to exert stimulatory effects on other Cell types through various mechanisms (eg, paracrine effects, Cell-Cell interactions). These characteristics make stem Cells worthy of investigation as a source of Cells for intervertebral disc (IVD) tissue engineering and Cell Therapy. Purpose To determine feasibility of a stem Cell Therapy of IVD degeneration. Study design In vitro studies of adult human Cells to examine interactions between nucleus pulposus Cells (NPCs) and mesenchymal stem Cells (MSCs) at different ratios in 3-D pellet culture. In vivo studies of healthy adult rabbit discs injected with allogenic adult rabbit MSCs to examine stem Cell survival and engraftment in living disc tissue. Methods In vitro study: Human NPCs were cocultured with human MSCs in different ratios (75:25, 50:50, 25:75) for 2 weeks in pellet culture, for comparison with pure NPC (100:0) and pure MSC (0:100) pellet cultures. Proteoglycan synthesis rate and glycosaminoglycan (GAG) content were measured by radioactive sulfate incorporation and dimethylmethylene blue assay, respectively. In vivo study: MSCs were isolated from the bone marrow of a New Zealand White (NZW) rabbit, retrovirally transduced with the lacZ marker gene, and injected into the nucleus pulposi of the L2–3, L3–4, and L4–5 lumbar discs of 12 other NZW rabbits. Three rabbits each were sacrificed at 3, 6, 12, or 24 weeks after Cell implantation, and X-Gal staining was done to assess survival and localization of MSCs in the disc tissues. Results In vitro study: the 75:25 and 50:50 NPC:MSC cocultures yielded the greatest increases in extraCellular matrix (ECM) production. In vivo study: MSCs were detected in histological sections of rabbit discs up to 24 weeks after allogenic stem Cell implantation, without evidence of systemic illness in the recipient rabbits. The 24-week results in particular suggested the possibility of stem Cell migration and engraftment into the inner annulus fibrosus. Conclusions These encouraging results support feasibility of a stem Cell Therapy approach toward supplementation/replenishment of IVD Cells and synthesis/maintenance of a more functional ECM in a degenerated disc. Moreover, the in vivo results demonstrate that transplanted MSCs survive and successfully engraft into the IVD tissue, and are effective vehicles for exogenous gene delivery to the IVD—thus there appear to be multiple mechanisms whereby stem Cells might able to confer therapeutic effects in a stem Cell Therapy of IVD degeneration.
Lars G Gilbertson - One of the best experts on this subject based on the ideXlab platform.
-
feasibility of a stem Cell Therapy for intervertebral disc degeneration
The Spine Journal, 2008Co-Authors: Satoshi Sobajima, Adam L. Shimer, Lars G Gilbertson, Gianluca Vadala, James D KangAbstract:BACKGROUND CONTEXT: Different strategies to supplement/replenish the disc Cell population have been proposed. Recently, adult stem Cells have shown promise as a Cell source for a variety of tissue engineering and Cell Therapy applications. A stem Cell can renew itself through Cell division and can be induced to develop into many different specialized Cell types. Moreover, stem Cells have shown ability to migrate and engraft within various tissues, as well as to exert stimulatory effects on other Cell types through various mechanisms (eg, paracrine effects, Cell-Cell interactions). These characteristics make stem Cells worthy of investigation as a source of Cells for intervertebral disc (IVD) tissue engineering and Cell Therapy. PURPOSE: To determine feasibility of a stem Cell Therapy of IVD degeneration. STUDY DESIGN: In vitro studies of adult human Cells to examine interactions between nucleus pulposus Cells (NPCs) and mesenchymal stem Cells (MSCs) at different ratios in 3-D pellet culture. In vivo studies of healthy adult rabbit discs injected with allogenic adult rabbit MSCs to examine stem Cell survival and engraftment in living disc tissue. METHODS: In vitro study: Human NPCs were cocultured with human MSCs in different ratios (75:25, 50:50, 25:75) for 2 weeks in pellet culture, for comparison with pure NPC (100:0) and pure MSC (0:100) pellet cultures. Proteoglycan synthesis rate and glycosaminoglycan (GAG) content were measured by radioactive sulfate incorporation and dimethylmethylene blue assay, respectively. In vivo study: MSCs were isolated from the bone marrow of a New Zealand White (NZW) rabbit, retrovirally transduced with the lacZ marker gene, and injected into the nucleus pulposi of the L2-3, L3-4, and L4-5 lumbar discs of 12 other NZW rabbits. Three rabbits each were sacrificed at 3, 6, 12, or 24 weeks after Cell implantation, and X-Gal staining was done to assess survival and localization of MSCs in the disc tissues. RESULTS: In vitro study: the 75:25 and 50:50 NPC:MSC cocultures yielded the greatest increases in extraCellular matrix (ECM) production. In vivo study: MSCs were detected in histological sections of rabbit discs up to 24 weeks after allogenic stem Cell implantation, without evidence of systemic illness in the recipient rabbits. The 24-week results in particular suggested the possibility of stem Cell migration and engraftment into the inner annulus fibrosus. CONCLUSIONS: These encouraging results support feasibility of a stem Cell Therapy approach toward supplementation/replenishment of IVD Cells and synthesis/maintenance of a more functional ECM in a degenerated disc. Moreover, the in vivo results demonstrate that transplanted MSCs survive and successfully engraft into the IVD tissue, and are effective vehicles for exogenous gene delivery to the IVD--thus there appear to be multiple mechanisms whereby stem Cells might able to confer therapeutic effects in a stem Cell Therapy of IVD degeneration.
-
feasibility of a stem Cell Therapy for intervertebral disc degeneration
The Spine Journal, 2008Co-Authors: Satoshi Sobajima, Adam L. Shimer, Lars G Gilbertson, Gianluca Vadala, Joseph S Kim, James D KangAbstract:Abstract: Editor's preface Background context Different strategies to supplement/replenish the disc Cell population have been proposed. Recently, adult stem Cells have shown promise as a Cell source for a variety of tissue engineering and Cell Therapy applications. A stem Cell can renew itself through Cell division and can be induced to develop into many different specialized Cell types. Moreover, stem Cells have shown ability to migrate and engraft within various tissues, as well as to exert stimulatory effects on other Cell types through various mechanisms (eg, paracrine effects, Cell-Cell interactions). These characteristics make stem Cells worthy of investigation as a source of Cells for intervertebral disc (IVD) tissue engineering and Cell Therapy. Purpose To determine feasibility of a stem Cell Therapy of IVD degeneration. Study design In vitro studies of adult human Cells to examine interactions between nucleus pulposus Cells (NPCs) and mesenchymal stem Cells (MSCs) at different ratios in 3-D pellet culture. In vivo studies of healthy adult rabbit discs injected with allogenic adult rabbit MSCs to examine stem Cell survival and engraftment in living disc tissue. Methods In vitro study: Human NPCs were cocultured with human MSCs in different ratios (75:25, 50:50, 25:75) for 2 weeks in pellet culture, for comparison with pure NPC (100:0) and pure MSC (0:100) pellet cultures. Proteoglycan synthesis rate and glycosaminoglycan (GAG) content were measured by radioactive sulfate incorporation and dimethylmethylene blue assay, respectively. In vivo study: MSCs were isolated from the bone marrow of a New Zealand White (NZW) rabbit, retrovirally transduced with the lacZ marker gene, and injected into the nucleus pulposi of the L2–3, L3–4, and L4–5 lumbar discs of 12 other NZW rabbits. Three rabbits each were sacrificed at 3, 6, 12, or 24 weeks after Cell implantation, and X-Gal staining was done to assess survival and localization of MSCs in the disc tissues. Results In vitro study: the 75:25 and 50:50 NPC:MSC cocultures yielded the greatest increases in extraCellular matrix (ECM) production. In vivo study: MSCs were detected in histological sections of rabbit discs up to 24 weeks after allogenic stem Cell implantation, without evidence of systemic illness in the recipient rabbits. The 24-week results in particular suggested the possibility of stem Cell migration and engraftment into the inner annulus fibrosus. Conclusions These encouraging results support feasibility of a stem Cell Therapy approach toward supplementation/replenishment of IVD Cells and synthesis/maintenance of a more functional ECM in a degenerated disc. Moreover, the in vivo results demonstrate that transplanted MSCs survive and successfully engraft into the IVD tissue, and are effective vehicles for exogenous gene delivery to the IVD—thus there appear to be multiple mechanisms whereby stem Cells might able to confer therapeutic effects in a stem Cell Therapy of IVD degeneration.
Shannon L Maude - One of the best experts on this subject based on the ideXlab platform.
-
optimizing chimeric antigen receptor t Cell Therapy for adults with acute lymphoblastic leukemia
Journal of Clinical Oncology, 2020Co-Authors: Noelle V Frey, S. Gill, Pamela A Shaw, Elizabeth O Hexner, Edward Pequignot, Selina M Luger, James K Mangan, Alison W Loren, Alexander E Perl, Shannon L MaudeAbstract:PURPOSEThe anti-CD19 chimeric antigen receptor T-Cell Therapy tisagenlecleucel (CTL019) has an 81% response rate in children with relapsed or chemoTherapy refractory (r/r) B-Cell acute lymphoblasti...
-
Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia
Critical care medicine, 2017Co-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. PorterAbstract: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.
