Stephan A Grupp

University of Pennsylvania, Philadelphia, Pennsylvania, United States

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Publications (120)814.02 Total impact

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    ABSTRACT: Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.
    New England Journal of Medicine 10/2014; 371(16):1507-17. · 54.42 Impact Factor
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    ABSTRACT: Idiopathic pneumonia syndrome (IPS) is an acute, non-infectious lung disorder associated with high morbidity and mortality following hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multi-center phase II trial investigating a soluble TNF binding protein, etanercept (Enbrel(®), Amgen) for the treatment of pediatric patients with IPS. Eligible patients were <18 years, within 120 days post-transplant, with radiographic evidence of a diffuse pneumonitis. All patients underwent a pre-therapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly x 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age 11y, range 1-17y) were enrolled, with 11 of 39 patients non-evaluable due to identification of pathogens from their pre-therapy BAL. In the remaining 28 patients, the median FiO2 at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response 10 days (range 1-24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% vs. 53%,p=0.01). Overall survival at 28 days and 1-year post-therapy were 89% (95% CI:70-96) and 63% (95% CI:42-79) respectively. Plasma levels of pro-inflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high dose corticosteroids was associated with high response rates and survival in children with IPS.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2014; · 3.15 Impact Factor
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    ABSTRACT: Chimeric antigen receptor (CAR) therapy has begun to demonstrate success as a novel treatment modality for hematologic malignancies. The success observed thus far has been with T cells permanently-engineered to express chimeric receptors. T cells engineered using RNA electroporation represent an alternative with the potential for similar efficacy and greater safety when initially targeting novel antigens. Neuroblastoma is a common pediatric solid tumor with the potential to be targeted using immunotherapy. We performed xenograft studies in NSG mice assessing the efficacy of both permanently-modified and transiently-modified CAR T cells directed against the neuroblastoma antigen GD2 in both local and disseminated disease models. Disease response was monitored by tumor volume measurement and histological examination, as well as in vivo bioluminescence. RNA-modified GD2 CAR T cells mediated rapid tumor destruction when delivered locally. A single infusion of lentivirally-modified GD2 CAR T cells resulted in long-term control of disseminated disease. Multiple infusions of RNA GD2 CAR T cells slowed progression of disseminated disease and improved survival, but did not result in long-term disease control. Histologic examination revealed that the transiently-modified cells were unable to significantly penetrate the tumor environment when delivered systemically, despite multiple CAR T cell infusions. Thus, we demonstrate that RNA-modified GD2 CAR T cells can mediate effective anti-tumor responses in vivo, and permanently-modified cells are able to control disseminated neuroblastoma in xenograft mice. Lack of long-term disease control by RNA-engineered cells resulted from an inability to penetrate the tumor microenvironment.
    Cancer immunology research. 08/2014;
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    ABSTRACT: Grade II-IV acute graft-vs.-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary endpoint of the trial was to compare 114 day grade II-IV acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There was no difference in the probability of day 114 grade II-IV acute GVHD-free survival (67% vs. 62%, p=0.38). Grade II-IV GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs. 34%, p=0.48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs. 16 days, p<0.001; 16 vs. 19 days, p=0.03). Oropharyngeal mucositis was less severe in Tac/Sir arm (peak OMAS score 0.70 vs. 0.96, p<0.001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival and overall survival at 2 years were no different between study arms (53% vs. 45%, p=0.06; 53% vs. 54%, p=0.77; 59% vs. 63%, p=0.36). Based on similar long-term outcomes, more rapid engraftment and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. (Funded by the National Heart, Lung, and Blood Institute and National Cancer Institute; ClinicalTrials.gov number, NCT00406393).
    Blood 06/2014; · 9.78 Impact Factor
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    ABSTRACT: It is now well established that the immune system can control and eliminate cancer cells. Adoptive T cell transfer has the potential to overcome the significant limitations associated with vaccine-based strategies in patients who are often immune compromised. Application of the emerging discipline of synthetic biology to cancer, which combines elements of genetic engineering and molecular biology to create new biological structures with enhanced functionalities, is the subject of this focused research review.
    Cancer immunology, immunotherapy : CII. 06/2014;
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    ABSTRACT: As immune based therapies for cancer become potent, more effective and more widely available, optimal management of their unique toxicities becomes increasingly important. Cytokine release syndrome (CRS) is a potentially life threatening toxicity that has been observed following administration of natural and bi-specific antibodies and more recently, following adoptive T cell therapies for cancer. CRS is associated with elevated circulating levels of several cytokines including IL-6 and IFNγ, and uncontrolled studies demonstrate that immunosuppression using tocilizumab, an anti-IL6R antibody, with or without corticosteroids, can reverse the syndrome. However because early and aggressive immunosuppression could limit the efficacy of the immunotherapy, current approaches seek to limit administration of immunosuppressive therapy to patients at risk for life threatening consequences of the syndrome. This report presents a novel system to grade the severity of CRS in individual patients, and a treatment algorithm for management of CRS based upon severity. The goal of our approach is to maximize the chance for therapeutic benefit from the immunotherapy while minimizing the risk for life threatening complications of CRS.
    Blood 05/2014; · 9.78 Impact Factor
  • Cytotherapy 04/2014; 16(4):S8. · 3.06 Impact Factor
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    ABSTRACT: Many patients with acute myeloid leukemia (AML) are incurable with chemotherapy and may benefit from novel approaches. One such approach involves the transfer of T cells engineered to express chimeric antigen receptors (CARs) for a specific cell surface antigen. This strategy depends upon preferential expression of the target on tumor cells. To date, the lack of AML-specific surface markers has impeded development of such CAR-based approaches. CD123, the transmembrane alpha chain of the interleukin-3 receptor, is expressed on the majority of AML but is also expressed on many normal hematopoietic cells. Here we show that CD123 is a good target for AML-directed CAR therapy, as its expression increases over time in vivo even in initially CD123(dim) populations, and that human CD123-redirected T cells (CART123) eradicate primary AML in immunodeficient mice. CART123 also eradicated normal human myelopoiesis, a surprising finding since anti-CD123 antibody-based strategies have been reportedly well-tolerated. As AML is likely preceded by clonal evolution in "pre-leukemic" hematopoietic stem cells, our observations support CART123 as a viable AML therapy, suggest that CART123-based myeloablation may be used as a novel conditioning regimen for hematopoietic cell transplantation, and raise concerns for the use of CART123 without such a rescue strategy.
    Blood 03/2014; · 9.78 Impact Factor
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    ABSTRACT: T cells redirected to specific antigen targets with engineered chimeric antigen receptors (CARs) are emerging as powerful therapies in hematologic malignancies. Various CAR designs, manufacturing processes, and study populations, among other variables, have been tested and reported in over 10 clinical trials. Here we review and compare the results of the reported clinical trials, and discuss the progress and key emerging factors that may play a role in effecting tumor responses. We also discuss the outlook for CAR T cell therapies, including managing toxicities and expanding the availability of personalized cell therapy as a promising approach to all hematologic malignancies. Many questions remain in the field of CAR T cells directed to hematologic malignancies, but the encouraging response rates pave a wide road for future investigation.
    Blood 02/2014; · 9.78 Impact Factor
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    ABSTRACT: Sirolimus, an mTOR inhibitor, has activity against human ALL in xenograft models and efficacy in preventing acute GVHD (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children undergoing transplantation for ALL would decrease aGVHD and relapse, thus improving survival. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 planned patients. The proportion of patients with Grade II-IV aGVHD was 31% vs. 18% in the standard vs. the experimental arm (p=0.04), however, grade III-IV aGVHD was not statistically different (13% vs. 10%, p=0.28). Rates of veno-occlusive disease and thrombotic microangiopathy were lower in the non-sirolimus arm (9% vs. 21% VOD, p=0.05; 1% vs. 10% TMA, p=0.06). At 2 years, EFS and OS were 56% vs 46%, and 65% vs 55% in the standard and experimental arms, respectively (p= 0.28 and 0.23). Multivariate analysis showed increased relapse risk in children with ≥0.1% MRD pre-transplant, and decreased risk in patients with grades I-III aGVHD (p=0.04). Grades I-III aGVHD were associated with improved EFS (p=0.02), while grade IV aGVHD and extramedullary disease at initial diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. The study is registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT00382109).
    Blood 02/2014; · 9.78 Impact Factor
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    ABSTRACT: Cytotoxic T lymphocytes modified with chimeric antigen receptors (CARs) for adoptive immunotherapy of hematologic malignancies are effective in pre-clinical models, and this efficacy has translated to success in several clinical trials. Many early trials were disappointing in large part because of the lack of proliferation and subsequent persistence of transferred cells. Recent investigations have pointed to the importance of delivering highly proliferative cells, whether of naive or early memory phenotypes. We investigated the influence of two common cell culturing methods used in early trials and their relationship to T-cell phenotype and pre-clinical efficacy. We observed that stimulation with soluble anti-CD3 antibody OKT-3 and high-dose interleukin-2 produces more effector memory-type T cells with shorter average telomeres when compared with cells generated with the use of CD3/CD28 beads. When used in xenograft models of leukemia, bead-stimulated cells proliferated earlier and to a higher degree than those generated with the use of OKT-3/IL2 and resulted in better disease control despite no difference in distribution or migration throughout the mouse. Inclusion of the known successful clinical 4-1BB endodomain in the CAR could not rescue the function of OKT-3/IL-2-cultured cells. T cells isolated from animals that survived long-term (>120 days) retained a central memory-like phenotype and demonstrated a memory response to a large re-challenge of CD19-positive leukemia. In summary, we confirm that cells with a younger phenotype or higher proliferative capacity perform better in pre-clinical models and that cell culturing influences cell phenotype seemingly independent of the 4-1BB endodomain in the CAR structure.
    Cytotherapy 01/2014; · 3.06 Impact Factor
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    ABSTRACT: Invariant natural killer T (iNKT) cells comprise a lineage of CD1d-restricted glycolipid-reactive T lymphocytes with important roles in host immunity to cancer. iNKT cells indirectly participate in antitumor responses by inducing dendritic cell maturation and producing cytokines that promote tumor clearance by CD8(+) T and NK cells. Although iNKT cells thereby act as potent cellular adjuvants, it is less clear whether they directly control the growth of tumors. To gain insights into the direct contribution of iNKT cells to tumor immune surveillance, we developed in vitro and in vivo systems to selectively examine the antitumor activity of iNKT cells in the absence of other cytolytic effectors. Using the EL4 T-lymphoma cell line as a model, we find that iNKT cells exert robust and specific lysis of tumor cells in vitro in a manner that is differentially-induced by iNKT cell agonists of varying TCR affinities, such as OCH, α-galactosyl ceramide and PBS44. In vitro blockade of CD1d-mediated lipid antigen presentation, disruption of T cell receptor (TCR) signaling, or loss of perforin expression significantly reduce iNKT cell killing. Consistent with these findings, iNKT cell reconstitution of T, B, and NK cell-deficient mice slows EL4 growth in vivo via TCR-CD1d and perforin-dependent mechanisms. Together, these observations establish that iNKT cells are sufficient to control the growth of T-lymphoma in vitro and in vivo. They also suggest that the induction of iNKT cell cytotoxic responses in situ might serve as a more effective strategy to prevent and/or treat CD1d(+) cancers, such as T-lymphoma.
    Cancer immunology research. 01/2014; 2(1):59-69.
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    ABSTRACT: Although allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some non-malignant disorders, there are still critical obstacles to overcome including relapse, engraftment failure, graft-versus-host disease (GvHD) and infection. Harnessing the immune system to induce a graft-versus-tumor (GvT) effect or rapidly restore anti-viral immunity through the use of donor lymphocyte infusion (DLI) has been remarkably successful in some settings. Unfortunately, the responses to DLI can be variable and GVHD is common. Hence, manipulations to minimize GVHD while restoring antiviral immunity and enhancing GvT are necessary to improve outcomes after allogeneic HSCT. Cellular therapies are defined as treatment modalities in which hematopoietic or non-hematopoietic cells are used as therapeutic agents and offer this promise to improve outcomes post HSCT. This review will present an overview of the field for pediatric cell therapies in the transplant setting and discuss how we can broaden applicability beyond phase I.
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 01/2014;
  • David M Barrett, David T Teachey, Stephan A Grupp
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    ABSTRACT: Recent clinical trials using T-cell engaging immunotherapies such as bispecific antibodies which target T cells and tumor cells, as well as engineered T cells that express targeting and activation molecules known as chimeric antigen receptors, have demonstrated powerful proof of concept. These therapies result in a significant degree of immune activation in the patient, which has correlated with greatly increased efficacy but also with notable toxicity. These therapies produce nonphysiologic T-cell activation, which is the hallmark of these new, highly active treatments. We and others have noted cytokine activation profiles that correlate with both toxicity and efficacy in patients receiving T-cell engaging therapies. Effector cytokines such as interferon-γ are elevated, but so are cytokines that are associated with macrophage activation syndrome/hemophagocytic lymphohistiocytosis, such as interleukin (IL)-10 and IL-6. Although corticosteroids can control some of these toxicities, a targeted approach may produce superior toxicity control without interfering with efficacy. One approach we have developed targets IL-6, a key cytokine in the toxicity response, using the IL-6 receptor antagonist tocilizumab. Detailed studies of the T-cell activation produced by these novel therapies has led to more targeted approaches that have the potential to control toxicity while maintaining efficacy.
    Current opinion in pediatrics 12/2013; · 2.01 Impact Factor
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    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. Expected final online publication date for the Annual Review of Medicine Volume 65 is January 14, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Annual review of medicine 11/2013; · 9.94 Impact Factor
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    ABSTRACT: Cytotoxic T lymphocytes (CTLs) modified with chimeric antigen receptors (CAR) for adoptive immunotherapy of hematologic malignancies have demonstrated activity in early phase clinical trials. While CTLs bearing stably expressed CARs are efficacious and have potential long-term persistence, temporary expression of a CAR via RNA electroporation is also potentially efficacious in pre-clinical models. Temporary CAR expression using RNA presents a method of testing CARs clinically with additional safety where there may be concerns about possible chronic "on-target, off-tumor" toxic effects as the degradation of RNA ensures complete removal of the CAR over time without relying on suicide induction systems. CD19-directed RNA CAR CTLs were tested in vivo for efficacy and comparison to lentivirally-generated stable CAR CTLs. We tested the hypothesis that multiple infusions of RNA CAR CTLs preceded by lymphodepleting chemotherapy could mediate improved survival and sustained anti-tumor responses in a robust leukemia xenograft model. The saturation strategy using rationally designed multiple infusions of RNA CARs based on multiple model iterations approached the efficacy of a stable lentiviral expression method. Two-color imaging revealed that relapse was a loco-regional phenomenon in both the temporary and stable expression models. In marked contrast to stably expressed CARs with retroviral or lentiviral technology, the efficacy of RNA CARs appears independent of the costimulatory signaling endodomains likely because they more influence proliferation and persistence rather than short term efficacy. The efficacy of the RNA CAR infusions may approach that of stably expressed CARs, offer theoretically safer initial clinical testing in addition to suicide systems, and allow for rapid and effective iterative pre-clinical modeling for the testing new targets.
    Human gene therapy 07/2013; · 4.20 Impact Factor
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    ABSTRACT: Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma. Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either non-purged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus meta-iodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188. 495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33-46) in the purged group versus 36% (30-42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43-56) in the purged group compared with 51% (44-57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group). Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma. National Cancer Institute and Alex's Lemonade Stand Foundation.
    The Lancet Oncology 07/2013; · 25.12 Impact Factor
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    ABSTRACT: Over 20% of allogeneic Hematopoietic Cell transplantations (HCT) are performed in children and adolescents at a large number of relatively small centers. Unlike adults, at least one third of HCT in children are performed for a number of rare non-malignant indications. Clinical trials to improve HCT outcomes in children have been limited by small numbers and these pediatric-specific features. The need for a larger number of pediatric HCT centers to participate in trials has highlighted the need for international collaborative groups. Representatives of the Pediatric BMT Consortium, EBMT Pediatric working Group, iBFM Stem Cell Transplantation Committee, and Children's Oncology Group HSCT Discipline Committee met in October 3, 2012 in Frankfurt, Germany to develop a consensus on the highest priorities in pediatric HCT. In addition, it explored the creation of an international consortium to develop studies focused on HCT in children and adolescents. There was a broad consensus that an international HCT network that worldwide priorities and strategies to address pediatric HCT issues should be created. The group formed by the meeting in Frankfurt has named itself the Westhafen Intercontinental Group. The manuscript outlines the priorities of need as identified by this consensus group.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2013; · 3.15 Impact Factor
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    ABSTRACT: Blinatumomab is a CD19/CD3-bispecific T cell receptor-engaging (BiTE(®)) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia (B-ALL). Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by TCR-activated cytotoxic T cells engaged by BiTE(®) antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement following IL-6 receptor-directed therapy with tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. (Registered on clinicaltrials.gov: NCT00103285).
    Blood 05/2013; · 9.78 Impact Factor
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    ABSTRACT: Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
    New England Journal of Medicine 03/2013; · 54.42 Impact Factor

Publication Stats

3k Citations
814.02 Total Impact Points

Institutions

  • 2009–2014
    • University of Pennsylvania
      • • Division of Hematology/Oncology
      • • Department of Pediatrics
      • • "Abramson" Cancer Center
      • • Department of Pathology and Laboratory Medicine
      Philadelphia, Pennsylvania, United States
    • Hospital of the University of Pennsylvania
      • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 1998–2014
    • The Children's Hospital of Philadelphia
      • • Division of Oncology
      • • Department of Pathology and Laboratory Medicine
      • • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 2012
    • National Institutes of Health
      • Branch of Pediatric Oncology
      Bethesda, MD, United States
  • 2010
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
  • 2008
    • Vanderbilt University
      • Department of Pediatrics
      Nashville, MI, United States
  • 2007
    • University of British Columbia - Vancouver
      • Department of Pediatrics
      Vancouver, British Columbia, Canada
  • 2000
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1994–1998
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Department of Pathology
      Boston, MA, United States