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Article ; Online: CD25-T

Solomon, Isabelle / Amann, Maria / Goubier, Anne / Arce Vargas, Frederick / Zervas, Dimitrios / Qing, Chen / Henry, Jake Y / Ghorani, Ehsan / Akarca, Ayse U / Marafioti, Teresa / Śledzińska, Anna / Werner Sunderland, Mariana / Franz Demane, Dafne / Clancy, Joanne Ruth / Georgiou, Andrew / Salimu, Josephine / Merchiers, Pascal / Brown, Mark Adrian / Flury, Reto /

Eckmann, Jan / Murgia, Claudio / Sam, Johannes / Jacobsen, Bjoern / Marrer-Berger, Estelle / Boetsch, Christophe / Belli, Sara / Leibrock, Lea / Benz, Joerg / Koll, Hans / Sutmuller, Roger / Peggs, Karl S / Quezada, Sergio A

Nature cancer

2020 Volume 1, Issue 12, Page(s) 1153–1166

Abstract: Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and ... receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here ... IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade ...

Abstract	Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Interleukin-2/pharmacology ; Mice ; Neoplasms ; Signal Transduction ; T-Lymphocytes, Regulatory
Chemical Substances	Antibodies, Monoclonal ; Interleukin-2
Language	English
Publishing date	2020-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-020-00133-0
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Article ; Online: Tsyn-seq: a T cell synapse-based antigen identification platform.

Cancer immunology research

2024

Abstract: Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T ... the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APCs) with a Fas ... inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter ...

Abstract	Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCRs) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APCs) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library.
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0467
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Article: Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R〿2-targeting CAR T cells: an interim analysis.

Wang, Leo / Oill, Angela Taravella / Blanchard, M / Wu, Melody / Hibbard, Jonathan / Sepulveda, Sean / Peter, Lance / Kilpatrick, Julie / Munoz, Margarita / Stiller, Tracey / Shulkin, Noah / Wagner, Jamie / Dolatabadi, Ally / Nisis, Monica / Shepphird, Jennifer / Sanchez, Gabriela / Lingaraju, Chetan / Manchanda, Mishika / Natri, Heini /

Kouakanou, Léonce / Sun, Grace / Oliver-Cervantes, Cheryl / Georges, Joseph / Aftabizadeh, Maryam / Forman, Stephen / Priceman, Saul / Ressler, Julie / Arvanitis, Leonidas / Cotter, Jennifer / D'Apuzzo, Massimo / Tamrazi, Benita / Badie, Behnam / Davidson, Tom / Banovich, Nicholas / Brown, Christine

Research square

2023

Abstract: ... antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six ... pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T ...

Abstract	Outcomes for pediatric brain tumor patients remain poor, and there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T cells delivered weekly into the lateral cerebral ventricles, identifying clonal expansion of endogenous CAR-negative CD8
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3454977/v1
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Article ; Online: Simultaneous T

Sharafi, Azadeh / Medina, Katherine / Zibetti, Marcelo W V / Rao, Smita / Cloos, Martijn A / Brown, Ryan / Regatte, Ravinder R

Magnetic resonance in medicine

2021 Volume 86, Issue 1, Page(s) 372–381

Abstract: ... to : Methods: We implemented a totally balanced spin-lock (TB-SL) module to encode T: Results: The phantom ...

Abstract	Purpose: To develop a novel MR-fingerprinting (MRF) pulse sequence that is insensitive to Methods: We implemented a totally balanced spin-lock (TB-SL) module to encode T Results: The phantom relaxation times measured with TB-SL and SC-SL MRF were in good agreement with reference values in regions with low B Conclusion: The proposed TB-SL MRF sequence is fast and insensitive to
MeSH term(s)	Humans ; Image Processing, Computer-Assisted ; Leg ; Magnetic Resonance Imaging ; Muscle, Skeletal/diagnostic imaging ; Phantoms, Imaging
Language	English
Publishing date	2021-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605774-3
ISSN	1522-2594 ; 0740-3194
ISSN (online)	1522-2594
ISSN	0740-3194
DOI	10.1002/mrm.28704
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Article: Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

Kimura, Shunsuke / Polonen, Petri / Montefiori, Lindsey / Park, Chun Shik / Iacobucci, Ilaria / Yeoh, Allen Ej / Attarbaschi, Andishe / Moore, Andrew S / Brown, Anthony / Manabe, Atsushi / Buldini, Barbara / Freeman, Burgess B / Chen, Chelsey / Cheng, Cheng / Kean Hui, Chiew / Li, Chi-Kong / Pui, Ching-Hon / Qu, Chunxu / Tomizawa, Daisuke /

Teachey, David T / Varotto, Elena / Paietta, Elisabeth M / Arnold, Elizabeth D / Locatelli, Franco / Escherich, Gabriele / Elisa Muhle, Hannah / Marquart, Hanne Vibeke / de Groot-Kruseman, Hester A / Rowe, Jacob M / Stary, Jan / Trka, Jan / Choi, John Kim / Meijerink, Jules P P / Yang, Jun J / Takita, Junko / Pawinska-Wasikowska, Katarzyna / Roberts, Kathryn G / Han, Katie / Caldwell, Kenneth J / Schmiegelow, Kjeld / Crews, Kristine R / Eguchi, Mariko / Schrappe, Martin / Zimmerman, Martin / Takagi, Masatoshi / Maybury, Mellissa / Svaton, Michael / Reiterova, Michaela / Kicinski, Michal / Prater, Mollie S / Kato, Motohiro / Reyes, Noemi / Spinelli, Orietta / Thomas, Paul / Mazilier, Pauline / Gao, Qingsong / Masetti, Riccardo / Kotecha, Rishi S / Pieters, Rob / Elitzur, Sarah / Luger, Selina M / Mitchell, Sharnise / Pruett-Miller, Shondra M / Shen, Shuhong / Jeha, Sima / Köhrer, Stefan / Kornblau, Steven M / Skoczeń, Szymon / Miyamura, Takako / Vincent, Tiffaney L / Imamura, Toshihiko / Conter, Valentino / Tang, Yanjing / Liu, Yen-Chun / Chang, Yunchao / Gu, Zhaohui / Cheng, Zhongshan / Yinmei, Zhou / Inaba, Hiroto / Mullighan, Charles G

medRxiv : the preprint server for health sciences

2023

Abstract: Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high ... risk but poorly characterized disease.: Methods: We studied clinical features of 200 pediatric γδ T ... ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were ...

Abstract	Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. Methods: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. Results: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], Conclusion: γδ T-ALL in children under the age of three is extremely high-risk and enriched for Support: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.
Language	English
Publishing date	2023-11-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.06.23298028
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Article ; Online: Obesity Differs from Diabetes Mellitus in Antibody and T Cell Responses Post COVID-19 Recovery.

Ali, Mohammad / Longet, Stephanie / Neale, Isabel / Rongkard, Patpong / Chowdhury, Forhad Uddin Hassan / Hill, Jennifer / Brown, Anthony / Laidlaw, Stephen / Tipton, Tom / Hoque, Ashraful / Hassan, Nazia / Hackstein, Carl-Philipp / Adele, Sandra / Akther, Hossain Delowar / Abraham, Priyanka / Paul, Shrebash / Rahman, Md Matiur / Alam, Md Masum / Parvin, Shamima /

Hoque Mollah, Forhadul / Hoque, Md Mozammel / Moore, Shona C / Biswas, Subrata K / Turtle, Lance / de Silva, Thushan I / Ogbe, Ane / Frater, John / Barnes, Eleanor / Tomic, Adriana / Carroll, Miles W / Klenerman, Paul / Kronsteiner, Barbara / Chowdhury, Fazle Rabbi / Dunachie, Susanna J

Clinical and experimental immunology

2024

Abstract: ... In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR ... 19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell ... production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell ...

Abstract	Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.
Language	English
Publishing date	2024-04-20
Publishing country	England
Document type	Journal Article
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxae030
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Article ; Online: Characterising Distinct Migratory Profiles of Infiltrating T-Cell Subsets in Human Glioblastoma.

Kollis, Paris M / Ebert, Lisa M / Toubia, John / Bastow, Cameron R / Ormsby, Rebecca J / Poonnoose, Santosh I / Lenin, Sakthi / Tea, Melinda N / Pitson, Stuart M / Gomez, Guillermo A / Brown, Michael P / Gargett, Tessa

Frontiers in immunology

2022 Volume 13, Page(s) 850226

Abstract: ... in the 5-year survival rate of 4.6% over the past three decades. T-cell-based immunotherapies ... such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival ... However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is T-cell ...

Abstract	Glioblastoma is the most common and aggressive form of primary brain cancer, with no improvements in the 5-year survival rate of 4.6% over the past three decades. T-cell-based immunotherapies such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival of patients with other cancers and have undergone early-phase clinical evaluation in glioblastoma patients. However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is T-cell infiltration into tumours. This process is mediated by chemokine-chemokine receptor and integrin-adhesion molecule interactions, yet the specific nature of the molecules that may facilitate T-cell homing into glioblastoma are unknown. Here, we have characterised chemokine receptor and integrin expression profiles of endogenous glioblastoma-infiltrating T cells, and the chemokine expression profile of glioblastoma-associated cells, by single-cell RNA-sequencing. Subsequently, chemokine receptors and integrins were validated at the protein level to reveal enrichment of receptors CCR2, CCR5, CXCR3, CXCR4, CXCR6, CD49a, and CD49d in glioblastoma-infiltrating T-cell populations relative to T cells in matched patient peripheral blood. Complementary chemokine ligand expression was then validated in glioblastoma biopsies and glioblastoma-derived primary cell cultures. Together, enriched expression of homing receptor-ligand pairs identified in this study implicate a potential role in mediating T-cell infiltration into glioblastoma. Importantly, our data characterising the migratory receptors on endogenous tumour-infiltrating T cells could be exploited to enhance the tumour-homing properties of future T-cell immunotherapies for glioblastoma.
MeSH term(s)	Chemokines/metabolism ; Glioblastoma/metabolism ; Glioblastoma/therapy ; Humans ; Integrins/metabolism ; Ligands ; T-Lymphocyte Subsets
Chemical Substances	Chemokines ; Integrins ; Ligands
Language	English
Publishing date	2022-04-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.850226
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Article ; Online: Assembly of a spatial circuit of T-bet-expressing T and B lymphocytes is required for antiviral humoral immunity.

Mendoza, Alejandra / Yewdell, William T / Hoyos, Beatrice / Schizas, Michail / Bou-Puerto, Regina / Michaels, Anthony J / Brown, Chrysothemis C / Chaudhuri, Jayanta / Rudensky, Alexander Y

Science immunology

2021 Volume 6, Issue 60

Abstract: Effective antiviral immunity requires generation of T and B lymphocytes expressing ... the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous ... marker for cells participating in a type 1 response, we report coordinated interactions of T-bet ...

Abstract	Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes on the basis of their dynamic colocalization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GCs) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of T
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Cell Communication/immunology ; Disease Models, Animal ; Female ; Germinal Center/cytology ; Germinal Center/metabolism ; Humans ; Immunity, Humoral ; Immunoglobulin Class Switching ; Influenza A virus/immunology ; Influenza, Human/immunology ; Influenza, Human/pathology ; Influenza, Human/virology ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Lung/immunology ; Lung/pathology ; Lung/virology ; Male ; Mice ; Mice, Transgenic ; Nippostrongylus/immunology ; Rats ; Receptors, CXCR3/metabolism ; Strongylida Infections/immunology ; Strongylida Infections/parasitology ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Th1 Cells/immunology ; Th1 Cells/metabolism
Chemical Substances	Cxcr3 protein, mouse ; IFNG protein, mouse ; Receptors, CXCR3 ; T-Box Domain Proteins ; T-box transcription factor TBX21 ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2021-06-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.abi4710
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Article ; Online: GATA-3 is a proto-oncogene in T-cell lymphoproliferative neoplasms.

Geng, Xiangrong / Wang, Chenguang / Gao, Xin / Chowdhury, Pinki / Weiss, Jonathan / Villegas, José A / Saed, Badeia / Perera, Thilini / Hu, Ying / Reneau, John / Sverdlov, Maria / Wolfe, Ashley / Brown, Noah / Harms, Paul / Bailey, Nathanael G / Inamdar, Kedar / Hristov, Alexandra C / Tejasvi, Trilokraj / Montes, Jaime /

Barrionuevo, Carlos / Taxa, Luis / Casavilca, Sandro / de Pádua Covas Lage, J Luís Alberto / Culler, Hebert Fabrício / Pereira, Juliana / Runge, John S / Qin, Tingting / Tsoi, Lam C / Hong, Hanna S / Zhang, Li / Lyssiotis, Costas A / Ohe, Rintaro / Toubai, Tomomi / Zevallos-Morales, Alejandro / Murga-Zamalloa, Carlos / Wilcox, Ryan A

Blood cancer journal

2022 Volume 12, Issue 11, Page(s) 149

Abstract: Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account ... for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and ... in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor ...

Abstract	Neoplasms originating from thymic T-cell progenitors and post-thymic mature T-cell subsets account for a minority of lymphoproliferative neoplasms. These T-cell derived neoplasms, while molecularly and genetically heterogeneous, exploit transcription factors and signaling pathways that are critically important in normal T-cell biology, including those implicated in antigen-, costimulatory-, and cytokine-receptor signaling. The transcription factor GATA-3 regulates the growth and proliferation of both immature and mature T cells and has recently been implicated in T-cell neoplasms, including the most common mature T-cell lymphoma observed in much of the Western world. Here we show that GATA-3 is a proto-oncogene across the spectrum of T-cell neoplasms, including those derived from T-cell progenitors and their mature progeny, and further define the transcriptional programs that are GATA-3 dependent, which include therapeutically targetable gene products. The discovery that p300-dependent acetylation regulates GATA-3 mediated transcription by attenuating DNA binding has novel therapeutic implications. As most patients afflicted with GATA-3 driven T-cell neoplasms will succumb to their disease within a few years of diagnosis, these findings suggest opportunities to improve outcomes for these patients.
MeSH term(s)	Humans ; Cell Differentiation ; DNA-Binding Proteins/genetics ; Neoplasms/metabolism ; Proto-Oncogenes/genetics ; T-Lymphocyte Subsets ; Leukemia, Lymphoid
Chemical Substances	DNA-Binding Proteins
Language	English
Publishing date	2022-11-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-022-00745-y
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Article ; Online: Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR).

Pediatric blood & cancer

2022 Volume 69, Issue 11, Page(s) e29901

Abstract: Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T ... over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary ... in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated ...

Abstract	Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100 mg/m<sup>2</sup> /day and cyclophosphamide at 330-400 mg/m<sup>2</sup> /day, each for 5 consecutive days in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated at three dose levels; 21 were evaluable for dose-limiting toxicities (DLT) and response. The recommended phase II doses (RP2D) for this regimen, when given daily ×5 every 3 weeks, were nelarabine 650 mg/m<sup>2</sup> /day, etoposide 100 mg/m<sup>2</sup> /day, and cyclophosphamide 400 mg/m<sup>2</sup> /day. DLTs included peripheral motor and sensory neuropathies. An expansion cohort to evaluate responses at the RP2D was terminated early due to slow accrual. The overall best response rate was 38% (8/21), with 33% (4/12) responses in the T-ALL cohort and 44% (4/9) responses in the T-LBL cohort. These response rates are comparable to those seen with single-agent nelarabine in this setting. These data suggest that the addition of cyclophosphamide and etoposide to nelarabine does not increase the incidence of neurologic toxicities or the response rate beyond that obtained with single-agent nelarabine in children with first relapse of T-ALL and T-LBL.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Arabinonucleosides/adverse effects ; Child ; Cyclophosphamide/adverse effects ; Etoposide/adverse effects ; Humans ; Lymphoma, Non-Hodgkin/drug therapy ; Nucleosides/therapeutic use ; Plant Nectar ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Recurrence
Chemical Substances	Arabinonucleosides ; Nucleosides ; Plant Nectar ; nelarabine (60158CV180) ; Etoposide (6PLQ3CP4P3) ; Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2022-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2131448-2
ISSN	1545-5017 ; 1545-5009
ISSN (online)	1545-5017
ISSN	1545-5009
DOI	10.1002/pbc.29901
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In stock of ZB MED Cologne/Königswinter

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