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Dive into the research topics where Cindy Delbrook is active.

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Featured researches published by Cindy Delbrook.


The Lancet | 2015

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.

Daniel W. Lee; James N. Kochenderfer; Maryalice Stetler-Stevenson; Yongzhi K Cui; Cindy Delbrook; Steven A. Feldman; Terry J. Fry; Rimas J. Orentas; Marianna Sabatino; Nirali N. Shah; Seth M. Steinberg; Dave Stroncek; Nick Tschernia; Constance Yuan; Hua Zhang; Ling Zhang; Steven A. Rosenberg; Alan S. Wayne; Crystal L. Mackall

BACKGROUND Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. METHODS This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 10(6) CAR-transduced T cells per kg (dose 1), 3 × 10(6) CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. FINDINGS Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 10(6) CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). INTERPRETATION CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. FUNDING National Institutes of Health Intramural funds and St Baldricks Foundation.


Nature Medicine | 2017

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy

Terry J. Fry; Nirali N. Shah; Rimas J. Orentas; Maryalice Stetler-Stevenson; Constance Yuan; Sneha Ramakrishna; Pamela L. Wolters; Staci Martin; Cindy Delbrook; Bonnie Yates; Haneen Shalabi; Thomas J. Fountaine; Jack F. Shern; Robbie G. Majzner; David F. Stroncek; Marianna Sabatino; Yang Feng; Dimiter S. Dimitrov; Ling Zhang; Sang Nguyen; Haiying Qin; Boro Dropulic; Daniel W. Lee; Crystal L. Mackall

Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre–B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving ≥1 × 106 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19dim or CD19− B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22+ cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function.Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)


Clinical Cancer Research | 2016

Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors

Melinda S. Merchant; Matthew Wright; Kristin Baird; Leonard H. Wexler; Carlos Rodriguez-Galindo; Donna Bernstein; Cindy Delbrook; Maya Lodish; Rachel J. Bishop; Jedd D. Wolchok; Howard Streicher; Crystal L. Mackall

Purpose: Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol. Experimental Design: This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m2 intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Results: Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). Conclusions: Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance. Clin Cancer Res; 22(6); 1364–70. ©2015 AACR.


Pediatric Blood & Cancer | 2015

Characterization of CD22 expression in acute lymphoblastic leukemia

Nirali N. Shah; Maryalice Stetler Stevenson; Constance Yuan; Kelly Richards; Cindy Delbrook; Robert J. Kreitman; Ira Pastan; Alan S. Wayne

CD22 is a B‐lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL).


Pediatric Blood & Cancer | 2016

Vincristine Sulfate Liposomes Injection (VSLI, Marqibo®): Results From a Phase I Study in Children, Adolescents, and Young Adults With Refractory Solid Tumors or Leukemias.

Nirali N. Shah; Melinda S. Merchant; Diane E. Cole; Nalini Jayaprakash; Donna Bernstein; Cindy Delbrook; Kelly Richards; Brigitte C. Widemann; Alan S. Wayne

Vincristine sulfate liposome injection (VSLI; Marqibo®) is an encapsulated preparation of standard vincristine in sphingomyelin/cholesterol liposomes. Clinical trials in adults have demonstrated safety, tolerability, and activity, leading to Food and Drug Administration (FDA) approval for adults with relapsed acute lymphoblastic leukemia (ALL). Pediatric experience with VSLI is limited.


Haematologica | 2018

Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma

Haneen Shalabi; Ira Lignugaris Kraft; Hao-Wei Wang; Constance Yuan; Bonnie Yates; Cindy Delbrook; Julie D. Zimbelman; Roger Giller; Maryalice Stetler-Stevenson; Elaine S. Jaffe; Daniel W. Lee; Jack F. Shern; Terry J. Fry; Nirali N. Shah

Chimeric antigen receptor (CAR) T cell therapy using an anti-CD19 binding domain has been shown to be effective in adults with lymphoma and may represent an alternative treatment strategy in pediatric lymphoma, although experience in this younger age group is limited. Loss of the target antigen, as a mechanism of tumor escape following immunotherapy, is an increasingly recognized phenomena which has limited the efficacy of immunotherapy in leukemia, however little is known about antigen loss in lymphoma. We present a case of a pediatric patient with multiply relapsed advanced stage DLBCL who developed sequential antigen loss disease following sequential CAR immunotherapy. This case provides a proof of concept of antigen loss as a mechanism for relapse following immunotherapy in lymphomas, and highlights the need for repeat biopsy and flow cytometric analysis in guiding sequential immunotherapeutic interventions.


Molecular therapy. Methods & clinical development | 2018

Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience

Kenneth Cornetta; Lisa Duffy; Steven A. Feldman; Crystal L. Mackall; Marco L. Davila; Kevin J. Curran; Richard P. Junghans; Jean Yuh Tang; James N. Kochenderfer; Roisin E. O’Cearbhaill; Gary E. Archer; Hans-Peter Kiem; Nirali N. Shah; Cindy Delbrook; Rosie Kaplan; Renier J. Brentjens; Isabelle Riviere; Michel Sadelain; Steven A. Rosenberg

Replication-competent retrovirus (RCR) is a safety concern for individuals treated with retroviral gene therapy. RCR detection assays are used to detect RCR in manufactured vector, transduced cell products infused into research subjects, and in the research subjects after treatment. In this study, we reviewed 286 control (n = 4) and transduced cell products (n = 282) screened for RCR in the National Gene Vector Biorepository. The transduced cell samples were submitted from 14 clinical trials. All vector products were previously shown to be negative for RCR prior to use in cell transduction. After transduction, all 282 transduced cell products were negative for RCR. In addition, 241 of the clinical trial participants were also screened for RCR by analyzing peripheral blood at least 1 month after infusion, all of which were also negative for evidence of RCR infection. The majority of vector products used in the clinical trials were generated in the PG13 packaging cell line. The findings suggest that screening of the retroviral vector product generated in PG13 cell line may be sufficient and that further screening of transduced cells does not provide added value.


Cancer Research | 2013

Abstract LB-138: Autologous-collected anti-cd19 chimeric antigen receptor (CAR) T cells for acute lymphocytic leukemia (ALL) and Non-Hodgkin's lymphoma (NHL) in children who have previously undergone allogeneic hematopoietic stem cell transplantation (HSCT).

Daniel W. Lee; Nirali Shah; Maryalice Stetler-Stevenson; Marianna Sabatino; Kelly Richards; Cindy Delbrook; James N. Kochenderfer; Steven A. Rosenberg; David F. Stroncek; Crystal L. Mackall; Alan S. Wayne

Introduction: Despite aggressive therapies such as HSCT, survival in relapsed and refractory pediatric ALL and NHL is poor. CAR modified T cells targeting CD19 have been effective in adult B-cell malignancies. These studies have employed T cells either collected directly from non-HSCT patients or donor-derived EBV-specific cytotoxic T lymphocytes cultured over a period of 6-12 weeks. To treat children who have relapsed after HSCT with CAR T cells in a reasonable time frame, we developed an anti-CD19 CAR Phase I trial (NCT01593696) where T cells are collected directly from patients and manufactured in 11 days. Both HSCT-naive and HSCT patients are eligible. Our CD19 CAR consists of a CD19-specific scFv and the CD28 and CD3ζ signaling domains. We report results with the first 4 patients (Pt), 3 of whom had undergone prior HSCT. Methods: Peripheral blood (PB) mononuclear cells were apheresed on Day -11. T cells were positively selected and activated using anti-CD3/anti-CD28 paramagnetic beads in IL-2 for 48 hours then transduced with the CD19-CAR gene via retroviral supernatant for an additional 48 hours. After an additional 7 days of expansion cells were harvested for infusion. Pts were treated with fludarabine (25 mg/m2/day on Days -4, -3, -2) and cyclophosphamide (900 mg/m2 on Day -2) prior to receiving 1x106 CAR transduced T cells/kg. Results: A 59- and 65-fold expansion of CAR T cells with 65% and 39% transduction efficiency was achieved in Pt 1 (ALL) and Pt 3 (NHL), respectively. Pt 1 achieved a complete response (CR) and experienced Gr 3 fever and Gr 2 hypotension correlating with mild elevation in IL-6, GM-CSF, INFγ and C-reactive protein (CRP) consistent with mild cytokine release syndrome (CRS). No other non-hematologic, CAR-related Gr 3 or 4 toxicities were observed. Pt 3 (ALL) only received 2.8% of the targeted CAR T cell dose due to lack of cell expansion, likely from recent prior therapy. Despite this, a transient CR with 0.01% MRD was observed at Day 19 with pronounced expansion of CAR T cells (15% of total T cells in PB, 5% in marrow, 6.2% in CSF). Pt 4 (primary refractory ALL, HSCT-naive) has recently been infused after a 14-fold expansion with 33% transduction efficiency. To date, PB flow demonstrated: A) 9%, 0.01%, and 0% blasts B) 2.3%, 0.8%, and 0% B-cells and C) 0%, 11%, and 38% CAR+ T cells on Days -1, +4 and +6, respectively. Pt 4 also had mild CRS with Gr 3 fever and elevated CRP. Conclusions: Importantly, CAR T cell therapy was well tolerated without graft versus host disease in all three HSCT patients. These initial results indicate that autologous-collected anti-CD19 CAR T cell therapy is feasible and potentially effective for children with relapsed/refractory ALL including after HSCT. Citation Format: Daniel W. Lee, Nirali Shah, Maryalice Stetler-Stevenson, Marianna Sabatino, Kelly Richards, Cindy Delbrook, James N. Kochenderfer, Steven A. Rosenberg, David Stroncek, Crystal L. Mackall, Alan S. Wayne. Autologous-collected anti-cd19 chimeric antigen receptor (CAR) T cells for acute lymphocytic leukemia (ALL) and Non-Hodgkin9s lymphoma (NHL) in children who have previously undergone allogeneic hematopoietic stem cell transplantation (HSCT). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-138. doi:10.1158/1538-7445.AM2013-LB-138


Blood | 2015

Safety and Response of Incorporating CD19 Chimeric Antigen Receptor T Cell Therapy in Typical Salvage Regimens for Children and Young Adults with Acute Lymphoblastic Leukemia

Daniel W. Lee; Maryalice Stetler-Stevenson; Constance Yuan; Terry J. Fry; Nirali N. Shah; Cindy Delbrook; Bonnie Yates; Hua Zhang; Ling Zhang; James N. Kochenderfer; Steven A. Rosenberg; David F. Stroncek; Crystal L. Mackall


Blood | 2016

Long-Term Outcomes Following CD19 CAR T Cell Therapy for B-ALL Are Superior in Patients Receiving a Fludarabine/Cyclophosphamide Preparative Regimen and Post-CAR Hematopoietic Stem Cell Transplantation

Daniel W. Lee; Maryalice Stetler-Stevenson; Constance Yuan; Nirali N. Shah; Cindy Delbrook; Bonnie Yates; Hua Zhang; Ling Zhang; James N. Kochenderfer; Steven A. Rosenberg; Terry J. Fry; David F. Stroncek; Crystal L. Mackall

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Nirali N. Shah

National Institutes of Health

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Terry J. Fry

National Institutes of Health

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Daniel W. Lee

National Institutes of Health

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Alan S. Wayne

University of Southern California

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Bonnie Yates

National Institutes of Health

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David F. Stroncek

National Institutes of Health

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Constance Yuan

National Institutes of Health

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James N. Kochenderfer

National Institutes of Health

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