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  • 1
    Online Resource
    Online Resource
    American Society for Clinical Investigation ; 2021
    In:  JCI Insight Vol. 6, No. 16 ( 2021-8-23)
    In: JCI Insight, American Society for Clinical Investigation, Vol. 6, No. 16 ( 2021-8-23)
    Type of Medium: Online Resource
    ISSN: 2379-3708
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2021
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  • 2
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 40, No. 6 ( 2008-6), p. 776-781
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
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  • 3
    In: Oncology, S. Karger AG, Vol. 87, No. 4 ( 2014), p. 224-231
    Abstract: We compared the three arms of the MM-015 randomized phase III clinical trial [melphalan and prednisone (MP), MP plus lenalidomide (MPR), and MPR plus lenalidomide maintenance (MPR-R)] to determine whether the addition of lenalidomide maintenance therapy for primary treatment of multiple myeloma is cost-effective. We used progression-free survival and adverse event data from the MM-015 study for the analysis. Two novel measures of cost-effectiveness termed the Average Cumulative Cost per Patient (ACCP) and the Average Cumulative Cost per Progression-Free Survivor (ACCPFS) were developed for the purpose of this analysis. The ACCP of MP was USD 18,218, compared to USD 167,862 for MPR and USD 309,173 for MPR-R. The ACCPFS was highest with MPR at USD 1,555,443, while MP was USD 313,592 and MPR-R was USD 690,111. MPR-R is superior to MPR in terms of preventing the first progression after initial therapy. However, the addition of lenalidomide to MP in the induction and also in the maintenance setting leads to significant costs.
    Type of Medium: Online Resource
    ISSN: 0030-2414 , 1423-0232
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    Language: English
    Publisher: S. Karger AG
    Publication Date: 2014
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2023
    In:  Blood Vol. 141, No. 21 ( 2023-05-25), p. 2546-2547
    In: Blood, American Society of Hematology, Vol. 141, No. 21 ( 2023-05-25), p. 2546-2547
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 5
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 652-652
    Abstract: Chimeric antigen receptor T (CART) cell therapy results in impressively high remission rates in B cell neoplasms but is limited by the development of cytokine release syndrome (CRS). CRS is characterized by the development of high-grade fevers, hypotension, fluid overload and respiratory compromise, coincides with T cell expansion and is associated with marked elevation of interleukin-6, interferon-ɣ and other inflammatory cytokines. Severe CRS is seen in 25-80% of patients treated with CD19 directed CART cell therapy and mortality has been reported. While the use of the anti-IL6 receptor antibody tocilizumab with or without steroids can usually reverse this syndrome, there is concern that the early introduction of immunosuppressive medications could impair the anti-tumor activity and therefore most investigators currently reserve tocilizumab as therapy for severe (grade 3-4) CRS. Ruxolitinib is a JAK/STAT pathway inhibitor that is FDA approved for myelofibrosis and polycythemia vera and has resulted in a significant reduction of inflammatory cytokines in clinical studies. In preclinical models, treatment with ruxolitinib ameliorates cytokine production and manifestations of hemophagocytic lymphohistiocytosis. Therefore, there is a compelling rationale to investigate and develop ruxolitinib as a modality to prevent CRS after CART cell therapy. To our knowledge, there are no relevant models for CRS after human CART therapy, thus severely limiting the development of CRS prevention modalities that would in turn enhance the clinical feasibility of CART therapy. In this study, we established a novel acute myeloid leukemia (AML) xenograft model to study the development of CRS. Here, NSG-S (Non Obese Diabetic, SCID ɣ -/- mice that are additionally transgenic for human stem cell factor, IL-3 and GM-CSF) are engrafted with blasts from AML patients and treated with 1x106 CD123-directed CART cells (CART123), ten-fold higher than we previously used in our primary AML xenograft models. These animals develop an illness characterized by progressive weight loss, generalized weakness, emaciation, hunched bodies, withdrawal and poor motor response. This illness starts within one week of CART cell injection, correlates with T cell expansion and rapidly evolves and results in the death of the animals in 7-14 days (Figure 1A). Serum from these mice seven days after CART123 shows an extreme elevation of human IL-6, Interferon-γ, tumor necrosis factor-α, and other inflammatory cytokines (Figure 1B), resembling human CRS after CART cell therapy. NSG-S mice bearing primary AML were treated with CART123 and randomized to receive different doses of ruxolitinib (30, 60, or 90 mg/kg) or vehicle by oral gavage twice a day. Treatment started on the day of CART123 injection and continued for a week. Mice treated with ruxolitinib 60 or 90 mg/kg exhibited less severe clinical illness as manifested by attenuated weight loss when compared with mice treated with CART123 alone (Figure 2A). With the exception of ruxolitinib-only treated mice, all other groups exhibited an equivalent anti-leukemic effect (Figure 2B). We therefore established ruxolitinib 60 mg/kg for further experimental use. Most importantly, ruxolitinib treatment attenuated inflammatory cytokines (figure 2C) and led to long-term survival (figure 2D). Here we have described for the first time a clinically relevant animal model of human CRS and demonstrated that the JAK/STAT inhibitor ruxolitinib can prevent the development of severe CRS without impairing the anti-tumor effect of CART cells. These findings provide a useful platform for the future study of CRS prevention and treatment modalities. These experiments indicate that ruxolitinib could also be combined with CART cell therapy for the prevention of CRS in patients identified to be at high risk for the development of CRS. Disclosures Kenderian: Novartis: Patents & Royalties, Research Funding. Ruella:novartis: Patents & Royalties: Novartis, Research Funding. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Patents & Royalties, Research Funding. June:Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; Pfizer: Honoraria; Johnson & Johnson: Research Funding; University of Pennsylvania: Patents & Royalties; Tmunity: Equity Ownership, Other: Founder, stockholder ; Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership. Gill:Novartis: Patents & Royalties, Resear\ch Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 6
    Online Resource
    Online Resource
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 845-845
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 845-845
    Abstract: Abstract 845 Background: Waldenstrom's macroglobulinemia (WM) is a relatively uncommon plasma cell disorder and most of previous literature is limited to small patient series. We have noted ethnic disparities in multiple myeloma, another plasma cell disorder. We undertook a large Surveillance Epidemiology and End Results (SEER) based analysis to describe outcome disparities in different subgroups of WM patients, with a focus on various ethnicities, so that therapeutic resources can be targeted more effectively. Methods: The SEER 17 Registry data (1973–2008) was utilized for patients with confirmed diagnosis of WM. To avoid bias of under representation of different ethnicities, analysis was restricted to patients with a diagnosis date of 1992 or later. Cases that received a diagnosis at death certificate or autopsy, no follow-up records, as well as lacking documentation on age at diagnosis, sex, or race/ethnicity were excluded. Cox proportional hazards models, adjusted for gender, age, race, year of diagnosis, marital status and stratified by SEER registries were used to evaluate associatio n between patient characteristics and survival. All statistical tests were two-sided and utilized the SAS software (v9.2) with a significance level of 0.05. Results: The final analysis included 2,840 WM patients (1,759 males; 62%, 1,081 females; 38%). The studied age-group cohorts included: 18–64 yrs (845; 30%), 65–74 yrs (795; 28%) and 〉 75 yrs (1,200; 42%). Patients were stratified by race/ethnicity: White (2,471; 87%), African-American (AA) (102; 4%), Hispanic (133; 5%), Asian (129; 5%), and Native American (5; 0.1%). Patients were also stratified based on year of diagnosis (before or after 2002) to study the impact of certain novel agents (proteasome inhibitors, IMiDs) on WM treatment. There was a significant difference in the age at diagnosis of WM patients across different ethnicities, with AA the youngest (median 61.5 years) and Whites the oldest (median 73 years) subgroup (p 〈 0.001). (Figure 1) Cause-specific mortality could not be evaluated due to variable documentation of reported causes of death for WM patients in the database. Survival analysis revealed that for all patients, females had better median overall survival (OS) than males (7.3 years vs. 6.2 years, HR 0.834; 95% CI 0.740, 0.939; p=0.003). Among the different age cohorts, patients with age ≥75 years had a significantly worse median OS (4.1 years) than those 65–74 year-old (7.3 years) or 18–64 year-old (10+ years) (p 〈 0.001). Patients diagnosed after 2002 had a significantly better median OS (7.3 years) as compared to patients diagnosed previously (6.1 years) (p=0.002). Hispanics had the worst median OS (5 years) and Whites had the best median OS (6.8 years) across various ethnicities. In a multivariate model using gender, age, marital status, year of diagnosis and race, a significant interaction was noted between race, age and survival, with Hispanics having a significantly worse OS than Whites (HR 1.86; 95% CI 1.269, 2.726; p=0.003) (Figure 2). Conclusions: Studies of outcome disparities are important for evaluating disease characteristics and management needs of specific patient populations as well as optimal triaging of healthcare resources. We have performed the largest population-based analysis for WM including various ethnicities in the novel therapeutic agent era. We observed that AA patients had a significantly younger age at WM diagnosis. Older patients had worse OS across all ethnic subgroups and patients diagnosed after 2002 had a better OS suggesting an impact of novel therapeutic agents (e.g., proteasome inhibitors, IMiDs). Hispanic WM patients had the worst OS among all ethnicities. This survival difference was more significant and pronounced in patients 〉 75 years. This suggests that the impact of race on survival is influenced by patient's age. These results will help in better understanding of various influences on disease biology and clinical behavior. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 7
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 22-23
    Abstract: Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative therapy for patients with high-risk and refractory acute myeloid leukemia (AML). Unfortunately, up to 50 percent of patients relapse after allo-HCT.Recent research has shown that 30-50 percent of AML samples from patients relapsing after allo-HCT have downregulation of MHC class II (MHC-II) expression, which may promote immune effector evasion and disease relapse. These studies also report that interferon gamma (IFNγ) can restore MHC-II expression. IFNγ has never been systemically administered after allo-HCT and would likely cause significant and potentially life-threatening toxicities. Reinduction of MHC-II expression may lead to re-engagement of immune effectors, restoration of the graft-versus-malignancy effect, and disease control. We hypothesized that T cell immunotherapies targeting AML cells will lead to T cell activation, localized IFNγ release, and upregulation of MHC-II on AML cells. Methods: For in vitro experiments, THP1 cells (THP1s), which have intermediate MHC-II expression, or primary human AML samples with low MHC-II expression from a patient relapsing after allo-HCT (AML-low cells) were co-cultured with or without T-cell immunotherapy and with or without human MHC-mismatched CD3+ T cells. The following T-cell immunotherapies were tested: flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule; a CD33 x CD3 bispecific molecule (Creative Biolabs, Shirley, NY); and CD123-directed chimeric antigen receptor (CAR) T cells. THP1 IFNγ receptor-1 (IFNγR1) knockout cell lines were generated using CRISPR-Cas9. MHC-II expression was measured by flow cytometry and IFNγ concentrations via Luminex immunoflourescence assay. In order to rescue THP1s from FLZ-induced death and allow for longitudinal evaluation, a transwell plate system was used, placing THP1s, human CD3+ T cells, and FLZ in the top well and THP1s in the bottom well. This allowed for diffusion of IFNγ but not human T cells to the bottom wells, permitting MHC-II upregulation while limiting death. The upper and lower wells were coincubated together for 24 hours prior to harvesting of the THP1s in the lower well for longitudinal studies and mixed-lymphocyte reactions. For in vivo experiments, NOD-scid IL2Rgammanull mice expressing human IL-3, GM-CSF, and SCF (NSG-S) were irradiated with 250 rads and injected with 10e6 primary AML-low cells per mouse. After 5.5 weeks, mice were divided into the following groups: 1) untreated control; 2) FLZ only (2mg/kg); 3) human mismatched T cells only (10e7 T cells per mouse); 4) FLZ and T cells. Results: In vitro co-culture of THP1 or AML-low cells with FLZ and T cells led to significantly increased MHC-II expression at 48 hours when compared with the control, FLZ only, and T cell only groups (Figure 1A-B). Co-culture of THP1s with the CD123 CAR-T cells led to similar results. Although co-incubation with a CD33 x CD3 bispecific led to a similar result, the MHC-II upregulation was not nearly as dramatic as that seen with CD123 targeting agents. Using a transwell system to rescue THP1s from FLZ-mediated toxicity, FLZ-induced MHC-II upregulation on THP1s peaked at 48-72 hours (similar kinetics to what is seen with IFNγ alone). These THP1s with upregulated MHC-II activated third-party donor mismatched human CD4+ T cells to a greater extent than untreated THP1s controls. Co-cultures of THP1s with CD4+ T cells and FLZ induced the secretion of very high concentrations of IFNγ, and blockade of IFNγ signaling through knockout of IFNγR1 led to abrogation of the effect (Figure 1C-D). Finally, in an in vivo model, NSG-S mice injected with AML-low samples and treated with FLZ and T cells showed significant upregulation of MHC-II expression on the AML cells. Single cell RNA-sequencing of AML cells purified from these mice is ongoing. Conclusions: Use of FLZ and other T-cell immunotherapies targeting AML antigens led to both direct AML killing as well as significant upregulation of MHC-II expression on AML cells both in vitro and in vivo. The effect appears to be mediated primarily by IFNγ. T-cell immunotherapies represent a promising treatment approach for AML patients relapsing after allo-HCT and may lead to enhanced immune recognition in the 30-50% of patients who relapse after allo-HCT. Based on these results, a clinical trial treating patients relapsing after allo-HCT with FLZ is planned. Disclosures Christopher: Boulder Bioscience: Patents & Royalties: IP around the use of interferon gamma to treat stem cell transplant. Kim:Tmunity: Patents & Royalties: methods for gene editing in hematopoietic stem cells to enhance the therapeutic efficacy of antigen-specific immunotherapy (Licensed by University of Pennsylvania); Neoimmune Tech: Patents & Royalties: use of long-acting IL-7 analogs to enhance CAR T cells (licensed by Washington University). Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson:MacroGenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 8
    In: Nature Biotechnology, Springer Science and Business Media LLC, Vol. 38, No. 8 ( 2020-08), p. 947-953
    Type of Medium: Online Resource
    ISSN: 1087-0156 , 1546-1696
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 9
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1758-1758
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1758-1758
    Abstract: Introduction: EphB4, a receptor tyrosine kinase, binds to ephrinB2, a cell surface ligand, resulting in bidirectional signaling through both receptor and ligand. EphB4 stimulates cell proliferation and migration through the phosphatidylinositol 3-kinase (PI3K) and Akt signaling pathway. MAb131 is a novel anti-EphB4 monoclonal antibody that induces degradation of EphB4 through receptor endocytosis. We investigated the use of MAb131 as a therapeutic agent for acute leukemia. Methods: Peripheral blood or bone marrow specimens from patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) were obtained after informed consent. EphB4 and ephrinB2 expression in cells were profiled using flow cytometry. Cell lines and patient samples were treated with MAb131 at 0, 10 and 100ug/ml concentrations. Blocking experiment was performed with 200ug/ml sEphB4-HSA in combination with 10ug/ml MAb131. Downregulation of EphB4 was evaluated by flow cytometry. Phosphorylated AKT (pAKT) levels were measured by Western blot. Cell viability was measured by trypan blue exclusion. Results: EphB4 was highly expressed on the cell surface in the majority of leukemia cell lines of both myeloid (K562, Molm14, U937) and lymphoid (REH, RS4;11, Jurkat) origin; only one leukemia cell line evaluated, KG-1, did not express EphB4. In contrast, none of the lymphoma cell lines (BJAB, Ramos, Namwala) expressed EphB4. Of 9 AML patient samples evaluated, 4 expressed high levels of EphB4, and 5 expressed low levels of EphB4. Of 7 ALL patient samples evaluated, 2 expressed high levels of EphB4, 3 had low expression and 2 did not express EphB4. None of the cells showed robust expression of ephrinB2. Treatment of ALL and AML cell lines with MAb131 induced downregulation of EphB4, decreased levels of pAKT, and & gt;90% cell death after 72h. Primary AML and ALL samples also showed downregulation of surface EphB4 and increased cell death with MAb131 treatment. A decoy receptor comprised of the soluble extracellular domain of EphB4 fused to albumin (sEphB4-HSA) was used to block MAb131 binding to EphB4 and confirm specificity of MAb131 activity. Conclusion: We present the first report that EphB4 signaling is active in acute leukemia and can be targeted therapeutically. MAb131, a novel anti-EphB4 antibody, has potent anti-leukemic activity as a single agent in vitro and is likely to sensitize leukemia to cytotoxic chemotherapy through downregulation of AKT signaling. Based on these results, clinical studies exploring the efficacy of EphB4/ephrinB2 antagonists in patients with acute leukemia should be pursued. Citation Format: Miriam Y. Kim, Aparna Jorapur, Amy R. McManus, Ren Liu, Valery Krasnoperov, Kranthi Naga, Parkash S. Gill, Akil Merchant. Targeting EphB4 with a novel antibody in acute leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1758. doi:10.1158/1538-7445.AM2014-1758
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 10
    In: Molecular Therapy, Elsevier BV, Vol. 30, No. 1 ( 2022-01), p. 209-222
    Type of Medium: Online Resource
    ISSN: 1525-0016
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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