22 results on '"Leonid Dubrovsky"'
Search Results
2. Supplementary Figure 1 from Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein
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David A. Scheinberg, Cheng Liu, Richard J. O'Reilly, Michael G. Kharas, Michael Curcio, Emily Casey, Victoria Zakhaleva, Tatyana Korontsvit, Sun-Mi Park, Joseph A. Whitten, Leonid Dubrovsky, Dmitry Pankov, Jingyi Xiang, Hong Liu, Tao Dao, and Nicholas Veomett
- Abstract
PDF file - 78KB, ESKM has a modified Fc glycosylation pattern, altering binding to FcgammaRs but not to the RMF/A2 target. Where applicable, data points are averages of each group, and error bars represent SEM. (A) Comparison of the oligosaccharide profile of ESK1 and ESKM. Peak assignment is based on the retention time and the monosaccharide composition analysis. G# indicates the number of terminal galactoses, F indicates presence of core fucose, Hex5GlcNAc2 denotes (GlcNAc)2 core with terminal Hexose 5 glycan structure (terminating in mannose and/or glucose). (B-C) Representative binding curves of ESK1 and ESKM against human FcgammaRI, FcgammaRIIa, FcgammaRIIb, FcgammaRIIIa - 158V, FcgammaRIIIa -158F, and FcRn (B), and mouse FcgammaRIIb and FcgammaRIV (C). (D) 125 I-labeled ESK1 and ESKM mAbs were titrated against JMN cells. All curves were fit with a non-linear single-site total binding saturation curve, and Kd was calculated using Prism software.
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- 2023
3. Supplementary Figure 4 from Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein
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David A. Scheinberg, Cheng Liu, Richard J. O'Reilly, Michael G. Kharas, Michael Curcio, Emily Casey, Victoria Zakhaleva, Tatyana Korontsvit, Sun-Mi Park, Joseph A. Whitten, Leonid Dubrovsky, Dmitry Pankov, Jingyi Xiang, Hong Liu, Tao Dao, and Nicholas Veomett
- Abstract
PDF file - 145KB, All human antibodies tested accumulated more in spleens of HLA-A2+ transgenic mice, but ESK1 did not bind specifically to isolated HLA-A2+ spleen, bone marrow or thymus cells. (A) Accumulation of 125 I-labeled antibodies in spleens of C57BL6/J or HLA-A2+ transgenic mice relative to antibody level in the blood. Mice were injected retroorbitally with 2microg indicated antibody, then sacrificed after 24 hours for blood and spleen collection. (B) Specific binding of 125I-labeled ESK1 to bone marrow, spleen, or thymus cells isolated from C57BL6/J or HLA-A2+ transgenic mice. Tissues were collected from 2 (C57) or 3 (HLA-A2+ transgenic) mice, then bound by 1microg/mL 125 I-labeled ESK1 either alone or after blocking with 50-fold excess unlabeled ESK1. Specific binding was determined, and #ESK1 bound per cell was calculated.
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- 2023
4. Supplementary Table 1 from Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein
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David A. Scheinberg, Cheng Liu, Richard J. O'Reilly, Michael G. Kharas, Michael Curcio, Emily Casey, Victoria Zakhaleva, Tatyana Korontsvit, Sun-Mi Park, Joseph A. Whitten, Leonid Dubrovsky, Dmitry Pankov, Jingyi Xiang, Hong Liu, Tao Dao, and Nicholas Veomett
- Abstract
PDF file - 38KB, Histopathologic report from ESKM- or isotype control human IgG1-treated HLA-A*02:01+ transgenic mice.
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- 2023
5. Data from Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein
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David A. Scheinberg, Cheng Liu, Richard J. O'Reilly, Michael G. Kharas, Michael Curcio, Emily Casey, Victoria Zakhaleva, Tatyana Korontsvit, Sun-Mi Park, Joseph A. Whitten, Leonid Dubrovsky, Dmitry Pankov, Jingyi Xiang, Hong Liu, Tao Dao, and Nicholas Veomett
- Abstract
Purpose: RMFPNAPYL (RMF), a Wilms' tumor gene 1 (WT1)–derived CD8 T-cell epitope presented by HLA-A*02:01, is a validated target for T-cell–based immunotherapy. We previously reported ESK1, a high avidity (Kd < 0.2 nmol/L), fully-human monoclonal antibody (mAb) specific for the WT1 RMF peptide/HLA-A*02:01 complex, which selectively bound and killed WT1+ and HLA-A*02:01+ leukemia and solid tumor cell lines.Experimental Design: We engineered a second-generation mAb, ESKM, to have enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. ESKM was compared with native ESK1 in binding assays, in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. ESKM toxicity was assessed in HLA-A*02:01+ transgenic mice.Results: ESK antibodies mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1 μg/mL, but ESKM was about 5- to 10-fold more potent in vitro against multiple cancer cell lines. ESKM was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9 days vs. 6.5 days), but an identical biodistribution pattern in C57BL/6J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A*02:01+ transgenic mice compared with the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage.Conclusions: The data provide proof of concept that an Fc-enhanced mAb can improve efficacy against a low-density, tumor-specific, peptide/MHC target, and support further development of this mAb against an important intracellular oncogenic protein. Clin Cancer Res; 20(15); 4036–46. ©2014 AACR.
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- 2023
6. Supplementary Figure 3 from Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein
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David A. Scheinberg, Cheng Liu, Richard J. O'Reilly, Michael G. Kharas, Michael Curcio, Emily Casey, Victoria Zakhaleva, Tatyana Korontsvit, Sun-Mi Park, Joseph A. Whitten, Leonid Dubrovsky, Dmitry Pankov, Jingyi Xiang, Hong Liu, Tao Dao, and Nicholas Veomett
- Abstract
PDF file - 183KB, (A) ESKM reduced individual tumor burden during the treatment course in 3 of 5 mice. Alternate representation of data in Figure 2A, where signal for each mouse is normalized to starting luminescence. (B) ESKM had no effect against JMN in a NOG mouse model. (C) Comparison of BV173 (Ph+ ALL) and SET2 (AML) cell lines in NSG mice.
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- 2023
7. Supplementary Figure 2 from Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein
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David A. Scheinberg, Cheng Liu, Richard J. O'Reilly, Michael G. Kharas, Michael Curcio, Emily Casey, Victoria Zakhaleva, Tatyana Korontsvit, Sun-Mi Park, Joseph A. Whitten, Leonid Dubrovsky, Dmitry Pankov, Jingyi Xiang, Hong Liu, Tao Dao, and Nicholas Veomett
- Abstract
PDF file - 142KB, Human PBMCs were separated into effector cell populations and tested for in vitro ADCC activity against BV173 cells, mediated by ESKM or isotype control mAb. Only fractionated NK cells showed activity relative to isotype control antibody. % Lysis is calculated based on spontaneous release (target cells, no effectors or mAb) as 0% and maximal release (target cells + SDS) as 100%.
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- 2023
8. Randomized Phase 3 LEAP-012 Study: Transarterial Chemoembolization With or Without Lenvatinib Plus Pembrolizumab for Intermediate-Stage Hepatocellular Carcinoma Not Amenable to Curative Treatment
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Josep M. Llovet, Arndt Vogel, David C. Madoff, Richard S. Finn, Sadahisa Ogasawara, Zhenggang Ren, Kalgi Mody, Jerry J. Li, Abby B. Siegel, Leonid Dubrovsky, and Masatoshi Kudo
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Adult ,Carcinoma, Hepatocellular ,Treatment Outcome ,Phenylurea Compounds ,Liver Neoplasms ,Quinolines ,Humans ,Radiology, Nuclear Medicine and imaging ,Prospective Studies ,Chemoembolization, Therapeutic ,Antibodies, Monoclonal, Humanized ,Cardiology and Cardiovascular Medicine - Abstract
Purpose Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC). Lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, have shown efficacy and tolerability in patients with HCC, and adding this combination to TACE may enhance clinical benefit. Protocol LEAP-012 is a prospective, double-blind randomized phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥ 1 measurable tumor per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), Eastern Cooperative Oncology Group performance status 0 or 1, Child–Pugh class A and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to lenvatinib once daily plus pembrolizumab every 6 weeks plus TACE or placebos plus TACE. Dual primary endpoints are overall survival and progression-free survival per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints are progression-free survival, objective response rate, disease control rate, duration of response and time to progression per modified RECIST by BICR; objective response rate, disease control rate, duration of response and time to progression per RECIST 1.1 by BICR; and safety. Statistics The planned sample size, 950 patients, was calculated to permit accumulation of sufficient overall survival events in 5 years to achieve 90% power for the overall survival primary endpoint. Discussion LEAP-012 will evaluate the clinical benefit of adding lenvatinib plus pembrolizumab to TACE in patients with intermediate-stage HCC not amenable to curative treatment. ClinicalTrials.gov NCT04246177.
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- 2022
9. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma
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Josep M. Llovet, Kenichi Saito, Ari David Baron, Abby B. Siegel, Andrew X. Zhu, Corina E. Dutcus, Leonid Dubrovsky, Hiromitsu Kumada, Masatoshi Kudo, Marc Pracht, Masafumi Ikeda, Tim Meyer, Kalgi Mody, Richard S. Finn, Tomoki Kubota, Shuichi Kaneko, Konstantin Mamontov, Takuji Okusaka, Max W. Sung, and Masahiro Kobayashi
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0301 basic medicine ,Male ,Cancer Research ,Carcinoma, Hepatocellular ,Time Factors ,Immunoglobulins ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,RAPID COMMUNICATIONS ,Gastrointestinal Cancer ,Carcinoma ,medicine ,Humans ,In patient ,Progression-free survival ,Aged ,Neoplasm Staging ,Tumors ,Aged, 80 and over ,Tumor microenvironment ,business.industry ,Phenylurea Compounds ,Liver Neoplasms ,Drugs ,Middle Aged ,medicine.disease ,Progression-Free Survival ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Monoclonal ,Cancer research ,Disease Progression ,Quinolines ,Female ,business ,Lenvatinib ,Immunoglobulines ,Medicaments - Abstract
PURPOSE The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti–PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.
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- 2020
10. Abstract No. 37 LEAP-012 trial in progress: pembrolizumab, lenvatinib, and transarterial chemoembolization combination therapy for intermediate-stage hepatocellular carcinoma not amenable to curative treatment
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Richard S. Finn, Kalgi Mody, D. Madoff, Anthony B. El-Khoueiry, Arndt Vogel, S. Ogasawara, Leonid Dubrovsky, Josep M. Llovet, J.J. Li, Masatoshi Kudo, Abby B. Siegel, and Zhenggang Ren
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Oncology ,medicine.medical_specialty ,Combination therapy ,business.industry ,Pembrolizumab ,medicine.disease ,Intermediate stage ,chemistry.chemical_compound ,chemistry ,Curative treatment ,Hepatocellular carcinoma ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Cardiology and Cardiovascular Medicine ,business ,Lenvatinib - Published
- 2021
11. 1016TiP LEAP-012 trial in progress: Pembrolizumab plus lenvatinib and transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC) not amenable to curative treatment
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D. Madoff, Sadahisa Ogasawara, Leonid Dubrovsky, Zhenggang Ren, Masatoshi Kudo, Richard S. Finn, Kalgi Mody, J.J. Li, Abby B. Siegel, Arndt Vogel, Anthony B. El-Khoueiry, and Josep M. Llovet
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Oncology ,medicine.medical_specialty ,business.industry ,Hematology ,Pembrolizumab ,medicine.disease ,Intermediate stage ,chemistry.chemical_compound ,chemistry ,Curative treatment ,Internal medicine ,Hepatocellular carcinoma ,medicine ,In patient ,Lenvatinib ,business - Published
- 2020
12. P-107 LEAP-012: A randomized, double-blind, phase 3 study of pembrolizumab plus lenvatinib in combination with transarterial chemoembolization (TACE) in patients with intermediate-stage hepatocellular carcinoma not amenable to curative treatment
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Leonid Dubrovsky, Josep M. Llovet, Zhenggang Ren, Abby B. Siegel, Richard S. Finn, J.J. Li, Anthony B. El-Khoueiry, K. Modi, D. Madoff, Sadahisa Ogasawara, Masatoshi Kudo, and Arndt Vogel
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Oncology ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Hematology ,Pembrolizumab ,medicine.disease ,Intermediate stage ,Double blind ,chemistry.chemical_compound ,chemistry ,Curative treatment ,Internal medicine ,Hepatocellular carcinoma ,medicine ,In patient ,Lenvatinib ,business - Published
- 2020
13. A phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results
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Hiromitsu Kumada, Tim Meyer, K.V. Shepard, Max W. Sung, Ari David Baron, Josep M. Llovet, Leonid Dubrovsky, M. Kobayashi, Kenichi Saito, Masatoshi Kudo, Tomoki Kubota, Kalgi Mody, Konstantin Mamontov, Abby B. Siegel, Richard S. Finn, Andrew X. Zhu, Marc Pracht, Masafumi Ikeda, Takuji Okusaka, and Shuichi Kaneko
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0301 basic medicine ,Antitumor activity ,business.industry ,Best Overall Response ,Hematology ,Management ,Multikinase inhibitor ,03 medical and health sciences ,Safety profile ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Partial response ,Release date ,Medicine ,Lenvatinib ,business ,Objective response - Abstract
Background LEN is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT. PEMBRO is an anti-PD-1 monoclonal antibody. LEN monotherapy is approved for first-line treatment of uHCC. PEMBRO monotherapy has shown significant efficacy in the second-line treatment of HCC. We report updated results from a phase 1b trial of LEN + PEMBRO in uHCC. Methods In this open-label, phase 1b study of LEN + PEMBRO in uHCC, 104 patients (pts) with BCLC stage B (not amenable for transarterial chemoembolization) or C, Child-Pugh class A, and ECOG PS≤1 received LEN (body wt≥60kg: 12mg/day; Results Pts received LEN + PEMBRO (DLT-evaluation part, n=6; expansion part, n=61). At data cutoff (June 30, 2019), 34 (50.7%) pts remained on study treatment; median duration of follow-up was 11.7 months (95% CI, 7.8-17.6). Serious adverse events occurred in 42 (62.7%) pts; no new safety signals emerged. Updated safety data will be provided. ORR (including unconfirmed responses) was 44.8% (Table) and compared favorably with LEN arm of REFLECT trial (24.1%; Kudo M. Lancet. 2018). Median DOR was 18.7 months (95% CI, 6.9-NE). Conclusions LEN + PEMBRO showed promising antitumor activity and an acceptable safety profile in pts with uHCC. Blinded independent central review is in progress. A phase 3 trial (LEAP-002; NCT03713593) is ongoing to assess LEN + PEMBRO vs LEN alone as first-line therapy for pts with uHCC.Table747PTableResponse Parameter, n (%)LEN + PEMBRO (n=67)mRECIST Per Investigator ORR (CR + PR + unconfirmed PR or CR)a Best Overall Response CR. PRa Stable disease Progressive disease Unknown/not evaluable 30 (44.8) 4 (6.0) 26 (38.8) 25 (37.3) 6 (9.0) 6 (9.0) aIncludes unconfirmed partial responses (2 patients). CR, complete response; (m)RECIST, (modified) Response Evaluation Criteria In Solid Tumors [Lencioni et al. Semin Liver Dis. 2010;30:52-60]; ORR, objective response rate; PR, partial response. Clinical trial identification NCT03006926; Release date: December 30, 2016. Editorial acknowledgement Medical writing support was provided by April Suriano, PhD, of Oxford PharmaGenesis, Newtown, PA, USA and was funded by Eisai Inc. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure J. Llovet: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Ipsen; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Celsion Corporation; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Merck; Advisory / Consultancy: Glycotest; Advisory / Consultancy: Navigant; Advisory / Consultancy: Leerink Swann LLC; Advisory / Consultancy: Midatech Ltd; Advisory / Consultancy: Fortess Biotech; Advisory / Consultancy: Sprink Pharmaceuticals; Advisory / Consultancy: Nucleix; Advisory / Consultancy: Can-Fite Biopharma. K.V. Shepard: Full / Part-time employment: Eisai Inc. R.S. Finn: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer. M. Ikeda: Honoraria (self): Abbott, Bayer, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eisai, Lilly, Nobelpharma, Novartis, Otsuka, Taiho Pharmaceutical, Teijin Pharma, Yakult Honsha; Advisory / Consultancy: Bayer, Daiichi Sankyo, Eisai, Kyowa Hakko Kirin, MSD, NanoCarrier, Novartis, Shire, Teijin Pharma, Lilly; Research grant / Funding (self): ASLAN Pharmaceuticals, AstraZeneca, Baxalta/Shire, Bayer, Bristol-Myers Squibb, Chugai Pharma, Eisai, Kowa, Kyowa Hakko Kirin, Lilly, Merck Serono, MSD, NanoCarrier, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takara Bio, Yakult Honsha. M. Sung: Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis. A.D. Baron: Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Genentech/Roche; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Merck. M. Kudo: Honoraria (self), Research grant / Funding (self): AbbVie; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self): EA Pharma; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self): Gilead Sciences; Honoraria (self): Merck Serono; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Chugai Pharma; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Otsuka. T. Okusaka: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Fujifilm, Lilly Japan, Nippon Chemiphar, Nobelpharma, Novartis, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon, Taiho Pharmaceutical, Teijin Pharma, Yakult; Advisory / Consultancy: Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Zeria Pharmaceutical; research funding from AstraZeneca, Baxter, Bayer, Chugai Pharma, Dainippon Sumitomo Pharma, Eisai, Kowa, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, NanoCarrier, Nippon Boeh. M. Kobayashi: Speaker Bureau / Expert testimony: Eisai Inc. H. Kumada: Honoraria (self): AbbVie; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Gilead Sciences; Honoraria (self): MSD; Honoraria (self): Sumitomo; Honoraria (self): Dainippon. S. Kaneko: Honoraria (self): EA Pharma, MSD, Aska Pharma, Astellas Pharma, AbbVie, Eisai, Eidia, Otsuka, Gilead Sciences, Sysmex Corporation, Daiichi Sankyo, Taisho Toyama, Sumitomo Dainippon, Taiho, Takeda, Chugai, Bayer, Bristol-Myers, Mylan EPD, Miyarisan, Mochida, Kowa, Mitsubis; Research grant / Funding (self): Gilead Sciences, AbbVie, Daiichi Sankyo, Astellas Pharma, Takeda, Nippon Boehringer Ingelheim, MSD, Ono Pharma, Pfizer, Shionogi, Teijin Pharma, Mitsubishi Tanabe, Zeria, Abbott Vascular Japan, Taisho Toyama, Novartis, Terumo Corporation, Taiho, Novo Nord. K. Mamontov: Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Medtronic; Honoraria (self): Roche. T. Meyer: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: BTG; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Tarveda; Advisory / Consultancy: MSD. K. Mody: Full / Part-time employment: Eisai Inc. T. Kubota: Full / Part-time employment: Eisai Co., Ltd. K. Saito: Full / Part-time employment: Eisai Inc. A.B. Siegel: Full / Part-time employment: Merck. L. Dubrovsky: Full / Part-time employment: Merck. A.X. Zhu: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Sanofi. All other authors have declared no conflicts of interest.
- Published
- 2019
14. A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias
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Elliott J. Brea, Leonid Dubrovsky, Richard J. O’Reilly, Andrew Scott, Dmitry Pankov, Su Yan, Cheng Liu, David A. Scheinberg, and Tao Dao
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Male ,medicine.drug_class ,Immunology ,Dasatinib ,Mice, SCID ,Biology ,Biochemistry ,Tyrosine-kinase inhibitor ,Cell Line ,Mice ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,HLA-A2 Antigen ,medicine ,Animals ,Humans ,WT1 Proteins ,Protein Kinase Inhibitors ,Acute leukemia ,Lymphoid Neoplasia ,fungi ,T-cell receptor ,Antibodies, Monoclonal ,Imatinib ,Cell Biology ,Hematology ,medicine.disease ,Thiazoles ,Leukemia ,Pyrimidines ,Drug Resistance, Neoplasm ,Cancer research ,Stem cell ,Tyrosine kinase ,medicine.drug - Abstract
Acute and chronic leukemias, including CD34(+) CML cells, demonstrate increased expression of the Wilms tumor gene 1 product (WT1), making WT1 an attractive therapeutic target. However, WT1 is a currently undruggable, intracellular protein. ESKM is a human IgG1 T-cell receptor mimic monoclonal antibody directed to a 9-amino acid sequence of WT1 in the context of cell surface HLA-A*02. ESKM was therapeutically effective, alone and in combination with tyrosine kinase inhibitors (TKIs), against Philadelphia chromosome-positive acute leukemia in murine models, including a leukemia with the most common, pan-TKI, gatekeeper resistance mutation, T315I. ESKM was superior to the first-generation TKI, imatinib. Combination therapy with ESKM and TKIs was superior to either drug alone, capable of curing mice. ESKM showed no toxicity to human HLA-A*02:01(+) stem cells under the conditions of this murine model. These features of ESKM make it a promising nontoxic therapeutic agent for sensitive and resistant Ph(+) leukemias.
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- 2014
15. Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1
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Leonid Dubrovsky, Richard J. O'Reilly, Yiyang Xu, Michael Curcio, Cheng Liu, Nicholas Veomett, Jingyi Xiang, Manuel Guerreiro, Ekaterina Doubrovina, Andrew Scott, Victoriya Zakhaleva, Dmitry Pankov, Su Yan, David A. Scheinberg, Tatyana Korontsvit, Vladimir Ponomarev, and Tao Dao
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medicine.drug_class ,T cell ,T-Lymphocytes ,Biomedical Engineering ,Bioengineering ,Biology ,Monoclonal antibody ,Applied Microbiology and Biotechnology ,Cancer Vaccines ,Epitope ,Article ,Mice ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Molecular Targeted Therapy ,WT1 Proteins ,Oncogene Proteins ,T-cell receptor ,Antibodies, Monoclonal ,Neoplasms, Experimental ,Molecular biology ,Repressor Proteins ,medicine.anatomical_structure ,Treatment Outcome ,Cancer research ,Molecular Medicine ,CD8 ,Intracellular ,Biotechnology - Abstract
Intracellular tumor antigens presented on the cell surface in the context of human leukocyte antigen (HLA) molecules have been targeted by T cell-based therapies, but there has been little progress in developing small-molecule drugs or antibodies directed to these antigens. Here we describe a bispecific T-cell engager (BiTE) antibody derived from a T-cell receptor (TCR)-mimic monoclonal antibody (mAb) ESK1, which binds a peptide derived from the intracellular oncoprotein WT1 presented on HLA-A*02:01. Despite the very low density of the complexes at the cell surface, ESK1-BiTE selectively activated and induced proliferation of cytolytic human T cells that killed cells from multiple leukemias and solid tumors in vitro and in mice. We also discovered that in an autologous in vitro setting, ESK1-BiTE induced a robust secondary CD8 T-cell response specific for tumor-associated antigens other than WT1. Our study provides an approach that targets tumor-specific intracellular antigens without using cell therapy and suggests that epitope spreading could contribute to the therapeutic efficacy of this BiTE.
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- 2015
16. A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens
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Tatyana Korontsvit, David A. Scheinberg, Ronald C. Hendrickson, Aaron Y. Chang, Andrew Scott, Cheng Liu, Michael Curcio, Tao Dao, Victoriya Zakhaleva, Casey A. Jarvis, Leonid Dubrovsky, Melissa Mathias, and Ron S. Gejman
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0301 basic medicine ,Male ,Receptors, Antigen, T-Cell ,Human leukocyte antigen ,Epitope ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,Cytotoxic T cell ,Animals ,Humans ,Receptor ,HLA-A1 Antigen ,030304 developmental biology ,PRAME ,0303 health sciences ,biology ,Chemistry ,T-cell receptor ,Neoplasms, Experimental ,General Medicine ,Xenograft Model Antitumor Assays ,3. Good health ,030104 developmental biology ,Immunoglobulin G ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,Antibody ,Corrigendum ,Research Article - Abstract
Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen that is expressed in many cancers and leukemias. In healthy tissue, PRAME expression is limited to the testes and ovaries, making it a highly attractive cancer target. PRAME is an intracellular protein that cannot currently be drugged. After proteasomal processing, the PRAME300-309 peptide ALYVDSLFFL (ALY) is presented in the context of human leukocyte antigen HLA-A*02:01 molecules for recognition by the T cell receptor (TCR) of cytotoxic T cells. Here, we have described Pr20, a TCR mimic (TCRm) human IgG1 antibody that recognizes the cell-surface ALY peptide/HLA-A2 complex. Pr20 is an immunological tool and potential therapeutic agent. Pr20 bound to PRAME+HLA-A2+ cancers. An afucosylated Fc form (Pr20M) directed antibody-dependent cellular cytotoxicity against PRAME+HLA-A2+ leukemia cells and was therapeutically effective against mouse xenograft models of human leukemia. In some tumors, Pr20 binding markedly increased upon IFN-γ treatment, mediated by induction of the immunoproteasome catalytic subunit β5i. The immunoproteasome reduced internal destructive cleavages within the ALY epitope compared with the constitutive proteasome. The data provide rationale for developing TCRm antibodies as therapeutic agents for cancer, offer mechanistic insight on proteasomal regulation of tumor-associated peptide/HLA antigen complexes, and yield possible therapeutic solutions to target antigens with ultra-low surface presentation.
- Published
- 2017
17. Therapeutic efficacy of an Fc-enhanced TCR-like antibody to the intracellular WT1 oncoprotein
- Author
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Emily Casey, Leonid Dubrovsky, Cheng Liu, Tatyana Korontsvit, Tao Dao, Joseph A. Whitten, Victoria Zakhaleva, Jingyi Xiang, David A. Scheinberg, Michael G. Kharas, Richard J. O’Reilly, Michael Curcio, Dmitry Pankov, Hong Liu, Nicholas Veomett, and Sun-Mi Park
- Subjects
Male ,Mesothelioma ,Cancer Research ,Biodistribution ,medicine.drug_class ,Receptors, Antigen, T-Cell ,Epitopes, T-Lymphocyte ,Mice, Transgenic ,Mice, SCID ,Biology ,CD8-Positive T-Lymphocytes ,Monoclonal antibody ,Epitope ,Article ,Mice ,Antigen ,In vivo ,Mice, Inbred NOD ,HLA-A2 Antigen ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,WT1 Proteins ,Antibody-dependent cell-mediated cytotoxicity ,Leukemia, Experimental ,Antibody-Dependent Cell Cytotoxicity ,Antibodies, Monoclonal ,Flow Cytometry ,Molecular biology ,Immunoglobulin Fc Fragments ,Mice, Inbred C57BL ,Oncology ,biology.protein ,Immunotherapy ,Antibody ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
Purpose: RMFPNAPYL (RMF), a Wilms' tumor gene 1 (WT1)–derived CD8 T-cell epitope presented by HLA-A*02:01, is a validated target for T-cell–based immunotherapy. We previously reported ESK1, a high avidity (Kd < 0.2 nmol/L), fully-human monoclonal antibody (mAb) specific for the WT1 RMF peptide/HLA-A*02:01 complex, which selectively bound and killed WT1+ and HLA-A*02:01+ leukemia and solid tumor cell lines. Experimental Design: We engineered a second-generation mAb, ESKM, to have enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. ESKM was compared with native ESK1 in binding assays, in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. ESKM toxicity was assessed in HLA-A*02:01+ transgenic mice. Results: ESK antibodies mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1 μg/mL, but ESKM was about 5- to 10-fold more potent in vitro against multiple cancer cell lines. ESKM was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9 days vs. 6.5 days), but an identical biodistribution pattern in C57BL/6J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A*02:01+ transgenic mice compared with the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage. Conclusions: The data provide proof of concept that an Fc-enhanced mAb can improve efficacy against a low-density, tumor-specific, peptide/MHC target, and support further development of this mAb against an important intracellular oncogenic protein. Clin Cancer Res; 20(15); 4036–46. ©2014 AACR.
- Published
- 2014
18. Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity
- Author
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Leonid Dubrovsky, Dmitry Pankov, Elliott J. Brea, Tao Dao, Emily Casey, Cheng Liu, and David A. Scheinberg
- Subjects
0301 basic medicine ,Antibody-dependent cell-mediated cytotoxicity ,Acute leukemia ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,Immunotherapy ,Biology ,medicine.disease ,Monoclonal antibody ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,Cell killing ,Oncology ,Downregulation and upregulation ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Immunology and Allergy ,Antibody ,Original Research - Abstract
Specific immunotherapy for acute leukemia remains a great unmet need. Native unmodified monoclonal antibody therapies, while promising, are inadequately effective for these malignancies, and multiple mechanisms for failure have been described. Antibody-dependent cellular cytotoxicity or phagocytosis is the primary modality of mAb-mediated cell killing in vivo, but ultimately leads to relapse of the leukemias, in model systems and in humans. By use of a T-cell receptor mimic mAb ESKM, derived against a WT1 peptide expressed in complex with HLA-A*02:01, whose only mechanism of therapeutic action is ADCC, we evaluated the mechanisms of leukemic relapse from its potent therapeutic action in mouse xenograft models of human leukemia. Leukemia escape was not associated with loss of the antigenic target, downregulation of cell surface HLA, antibody pharmacokinetic or biodistribution issues, or development of leukemia cell-intrinsic resistance to ADCC. Interestingly, the rapidity of leukemic growth determined whether leukemia was able to evade cytotoxicity independent of the presence of sufficient effector cells. By engineering leukemia cells with upregulated p27Kip1 and slower cell cycling times, we show that relapse was inversely correlated with growth rates resulting in the eventual inadequacy of effector to target ratio. Moreover, lack of migration of effector cells into lymphomatous pockets of ALL also allowed local escape. Successful leukemia therapy with mAb might therefore be improved in similar situations by combination with measures to reduce burden and slow leukemia cell growth.
- Published
- 2016
19. A Therapeutic TCR Mimic Monoclonal Antibody for Intracellular PRAME Protein in Leukemias
- Author
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Leonid Dubrovsky, Cheng Liu, Aaron Chang, Tao Dao, David A. Scheinberg, and Andrew Scott
- Subjects
Antibody-dependent cell-mediated cytotoxicity ,PRAME ,Retinoic acid receptor binding ,medicine.drug_class ,Immunology ,T-cell receptor ,Cell Biology ,Hematology ,Human leukocyte antigen ,Biology ,Monoclonal antibody ,Biochemistry ,Molecular biology ,Epitope ,Antigen ,medicine - Abstract
Preferentially expressed antigen in melanoma (PRAME) is a well-validated target for T cell-based immunotherapy in leukemias and solid tumors. PRAME is a retinoic acid receptor binding protein that prevents retinoic acid-mediated differentiation, proliferation arrest, and apoptosis. As a cancer-testis antigen, PRAME has limited expression in healthy adult tissue that is restricted to the testes, ovaries, and endometrium. However, PRAME is over-expressed in multiple cancers including ALL, AML, melanomas, and breast cancers, making it a specific and highly attractive therapeutic target. PRAME is an intracellular protein making it impossible to target using traditional antibodies and it is not currently druggable. After proteasomal processing, the PRAME300-309 peptide is presented on the cell surface in the context of HLA*A02:01 molecules, for recognition by CD8 T cells. We therefore hypothesized that a TCR-mimic (TCRm) monoclonal antibody that recognizes surface PRAME300-309 presented by HLA*A02:01 could have therapeutic activity. Here, we describe Pr20, a therapeutic TCRm antibody, specific for the PRAME300-309 peptide in complex with HLA*A02:01, identified through a human scFv phage display library screen. Pr20 was engineered into full length human IgG1. Pr20 exhibited specific binding to PRAME300-309 -pulsed TAP-deficient T2 cells and bound PRAME+/ HLA*A02:01+ Ph+ ALL and AML, demonstrating that endogenously presented PRAME300-309 could be recognized by Pr20. Pr20 was determined to have 4 nM binding affinity by scatchard plot analysis. The specific epitope was mapped using alanine substitutions of non-anchor residues in the PRAME300-309 peptide and determined to primarily require the C-terminal residues. Pr20M, an afucosylated form of the antibody with enhanced Fc binding, mediated antibody-dependent cellular cytotoxicity (ADCC) in-vitro in a PRAME+/ HLA*A02:01+ restricted manner. Pharmacokinetic studies in C57BL/6 mice indicated that Pr20M was stable in-vivo and biodistribution studies in HLA*A02:01 transgenic mice suggested that there was no significant antibody sink. Pr20M was therapeutically active in established xenograft leukemia models in NSG mice (T, B, and NK-deficient). Interestingly, Pr20 binding to PRAME+/HLA*A02:01+ melanomas was minimally detectable, but was dramatically increased upon treatment with IFNγ, which also led to an increased sensitivity to ADCC. The data provide rationale for developing TCRm antibodies against intracellular oncoproteins as therapeutics. Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
20. T cell receptor mimic antibodies for cancer therapy
- Author
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Ron S. Gejman, Leonid Dubrovsky, Dmitry Pankov, Claire Y. Oh, David A. Scheinberg, Aaron Y. Chang, Tao Dao, Emily Casey, and Elliott J. Brea
- Subjects
0301 basic medicine ,medicine.drug_class ,medicine.medical_treatment ,Immunology ,Cell ,T-cell receptor ,Review ,Human leukocyte antigen ,Immunotherapy ,Biology ,Monoclonal antibody ,Molecular biology ,Epitope ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Cancer cell ,medicine ,biology.protein ,Cancer research ,Immunology and Allergy ,Antibody ,030215 immunology - Abstract
The major hurdle to the creation of cancer-specific monoclonal antibodies (mAb) exhibiting limited cross-reactivity with healthy human cells is the paucity of known tumor-specific or mutated protein epitopes expressed on the cancer cell surface. Mutated and overexpressed oncoproteins are typically cytoplasmic or nuclear. Cells can present peptides from these distinguishing proteins on their cell surface in the context of human leukocyte antigen (HLA). T cell receptor mimic (TCRm) mAb can be discovered that react specifically to these complexes, allowing for selective targeting of cancer cells. The state-of-the-art for TCRm and the challenges and opportunities are discussed. Several such TCRm are moving toward clinical trials now.
- Published
- 2015
21. Therapeutic Efficacy and Cure Of Sensitive and T315I Pan-Resistant Human Ph+ Leukemia In Mice Using a TCR-Like Antibody To WT1/HLA-A0201 Alone, Or In Combination With Tyrosine Kinase Inhibitors
- Author
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Leonid Dubrovsky, Elliott Brea, Dmitry Pankov, Nicholas Veomett, Tao Dao, Su Yan, Cheng Liu, and David A. Scheinberg
- Subjects
Combination therapy ,medicine.drug_class ,business.industry ,Immunology ,Ponatinib ,Imatinib ,Cell Biology ,Hematology ,Pharmacology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Tyrosine-kinase inhibitor ,Dasatinib ,Leukemia ,chemistry.chemical_compound ,chemistry ,hemic and lymphatic diseases ,medicine ,business ,Tyrosine kinase ,medicine.drug - Abstract
Acute and chronic leukemias, including CD34+ CML stem cells, overexpress the Wilms tumor gene 1 (WT1) protein, making WT1 an attractive therapeutic target. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201, allowing it to target an undruggable, widely expressed, intracellular oncogene product. BV173 is an HLA-A0201+, human Ph+ ALL cell line that expresses WT1, and tagged by our lab with luciferase. We engineered a tyrosine kinase inhibitor (TKI) resistant BV173-R cell line by transducing BV173 with the resistant T315I Bcr-Abl plasmid. Antibody-dependent cellular cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. Tumor growth in vivo was assessed in NOD/SCID gamma (NSG) mice with bioluminescence imaging (BLI). RT-PCR was used to evaluate minimal residual disease in mice with negative BLI signal at the end of therapy. Imatinib, dasatinib, and ponatinib were used at up to maximally tolerated doses, given IP once daily. ESKM was administered at 100 µg twice weekly IP. ESKM mediated ADCC against both BV173 and BV173-R cell lines in vitro. In a BV173 engrafted human leukemia xenograft model, ESKM was more potent than imatinib, with median tumor growth reduction of 78% vs 52%. Combination of imatinib and ESKM therapy resulted in a 94% reduction in leukemic growth. High dose dasatinib (40 mg/kg daily) was more potent than ESKM, but discontinuation of therapy due to dasatinib toxicity resulted in relapse. Combination with ESKM therapy with dasatinib resulted in cure in 75% of mice, confirmed by bone marrow RT-PCR three weeks after termination of therapy. For mice cytoreduced with dasatinib followed by consolidation therapy with ESKM, delayed relapse was observed, but no cures. ESKM was highly superior to imatinib and dasatinib against the T315I BV173-R leukemia in vivo. Cures were not achieved with combination therapy of ESKM and either first or second generation TKIs against resistant T315I leukemia. Ponatinib at 10 mg/kg had higher efficacy than ESKM alone against BV173-R, but mice treated with combination of ESKM and ponatinib had superior tumor reduction. CONCLUSION: ESKM is an effective therapeutic antibody for sensitive and T315I Ph+ ALL. Resistant T315I Ph+ leukemic growth is inhibited more effectively by ESKM therapy compared to imatinib and dasatinib, and combination therapy with ESKM is superior to ponatinib. Supported by the Leukemia and Lymphoma Society, NIH R01CA55349, P01 23766 and T32CA62948-18. Disclosures: Yan: Eureka Therapeutics: Employment. Liu:Eureka Therapeutics: Employment, Equity Ownership.
- Published
- 2013
22. Pediatric Autologous Peripheral Blood Stem Cell Harvest Factors Affecting Time To Engraftment And Transplant Toxicity
- Author
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Terry J. Fry, R.J. McCarter, Evelio Perez-Albuerne, Leonid Dubrovsky, Edward C.C. Wong, and Y. Cheng
- Subjects
Transplantation ,business.industry ,Immunology ,Toxicity ,Medicine ,Peripheral blood stem cell harvest ,Hematology ,business - Published
- 2010
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