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Amy Musiek - One of the best experts on this subject based on the ideXlab platform.
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modeling Sezary syndrome for immunophenotyping and anti tumor effect of ucart and long acting interleukin 7 combination therapy
Biology of Blood and Marrow Transplantation, 2019Co-Authors: Karl Staser, Matthew L Cooper, Jaebok Choi, Anand Chukka, Kidist Ashami, Jessica Niswonger, Jaehan Park, Byung Ha Lee, Amanda F Cashen, Amy MusiekAbstract:Background Sezary syndrome (SS) is a highly-morbid T Cell leukemic lymphoma with no widely-effective treatments and few preclinical models. SS T Cells typically lose CD7 but maintain ubiquitous high CD2 expression. Thus, we generated CD2- and TRAC-deleted anti-CD2 universal CARTs (UCART2) and multiple SS xenograft models (PDXs) as preclinical UCART2 testing platforms. We further tested a stable homodimeric interleukin-7 molecule, the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (rhIL-7-hyFc, NT-I7), to potentiate UCART2 killing of an SS xenograft in vivo. Methods To generate SS PDX models, we injected NSG-SGM3 mice with ∼2 × 106 mononuclear Cells derived from SS patients. We immunophenotyped SS patient blood and PDX engraftment with two 21-color flow cytometry panels assessing major immune subsets, CTCL, and exhaustion markers. To generate UCART2s, we CRISPR/Cas9 multiplexed edited CD2 and TRAC from CART2. For initial testing, we injected NSG mice with 5 × 105 Cells from a human Sezary Cell line (HH) on day -4 from UCART2 treatment, followed by NT-I7 (10mg/kg SC) on days +1, +15 and +29. Results SS patient blood showed specific defects in monocyte, monocytic dendritic Cell, and natural killer Cell differentiation, increased skewing toward granulocytes and non-classical CD16+ monocytes (p 90% vs ∼20%, p UCART2-treated HHCBR-GFP mice showed dramatically reduced tumor burden as compared to control UCART19-treated HHCBR-GFP mice (BLI; 10^7 vs. 10^11 photon flux/s at 3 weeks, p Discussion We describe the generation of physiologically-relevant SS preclinical models and the highly effective anti-tumor activity of UCART2- plus NT-I7-mediated killing of SS Cells in vivo using an NSG xenograft model.
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modeling Sezary syndrome for immunophenotyping and anti tumor effect of ucart and long acting interleukin 7 combination therapy
Blood, 2018Co-Authors: Karl Staser, Matthew L Cooper, Jaebok Choi, Anand Chukka, Kidist Ashami, Jessica Niswonger, Jaehan Park, Byung Ha Lee, Amanda F Cashen, Amy MusiekAbstract:Background: Sezary syndrome (SS) is a highly-morbid T Cell leukemic lymphoma with no widely-effective treatments and few preclinical models. We demonstrated effective T Cell lymphoma therapy with allogeneic gene-edited anti-CD7 CARTs (Cooper et al, Leukemia, 2018). However, SS T Cells typically lose CD7 but maintain ubiquitous high CD2 expression. Thus, we generated CD2- and TRAC-deleted anti-CD2 universal CARTs (UCART2) and multiple SS xenograft models (PDXs) as preclinical UCART2 testing platforms. We further tested a stable homodimeric interleukin-7 molecule, the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (rhIL-7-hyFc, NT-I7), to potentiate UCART2 killing of an SS xenograft in vivo. Methods: To generate SS PDX models, we injected NOD scid IL2Rgammanull (NSG) mice expressing SCF, GM-CSF, and IL-3 (NSG-SGM3) with ~2x106 mononuclear Cells derived from SS patients. We immunophenotyped SS patient blood and PDX engraftment with two 21-color flow cytometry panels assessing major immune subsets, CTCL, and exhaustion markers (Staser et al, Cytometry A, 2018). To generate UCART2s, we activated human T Cells on CD3/CD28 beads, electroporated the T Cells with Cas9, a TRAC-targeted gRNA, and a CD2-targeted gRNA followed by viral transduction with an anti-CD2 scFv 3rd generation CAR. For initial UCART2 testing, we injected NSG mice with 5x105 Cells from a human Sezary Cell line transduced with click beetle red luciferase (HHCBR-GFP) four days prior to UCART2 treatment. Mice were treated with NT-I7 (10mg/kg SC) on days +1, +15 and +29 post UCART2 infusion. Results: SS patient blood showed specific defects in monocyte, monocytic dendritic Cell, and natural killer Cell differentiation, increased skewing toward granulocytes and non-classical CD16+ monocytes (p 90% vs ~20%, p To test UCART29s efficacy in killing SS Cells in vivo, we injected NSG mice with HHCBR-GFP+ Cells. UCART2-treated HHCBR-GFP mice showed dramatically reduced tumor burden as compared to control UCART19-treated HHCBR-GFP mice (BLI; 10^7 vs. 10^11 photon flux/s at 3 weeks, p Discussion: We describe the generation of physiologically-relevant SS preclinical models, comprehensive immunophenotyping of patient SS samples, clonal SS PDX outgrowth, and the highly effective anti-tumor activity of UCART2- plus NT-I7-mediated killing of SS Cells in vivo using an NSG xenograft model. Ongoing studies involve treating primary SS and CTCL PDX models with UCART2 and NT-I7. These preclinical data validate the use of allogeneic "off-the-shelf" adoptive immunotherapy for the treatment of Sezary syndrome, while demonstrating the dramatic enhancement of CART efficacy using a dose-adjustable, clinic-ready long-acting interleukin-7 agonist given in an adjuvant setting. Disclosures Park:NeoImmuneTech: Employment. Lee:NeoImmuneTech: Employment. Musiek:Seattle Genetics: Honoraria; Actelion: Other: Scientific Advisory Committee ; Kyowa Kirin: Honoraria.
Sean Whittaker - One of the best experts on this subject based on the ideXlab platform.
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brentuximab vedotin demonstrates significantly superior clinical outcomes in patients with cd30 expressing cutaneous t Cell lymphoma versus physician s choice methotrexate or bexarotene the phase 3 alcanza study
Blood, 2016Co-Authors: Youn H Kim, Sean Whittaker, Madeleine Duvic, Steven M Horwitz, Reinhard Dummer, Julia Scarisbrick, Pietro Quaglino, Pier Luigi Zinzani, Pascal Wolter, Yinghui WangAbstract:Background Cutaneous T Cell lymphoma (CTCL) is a chronic disease that negatively impacts quality of life (QoL) and, in advanced stages, has poor prognosis. Current systemic therapies rarely provide reliable and durable responses, and to date, no systemic agent has shown outcomes superior to standard-of-care therapy such as methotrexate (MTX) or bexarotene (Bex). CD30-directed antibody-drug conjugate brentuximab vedotin (BV) has demonstrated marked clinical activity in two phase 2 single-arm trials in CTCL with overall response rates (ORR) of about 70%. These results led to ALCANZA, a randomized, open-label, multicenter phase 3 trial of the efficacy and safety of BV vs physician9s choice (PC) of MTX or Bex, in previously treated patients with CD30-expressing CTCL (NCT01578499). This is the first reported randomized phase 3 trial testing a new agent against standard-of-care therapy in CTCL. Methods Adults with CD30-expressing (≥10% of infiltrate by central review) mycosis fungoides (MF) who received ≥1 prior systemic therapy or primary cutaneous anaplastic large Cell lymphoma (pcALCL) who received ≥1 prior systemic therapy or radiotherapy were enrolled. Patients were stratified by diagnosis and randomized 1:1 to receive BV 1.8 mg/kg IV, once every 3 weeks, or PC of either MTX 5-50 mg PO, once weekly, or Bex 300 mg/m² (target dose) PO, once daily, for up to 16 three-week cycles, until disease progression or unacceptable toxicity. Primary endpoint was ORR4, defined as ORR lasting ≥4 months, an endpoint that captures response rate and duration as a single measurement. ORR4 was determined by independent review of global response using the ISCL/EORTC consensus guidelines. Global response is a composite of skin evaluation (modified severity weighted assessment tool), radiographic assessment, and Sezary Cell enumeration. Key secondary endpoints were CR rate, PFS, and symptom burden measured by the symptom domain of the Skindex-29 QoL tool. Sample size was calculated to provide 90% power to detect a 30% improvement in ORR4. Treatment-emergent adverse events (AEs) were evaluated according to NCI CTCAE v4.03. Results 131 patients were randomized with 128 patients in the intent-to-treat population (97 MF, 31 pcALCL; 3 excluded for insufficient CD30 expression) and assigned to BV (n=64) or PC (n=64). Baseline characteristics were generally balanced between arms with the exception of more patients with extracutaneous disease in the BV arm (Table). In BV vs PC arms, respectively, median age was 62 (22-83) vs 58 (22-83) years; ECOG performance status 0-1 was 95% vs 97%. Patients in each arm had a median of 2 prior systemic therapies. At a median follow-up of 17.5 months, ORR4 (primary endpoint) and PFS strongly favored BV vs PC with ORR4 of 56% vs 13% (p Patients received a median of 12 (1-16) cycles of BV vs 5.5 (1-16) Bex and 3 (1-16) cycles of MTX. Grade 3-4 AEs, all cause / drug-related, were seen in 41% / 29% with BV vs 47% / 29% with PC. Serious AEs were seen in 29% of patients in each arm. Peripheral neuropathy (PN), any grade, was seen in 67% in the BV arm (32% grade 2, 9% grade 3) and 6% in the PC arm. At last follow-up, 36/44 (82%) patients in the BV arm had improvement or resolution of PN. Discontinuation due to AEs occurred in 24% (BV) vs 8% (PC). Four deaths in the BV arm (3 unrelated to study drug) occurred within 30 days of the last dose. Other AEs were consistent with reported safety profiles for the individual agents. Conclusions In this first report of a randomized phase 3 trial evaluating a new agent vs standard-of-care options in CTCL, the clinical outcome of BV was far superior to PC (MTX or Bex). Highly statistically significant improvements in ORR4 (44%) and median PFS (13.2 months) were observed with BV. Greater ORR with higher CR rate and reduction in symptoms per Skindex-29 symptom domain were also observed in the BV arm. Safety data for BV were consistent with the established tolerability profile. The data from this randomized trial provide compelling evidence favoring BV over PC of Bex or MTX in CD30-expressing CTCL. Disclosures Kim:Kyowa Kirin Pharma: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Membership on an entity9s Board of Directors or advisory committees; miRagen: Research Funding; Merck: Research Funding; Soligenix: Research Funding; Takeda: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Neumedicine: Research Funding; Forty Seven Inc: Membership on an entity9s Board of Directors or advisory committees; Innate: Research Funding; Portola: Consultancy; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding. Whittaker:Takeda: Membership on an entity9s Board of Directors or advisory committees; Innate Pharma: Other: Investigator in a clinical trial; Seattle Genetics: Other: Investigator in a clinical trial; Galderma: Research Funding. Horwitz:ADCT Therapeutics: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Huya: Consultancy; Takeda: Consultancy, Research Funding; Infinity: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy. Dummer:Allos: Research Funding; Shape: Research Funding; Jonathan Wood & Assoc: Speakers Bureau; Soligenetics: Research Funding; Cell Medica: Consultancy, Honoraria; Therakos: Speakers Bureau; Mallinckrodt Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Covance Laboratory Services: Consultancy; Oncoceuticals: Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Huya: Consultancy; Eisai: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Millennium: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Array: Consultancy, Honoraria; Seattle Genetics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Scarisbrick:Millennium: Consultancy; 4SC: Consultancy. Zinzani:Karyopharm: Membership on an entity9s Board of Directors or advisory committees; Sandoz: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees; Abbvie: Membership on an entity9s Board of Directors or advisory committees; Infinity: Membership on an entity9s Board of Directors or advisory committees; Takeda: Membership on an entity9s Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity9s Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Millennium: Membership on an entity9s Board of Directors or advisory committees. Wang:Seattle Genetics: Employment, Equity Ownership. Palanca-Wessels:Seattle Genetics: Employment, Equity Ownership. Zagadailov:Takeda Pharmaceuticals: Employment, Equity Ownership; Amerisource Bergen: Equity Ownership. Trepicchio:Takeda Pharmaceuticals: Employment. Liu:Takeda Pharmaceuticals: Employment, Equity Ownership. Little:Takeda Pharmaceuticals: Employment, Equity Ownership.
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case report of four patients with erythrodermic cutaneous t Cell lymphoma and severe photosensitivity mimicking chronic actinic dermatitis
British Journal of Dermatology, 2009Co-Authors: N Agar, J. L. M. Hawk, R Russelljones, S D Morris, Sean WhittakerAbstract:The marked photosensitivity associated with chronic actinic dermatitis (CAD) is presumed to be due to a T Cell-mediated response to ultraviolet (UV)-induced epidermal neoantigens. Photosensitivity is, however, a rare occurrence in cutaneous T-Cell lymphoma (CTCL). We discuss a series of four patients with erythrodermic CTCL who exhibited marked photosensitivity mimicking CAD. Significantly, the tumour Cells had a CD8 phenotype in half of these patients. All patients had T-Cell clones in skin and also demonstrated identical peripheral T-Cell clones in blood or lymph node involvement. Sezary Cell counts ranged from 6% to 20%, CD4/CD8 ratios from 0.22 to 23.5. Clinical presentation was striking for a marked photosensitive distribution. Monochromator irradiation testing revealed reduced minimal erythema doses throughout UVB and UVA ranges, findings consistent with those seen in CAD. All patients subsequently died from systemic disease. These findings suggest that, rarely, malignant clonal T-Cell populations may recognize a unique UV-induced neoantigen, resulting in the clinical features of severe photosensitivity mimicking those seen in CAD.
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extracorporeal photopheresis in Sezary syndrome no significant effect in the survival of 44 patients with a peripheral blood t Cell clone
Archives of Dermatology, 1998Co-Authors: Elisabeth A Fraserandrews, Sean Whittaker, Paul T. Seed, R RusselljonesAbstract:Background Several retrospective studies have claimed that extracorporeal photopheresis (ECP) prolongs survival in patients with erythrodermic cutaneous T-Cell lymphoma. In a retrospective study of 44 patients with Sezary syndrome, we compared survival in patients treated with ECP with that of patients treated conventionally at the same institute. All patients had genotypic evidence of a peripheral blood T-Cell clone. Observations Twenty-nine patients received ECP (group 1); 15 patients did not receive ECP, 8 patients when ECP was available (group 2) and 7 before ECP was available (group 3). Forty-three of 44 patients received other conventional treatments. Median survival from diagnosis of Sezary syndrome was 39 months in group 1, 22 months in group 2, and 27.5 months in group 3 (Kaplan-Meier analysis). Cox regression analysis showed no significant difference between the 3 groups after correcting for age, sex, and initial Sezary Cell count (hazard ratio, 0.56; 95% confidence interval, 0.26-1.17; P =.12). Conclusions This study does not support the contention that ECP prolongs survival in patients with Sezary syndrome. The median survival in the ECP-treated group is considerably less than that reported in other published series, possibly because genotypic evidence of clonality in the peripheral blood was required for inclusion in this study. We believe that a randomized trial comparing ECP with standard chemotherapy is urgently needed.
R Russelljones - One of the best experts on this subject based on the ideXlab platform.
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case report of four patients with erythrodermic cutaneous t Cell lymphoma and severe photosensitivity mimicking chronic actinic dermatitis
British Journal of Dermatology, 2009Co-Authors: N Agar, J. L. M. Hawk, R Russelljones, S D Morris, Sean WhittakerAbstract:The marked photosensitivity associated with chronic actinic dermatitis (CAD) is presumed to be due to a T Cell-mediated response to ultraviolet (UV)-induced epidermal neoantigens. Photosensitivity is, however, a rare occurrence in cutaneous T-Cell lymphoma (CTCL). We discuss a series of four patients with erythrodermic CTCL who exhibited marked photosensitivity mimicking CAD. Significantly, the tumour Cells had a CD8 phenotype in half of these patients. All patients had T-Cell clones in skin and also demonstrated identical peripheral T-Cell clones in blood or lymph node involvement. Sezary Cell counts ranged from 6% to 20%, CD4/CD8 ratios from 0.22 to 23.5. Clinical presentation was striking for a marked photosensitive distribution. Monochromator irradiation testing revealed reduced minimal erythema doses throughout UVB and UVA ranges, findings consistent with those seen in CAD. All patients subsequently died from systemic disease. These findings suggest that, rarely, malignant clonal T-Cell populations may recognize a unique UV-induced neoantigen, resulting in the clinical features of severe photosensitivity mimicking those seen in CAD.
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update on erythrodermic cutaneous t Cell lymphoma report of the international society for cutaneous lymphomas
Journal of The American Academy of Dermatology, 2002Co-Authors: Eric C Vonderheid, R Russelljones, Maria Grazia Bernengo, Gunter Burg, Madeleine Duvic, Peter Heald, L Laroche, Elise A Olsen, Mark R Pittelkow, Masahiro TakigawaAbstract:Two conferences were sponsored by the International Society for Cutaneous Lymphomas (ISCL) to gain consensus on definitions and terminology for clinical use in erythrodermic cutaneous T-Cell lymphoma (E-CTCL). Three subsets of E-CTCL were defined: Sezary syndrome ("leukemic phase" E-CTCL), erythrodermic mycosis fungoides (secondary E-CTCL that develops in patients with mycosis fungoides), and E-CTCL, not otherwise defined. The hematologic criteria recommended for Sezary syndrome are intended to identify patients with a worse prognosis compared with the other E-CTCL subsets and consist of one or more of the following: (1) an absolute Sezary Cell count of 1000 Cells/mm3 or more; (2) a CD4/CD8 ratio of 10 or higher caused by an increase in circulating T Cells and/or an aberrant loss or expression of pan-T Cell markers by flow cytometry; (3) increased lymphocyte counts with evidence of a T-Cell clone in the blood by the Southern blot or polymerase chain reaction technique; or (4) a chromosomally abnormal T-Cell clone. For staging purposes, it is proposed that these criteria define the B2 blood rating and that the B2 rating be considered equivalent to nodal involvement.
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extracorporeal photopheresis in Sezary syndrome no significant effect in the survival of 44 patients with a peripheral blood t Cell clone
Archives of Dermatology, 1998Co-Authors: Elisabeth A Fraserandrews, Sean Whittaker, Paul T. Seed, R RusselljonesAbstract:Background Several retrospective studies have claimed that extracorporeal photopheresis (ECP) prolongs survival in patients with erythrodermic cutaneous T-Cell lymphoma. In a retrospective study of 44 patients with Sezary syndrome, we compared survival in patients treated with ECP with that of patients treated conventionally at the same institute. All patients had genotypic evidence of a peripheral blood T-Cell clone. Observations Twenty-nine patients received ECP (group 1); 15 patients did not receive ECP, 8 patients when ECP was available (group 2) and 7 before ECP was available (group 3). Forty-three of 44 patients received other conventional treatments. Median survival from diagnosis of Sezary syndrome was 39 months in group 1, 22 months in group 2, and 27.5 months in group 3 (Kaplan-Meier analysis). Cox regression analysis showed no significant difference between the 3 groups after correcting for age, sex, and initial Sezary Cell count (hazard ratio, 0.56; 95% confidence interval, 0.26-1.17; P =.12). Conclusions This study does not support the contention that ECP prolongs survival in patients with Sezary syndrome. The median survival in the ECP-treated group is considerably less than that reported in other published series, possibly because genotypic evidence of clonality in the peripheral blood was required for inclusion in this study. We believe that a randomized trial comparing ECP with standard chemotherapy is urgently needed.
Karl Staser - One of the best experts on this subject based on the ideXlab platform.
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modeling Sezary syndrome for immunophenotyping and anti tumor effect of ucart and long acting interleukin 7 combination therapy
Biology of Blood and Marrow Transplantation, 2019Co-Authors: Karl Staser, Matthew L Cooper, Jaebok Choi, Anand Chukka, Kidist Ashami, Jessica Niswonger, Jaehan Park, Byung Ha Lee, Amanda F Cashen, Amy MusiekAbstract:Background Sezary syndrome (SS) is a highly-morbid T Cell leukemic lymphoma with no widely-effective treatments and few preclinical models. SS T Cells typically lose CD7 but maintain ubiquitous high CD2 expression. Thus, we generated CD2- and TRAC-deleted anti-CD2 universal CARTs (UCART2) and multiple SS xenograft models (PDXs) as preclinical UCART2 testing platforms. We further tested a stable homodimeric interleukin-7 molecule, the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (rhIL-7-hyFc, NT-I7), to potentiate UCART2 killing of an SS xenograft in vivo. Methods To generate SS PDX models, we injected NSG-SGM3 mice with ∼2 × 106 mononuclear Cells derived from SS patients. We immunophenotyped SS patient blood and PDX engraftment with two 21-color flow cytometry panels assessing major immune subsets, CTCL, and exhaustion markers. To generate UCART2s, we CRISPR/Cas9 multiplexed edited CD2 and TRAC from CART2. For initial testing, we injected NSG mice with 5 × 105 Cells from a human Sezary Cell line (HH) on day -4 from UCART2 treatment, followed by NT-I7 (10mg/kg SC) on days +1, +15 and +29. Results SS patient blood showed specific defects in monocyte, monocytic dendritic Cell, and natural killer Cell differentiation, increased skewing toward granulocytes and non-classical CD16+ monocytes (p 90% vs ∼20%, p UCART2-treated HHCBR-GFP mice showed dramatically reduced tumor burden as compared to control UCART19-treated HHCBR-GFP mice (BLI; 10^7 vs. 10^11 photon flux/s at 3 weeks, p Discussion We describe the generation of physiologically-relevant SS preclinical models and the highly effective anti-tumor activity of UCART2- plus NT-I7-mediated killing of SS Cells in vivo using an NSG xenograft model.
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modeling Sezary syndrome for immunophenotyping and anti tumor effect of ucart and long acting interleukin 7 combination therapy
Blood, 2018Co-Authors: Karl Staser, Matthew L Cooper, Jaebok Choi, Anand Chukka, Kidist Ashami, Jessica Niswonger, Jaehan Park, Byung Ha Lee, Amanda F Cashen, Amy MusiekAbstract:Background: Sezary syndrome (SS) is a highly-morbid T Cell leukemic lymphoma with no widely-effective treatments and few preclinical models. We demonstrated effective T Cell lymphoma therapy with allogeneic gene-edited anti-CD7 CARTs (Cooper et al, Leukemia, 2018). However, SS T Cells typically lose CD7 but maintain ubiquitous high CD2 expression. Thus, we generated CD2- and TRAC-deleted anti-CD2 universal CARTs (UCART2) and multiple SS xenograft models (PDXs) as preclinical UCART2 testing platforms. We further tested a stable homodimeric interleukin-7 molecule, the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (rhIL-7-hyFc, NT-I7), to potentiate UCART2 killing of an SS xenograft in vivo. Methods: To generate SS PDX models, we injected NOD scid IL2Rgammanull (NSG) mice expressing SCF, GM-CSF, and IL-3 (NSG-SGM3) with ~2x106 mononuclear Cells derived from SS patients. We immunophenotyped SS patient blood and PDX engraftment with two 21-color flow cytometry panels assessing major immune subsets, CTCL, and exhaustion markers (Staser et al, Cytometry A, 2018). To generate UCART2s, we activated human T Cells on CD3/CD28 beads, electroporated the T Cells with Cas9, a TRAC-targeted gRNA, and a CD2-targeted gRNA followed by viral transduction with an anti-CD2 scFv 3rd generation CAR. For initial UCART2 testing, we injected NSG mice with 5x105 Cells from a human Sezary Cell line transduced with click beetle red luciferase (HHCBR-GFP) four days prior to UCART2 treatment. Mice were treated with NT-I7 (10mg/kg SC) on days +1, +15 and +29 post UCART2 infusion. Results: SS patient blood showed specific defects in monocyte, monocytic dendritic Cell, and natural killer Cell differentiation, increased skewing toward granulocytes and non-classical CD16+ monocytes (p 90% vs ~20%, p To test UCART29s efficacy in killing SS Cells in vivo, we injected NSG mice with HHCBR-GFP+ Cells. UCART2-treated HHCBR-GFP mice showed dramatically reduced tumor burden as compared to control UCART19-treated HHCBR-GFP mice (BLI; 10^7 vs. 10^11 photon flux/s at 3 weeks, p Discussion: We describe the generation of physiologically-relevant SS preclinical models, comprehensive immunophenotyping of patient SS samples, clonal SS PDX outgrowth, and the highly effective anti-tumor activity of UCART2- plus NT-I7-mediated killing of SS Cells in vivo using an NSG xenograft model. Ongoing studies involve treating primary SS and CTCL PDX models with UCART2 and NT-I7. These preclinical data validate the use of allogeneic "off-the-shelf" adoptive immunotherapy for the treatment of Sezary syndrome, while demonstrating the dramatic enhancement of CART efficacy using a dose-adjustable, clinic-ready long-acting interleukin-7 agonist given in an adjuvant setting. Disclosures Park:NeoImmuneTech: Employment. Lee:NeoImmuneTech: Employment. Musiek:Seattle Genetics: Honoraria; Actelion: Other: Scientific Advisory Committee ; Kyowa Kirin: Honoraria.
Eric C Vonderheid - One of the best experts on this subject based on the ideXlab platform.
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Sezary Cell counts in erythrodermic cutaneous t Cell lymphoma implications for prognosis and staging
Leukemia & Lymphoma, 2006Co-Authors: Eric C Vonderheid, Jane Pena, Peter C NowellAbstract:In this retrospective study, quantitative Sezary Cell counts were performed at presentation on 192 patients with erythrodermic cutaneous T-Cell lymphoma (E-CTCL). Per recommendation of the International Society of Cutaneous Lymphomas (ISCL), the impact on staging of using an absolute Sezary Cell count of 1.0 K microL-1 or more as equivalent to lymph node involvement was investigated. Of 132 patients with disease initially classified at stage III using the current TNM staging system, 25% were up staged to IVa, resulting in a clearer separation of associated survival curves between the stages. Furthermore, the current ISCL definition of B0, B1 and B2 ratings were improved using Sezary Cell count levels of or = 1.0 - 4.99 K microL-1 and > or = 5.0 K microL-1, respectively. These modified B ratings potentially could be used in an alternative staging system for E-CTCL without N rating. Advanced age, prior exposure to multiple systemic drugs, enlargement of peripheral lymph nodes (>3 cm), other measures of blood tumor burden (CD4/CD8 ratio > or = 10, chromosomally-abnormal clone) and 2-fold increase in serum LDH level were other factors of prognostic significance. The clinical importance of these variables vis-a-vis the modified TNBM staging system will need to be clarified in future studies.
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update on erythrodermic cutaneous t Cell lymphoma report of the international society for cutaneous lymphomas
Journal of The American Academy of Dermatology, 2002Co-Authors: Eric C Vonderheid, R Russelljones, Maria Grazia Bernengo, Gunter Burg, Madeleine Duvic, Peter Heald, L Laroche, Elise A Olsen, Mark R Pittelkow, Masahiro TakigawaAbstract:Two conferences were sponsored by the International Society for Cutaneous Lymphomas (ISCL) to gain consensus on definitions and terminology for clinical use in erythrodermic cutaneous T-Cell lymphoma (E-CTCL). Three subsets of E-CTCL were defined: Sezary syndrome ("leukemic phase" E-CTCL), erythrodermic mycosis fungoides (secondary E-CTCL that develops in patients with mycosis fungoides), and E-CTCL, not otherwise defined. The hematologic criteria recommended for Sezary syndrome are intended to identify patients with a worse prognosis compared with the other E-CTCL subsets and consist of one or more of the following: (1) an absolute Sezary Cell count of 1000 Cells/mm3 or more; (2) a CD4/CD8 ratio of 10 or higher caused by an increase in circulating T Cells and/or an aberrant loss or expression of pan-T Cell markers by flow cytometry; (3) increased lymphocyte counts with evidence of a T-Cell clone in the blood by the Southern blot or polymerase chain reaction technique; or (4) a chromosomally abnormal T-Cell clone. For staging purposes, it is proposed that these criteria define the B2 blood rating and that the B2 rating be considered equivalent to nodal involvement.
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analysis of clinical histopathologic and immunopathologic parameters in erythrodermic variants of cutaneous t Cell lymphoma with implications for staging
1994Co-Authors: Eric C Vonderheid, Peter C Nowell, Gary R Kantor, Edward C Pequignot, Stuart R Lessin, Bruce J Elfenbein, Kathleen Kerrigan, Marshall E KadinAbstract:In a 5-year interval (1984 to 1989), 32 patients with erythroderma caused by cutaneous T-Cell lymphoma (CTCL) were evaluated in the Cutaneous Lymphoma Center at Hahnemann University. These patients were classified further as erythrodermic mycosis fungoides (E-MF) or Sezary syndrome (SS) on the basis of quantitative counts of Sezary Cells on peripheral blood smears, and the two groups were compared using multiple clinical, histopathologic, and immuno-pathologic findings obtained at the time of presentation. Apart from differences related to leukemic involvement, statistically significant differences between the two subgroups of erythrodermic CTCL were found for the frequency of (i) documented lymph node involvement, (ii) a marked degree of tumor Cell pleomorphism in skin biopsy specimens, and (iii) complete response to treatment lasting more than 6 months. The prognostic importance of these clinical and pathologic parameters was also determined by univariate analysis using the entire data set. The individual variables identified as possibly being associated with a favorable prognosis included (i) younger age of the patient, (ii) long duration of disease prior to study, (iii) 15 or fewer Sezary Cells per 100 lymphocytes [the definition of the E-MF clinical subtype], (iv) presence of epidermal edema, (v) a dermal infiltrate composed predominantly of small lymphocytes, (vi and vii) absence of CD71 and CD30 positive tumor Cells in the skin, and (viii) complete response to treatment. These variables were then entered into a Cox model for multivariate analysis. The patient’s age, clinical subtype of erythrodermic CTCL, presence or absence of tumor Cells expressing the transferrin receptor (CD71, T9) in the skin, and response to treatment were the variables that correlated best with survival. The results of this study suggest that the differences between E-MF and SS are related more to degree of tumor burden than to etiopathogenesis. In addition, demonstration of blood involvement by quantitative Sezary Cell counts is useful to define at least two prognostic groups within the erythrodermic CTCL spectrum and should be adopted for staging purposes.