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Start Over Author "Toloczko, A" Publisher american association for cancer research (aacr)
12 results on '"Toloczko, A"'

1. MEDI5752FINALSupplementaryMaterial.docx from Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Dovedi, Simon J., primary, Elder, Matthew J., primary, Yang, Chunning, primary, Sitnikova, Suzanne I., primary, Irving, Lorraine, primary, Hansen, Anna, primary, Hair, James, primary, Jones, Des C., primary, Hasani, Sumati, primary, Wang, Bo, primary, Im, Seock-Ah, primary, Tran, Ben, primary, Subramaniam, Deepa S., primary, Gainer, Shelby D., primary, Vashisht, Kapil, primary, Lewis, Arthur, primary, Jin, Xiaofang, primary, Kentner, Stacy, primary, Mulgrew, Kathy, primary, Wang, Yaya, primary, Overstreet, Michael G., primary, Dodgson, James, primary, Wu, Yanli, primary, Palazon, Asis, primary, Morrow, Michelle, primary, Rainey, Godfrey J., primary, Browne, Gareth J., primary, Neal, Frances, primary, Murray, Thomas V., primary, Toloczko, Aleksandra D., primary, Dall'Acqua, William, primary, Achour, Ikbel, primary, Freeman, Daniel J., primary, Wilkinson, Robert W., primary, and Mazor, Yariv, primary

Published
2023
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2. Data from Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Dovedi, Simon J., primary, Elder, Matthew J., primary, Yang, Chunning, primary, Sitnikova, Suzanne I., primary, Irving, Lorraine, primary, Hansen, Anna, primary, Hair, James, primary, Jones, Des C., primary, Hasani, Sumati, primary, Wang, Bo, primary, Im, Seock-Ah, primary, Tran, Ben, primary, Subramaniam, Deepa S., primary, Gainer, Shelby D., primary, Vashisht, Kapil, primary, Lewis, Arthur, primary, Jin, Xiaofang, primary, Kentner, Stacy, primary, Mulgrew, Kathy, primary, Wang, Yaya, primary, Overstreet, Michael G., primary, Dodgson, James, primary, Wu, Yanli, primary, Palazon, Asis, primary, Morrow, Michelle, primary, Rainey, Godfrey J., primary, Browne, Gareth J., primary, Neal, Frances, primary, Murray, Thomas V., primary, Toloczko, Aleksandra D., primary, Dall'Acqua, William, primary, Achour, Ikbel, primary, Freeman, Daniel J., primary, Wilkinson, Robert W., primary, and Mazor, Yariv, primary

Published
2023
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4. MEDI5752FINALSupplementaryMaterial.docx from Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Yariv Mazor, Robert W. Wilkinson, Daniel J. Freeman, Ikbel Achour, William Dall'Acqua, Aleksandra D. Toloczko, Thomas V. Murray, Frances Neal, Gareth J. Browne, Godfrey J. Rainey, Michelle Morrow, Asis Palazon, Yanli Wu, James Dodgson, Michael G. Overstreet, Yaya Wang, Kathy Mulgrew, Stacy Kentner, Xiaofang Jin, Arthur Lewis, Kapil Vashisht, Shelby D. Gainer, Deepa S. Subramaniam, Ben Tran, Seock-Ah Im, Bo Wang, Sumati Hasani, Des C. Jones, James Hair, Anna Hansen, Lorraine Irving, Suzanne I. Sitnikova, Chunning Yang, Matthew J. Elder, and Simon J. Dovedi

Abstract

Supplementary Materials and Methods, and Supplementary Figures

Published
2023
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5. Data from Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Yariv Mazor, Robert W. Wilkinson, Daniel J. Freeman, Ikbel Achour, William Dall'Acqua, Aleksandra D. Toloczko, Thomas V. Murray, Frances Neal, Gareth J. Browne, Godfrey J. Rainey, Michelle Morrow, Asis Palazon, Yanli Wu, James Dodgson, Michael G. Overstreet, Yaya Wang, Kathy Mulgrew, Stacy Kentner, Xiaofang Jin, Arthur Lewis, Kapil Vashisht, Shelby D. Gainer, Deepa S. Subramaniam, Ben Tran, Seock-Ah Im, Bo Wang, Sumati Hasani, Des C. Jones, James Hair, Anna Hansen, Lorraine Irving, Suzanne I. Sitnikova, Chunning Yang, Matthew J. Elder, and Simon J. Dovedi

Abstract

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1− T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells.Significance:The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy.See related commentary by Burton and Tawbi, p. 1008.This article is highlighted in the In This Issue feature, p. 995

Published
2023
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6. Data from Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Proliferation of Tumor Cells with Receptor-Proximal Apoptosis Defects

Author

Irmela Jeremias, Klaus-Michael Debatin, Harald Ehrhardt, Christian Beltinger, Irene Schmid, Uta Fuchs, Agnieszka Toloczko, and Eva Baader

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) might represent a future cytotoxic drug to treat cancer as it induces apoptosis in tumor cells without toxicity in animal trials. We recently described that in contrast to apoptosis, TRAIL mediates tumor cell survival and proliferation in certain tumor cells. Here we studied the effect of TRAIL on 18 cell lines and 53 primary leukemia cells and classified these tumor cells into four groups: TRAIL, anti-DR4 or anti-DR5 induced apoptosis in group A cells, whereas they had no effect on group 0 cells and mediated proliferation in group P cells. To our surprise, TRAIL induced simultaneous apoptosis and proliferation in group AP cells. More than 20% of all cells tested belonged to group P and showed TRAIL-mediated proliferation even in the presence of certain cytotoxic drugs but not inhibitors of nuclear factor-κB. Transfection with B-cell leukemia/lymphoma protein 2 transformed group A cells into group 0 cells, whereas transfection with Fas-associated polypeptide with death domain (FADD)–like interleukin-1-converting enzyme–inhibitory protein (FLIP) transformed them into group AP cells. Loss of caspase-8 or transfection of dominant-negative FADD transformed group A cells into group P cells. Taken together, our data suggest that proliferation is a frequent effect of TRAIL on tumor cells, which is related to receptor-proximal apoptosis defects at the level of the death-inducing signaling complex and should be prevented during antitumor therapy with TRAIL.

Published
2023
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7. Supplementary Figures 1-3 from Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Proliferation of Tumor Cells with Receptor-Proximal Apoptosis Defects

Author

Irmela Jeremias, Klaus-Michael Debatin, Harald Ehrhardt, Christian Beltinger, Irene Schmid, Uta Fuchs, Agnieszka Toloczko, and Eva Baader

Abstract

Supplementary Figures 1-3 from Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Proliferation of Tumor Cells with Receptor-Proximal Apoptosis Defects

Published
2023
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8. Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Bo Wang, Frances Neal, Arthur Lewis, Kapil Vashisht, Deepa S. Subramaniam, Des C. Jones, Sumati Hasani, Daniel J. Freeman, Chunning Yang, Lorraine Irving, Michael G. Overstreet, Gareth J. Browne, Suzanne I. Sitnikova, James Hair, Robert W. Wilkinson, Yaya Wang, Ben Tran, Ikbel Achour, James Dodgson, Shelby D. Gainer, Xiaofang Jin, Seock-Ah Im, William F Dall'Acqua, Yariv Mazor, Godfrey Rainey, Asis Palazon, Anna Hansen, Yanli Wu, Matthew J. Elder, Stacy Kentner, Aleksandra D. Toloczko, Michelle Morrow, Murray Thomas Vincent, Simon J. Dovedi, and Kathy Mulgrew

Subjects
0301 basic medicine, biology, medicine.drug_class, Chemistry, medicine.medical_treatment, media_common.quotation_subject, Rational design, chemical and pharmacologic phenomena, Immunotherapy, Monoclonal antibody, Blockade, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, In vivo, 030220 oncology & carcinogenesis, medicine, biology.protein, Cancer research, Secretion, Antibody, Internalization, media_common
Abstract

The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1+ activated T cells. We show that MEDI5752 preferentially saturates CTLA4 on PD-1+ T cells versus PD-1− T cells, reducing the dose required to elicit IL2 secretion. Unlike conventional PD-1/CTLA4 mAbs, MEDI5752 leads to the rapid internalization and degradation of PD-1. Moreover, we show that MEDI5752 preferentially localizes and accumulates in tumors providing enhanced activity when compared with a combination of mAbs targeting PD-1 and CTLA4 in vivo. Following treatment with MEDI5752, robust partial responses were observed in two patients with advanced solid tumors. MEDI5752 represents a novel immunotherapy engineered to preferentially inhibit CTLA4 on PD-1+ T cells. Significance: The unique characteristics of MEDI5752 represent a novel immunotherapy engineered to direct CTLA4 inhibition to PD-1+ T cells with the potential for differentiated activity when compared with current conventional mAb combination strategies targeting PD-1 and CTLA4. This molecule therefore represents a step forward in the rational design of cancer immunotherapy. See related commentary by Burton and Tawbi, p. 1008. This article is highlighted in the In This Issue feature, p. 995

Published
2021
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9. Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

Author

Sven Mahner, Robertson Mackenzie, Aline Talhouk, Linda E. Kelemen, Gottfried E. Konecny, Jennifer Alsop, Rosalind Glasspool, Chiu-Chen Tseng, Joy Hendley, Dennis J. Slamon, Jennifer A. Doherty, Andrew Berchuck, Anna H. Wu, Anna M. Piskorz, Chen Wang, Cristina Rodríguez-Antona, D.G.H. de Silva, Valerie Rhenius, Peter A. Fasching, Stacey J. Winham, Gary L. Keeney, Teodora Goranova, Joshy George, Jan Lubinski, Michelle J. Henderson, Rex C. Bentley, Jenny Lester, Sabine Behrens, Joellen M. Schildkraut, Michael E. Carney, Timothy Budden, David G. Huntsman, Oleg Oszurek, Michael S. Anglesio, Jacek Gronwald, Ruby Yun-Ju Huang, Martin Köbel, Javier Benitez, Martin Widschwendter, Melissa C. Larson, Raghwa Sharma, Clara Bodelon, Usha Menon, Janusz Menkiszak, Blake Gilks, María Josefa Mosteiro García, Jesús García-Donas, Wafaa Elatre, Scott H. Kaufmann, Paul Haluska, Pamela J. Thompson, Boris Winterhoff, Susan J. Ramus, Louise A. Brinton, Simon A. Gayther, Mary Anne Rossing, Georgia Chenevix-Trench, Hugh Luk, Jolanta Lissowska, Marc T. Goodman, Billy Chen, Beth Y. Karlan, Naveena Singh, Sian Fereday, Mark E. Sherman, Ana Osorio, Lynne R. Wilkens, Maria P. Intermaggio, Brenda Y. Hernandez, Britton Trabert, Esther Herpel, Mercedes Jimenez-Linan, Janine Senz, Geyi Liu, Celeste Leigh Pearce, Samuel C Y Leong, Iain A. McNeish, Isabelle Ray-Coquard, Susana Banerjee, Malcolm C. Pike, Liz-Anne Lewsley, Helen Steed, Honglin Song, Samantha Hinsley, David D.L. Bowtell, James D. Brenton, Holly R. Harris, Tuan Zea Tan, Cezary Cybulski, Alicia Beeghly-Fadiel, A. Toloczko, Nikilyn Nevins, Robert S. Brown, Darren Ennis, Stephanie Chen, Euan A. Stronach, José Palacios, Sandra Orsulic, Anna deFazio, Geoff Macintyre, Kara L. Cushing-Haugen, Mila Volchek, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Paul D.P. Pharoah, Hanwei Sudderuddin, Stefan Kommoss, Derek S. Chiu, Huei San Leong, Peter Sinn, Catherine J. Kennedy, Chloe Karpinskyj, Alison Brand, Amy Lum, Veronica Chow, Nicolas Wentzensen, Tayyebeh M. Nazeran, Nadia Traficante, Dustin Johnson, Yoke-Eng Chiew, Casey S. Greene, Jennifer M Koziak, Renée T. Fortner, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action, Talhouk, Aline [0000-0001-7760-410X], George, Joshy [0000-0001-8510-8229], Wang, Chen [0000-0003-2638-3081], Tan, Tuan Zea [0000-0001-6624-1593], Behrens, Sabine [0000-0002-9714-104X], Bodelon, Clara [0000-0002-6578-2678], Brinton, Louise [0000-0003-3853-8562], Fortner, Renée T [0000-0002-1426-8505], García-Donas, Jesús [0000-0001-7731-3601], Gentry-Maharaj, Aleksandra [0000-0001-7270-9762], Glasspool, Rosalind [0000-0002-5000-1680], Greene, Casey S [0000-0001-8713-9213], Harris, Holly R [0000-0002-2572-6727], Kaufmann, Scott H [0000-0002-4900-7145], Kennedy, Catherine J [0000-0002-4465-5784], Köbel, Martin [0000-0002-6615-2037], Koziak, Jennifer M [0000-0001-5830-0397], Lissowska, Jolanta [0000-0003-2695-5799], McNeish, Iain A [0000-0002-9387-7586], Menkiszak, Janusz [0000-0001-8279-7196], Hinsley, Samantha [0000-0001-6903-4688], Pike, Malcolm C [0000-0003-4891-1199], Rodriguez-Antona, Cristina [0000-0001-8750-7338], Sinn, Peter [0000-0003-2836-6699], Trabert, Britton [0000-0002-1539-6090], Widschwendter, Martin [0000-0002-7778-8380], Winham, Stacey J [0000-0002-8492-9102], Brenton, James D [0000-0002-5738-6683], Brown, Robert [0000-0001-7960-5755], Chang-Claude, Jenny [0000-0001-8919-1971], deFazio, Anna [0000-0003-0057-4744], Fasching, Peter A [0000-0003-4885-8471], Kelemen, Linda E [0000-0003-4362-9784], Menon, Usha [0000-0003-3708-1732], Pharoah, Paul DP [0000-0001-8494-732X], Ramus, Susan J [0000-0003-0005-7798], Doherty, Jennifer A [0000-0002-1454-8187], Anglesio, Michael S [0000-0003-1639-5003], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Neoplasm, Residual, Bevacizumab, 03 medical and health sciences, Ovarian tumor, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Ovarian carcinoma, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Stage (cooking), Aged, Ovarian Neoplasms, business.industry, Cystadenoma, Serous, Cancer, Middle Aged, Precision medicine, Omics, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Serous fluid, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Neoplasm Grading, Transcriptome, business, Algorithms, medicine.drug
Abstract

Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Published
2020
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10. Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1+ Activated T Cells

Author

Dovedi, Simon J., primary, Elder, Matthew J., additional, Yang, Chunning, additional, Sitnikova, Suzanne I., additional, Irving, Lorraine, additional, Hansen, Anna, additional, Hair, James, additional, Jones, Des C., additional, Hasani, Sumati, additional, Wang, Bo, additional, Im, Seock-Ah, additional, Tran, Ben, additional, Subramaniam, Deepa S., additional, Gainer, Shelby D., additional, Vashisht, Kapil, additional, Lewis, Arthur, additional, Jin, Xiaofang, additional, Kentner, Stacy, additional, Mulgrew, Kathy, additional, Wang, Yaya, additional, Overstreet, Michael G., additional, Dodgson, James, additional, Wu, Yanli, additional, Palazon, Asis, additional, Morrow, Michelle, additional, Rainey, Godfrey J., additional, Browne, Gareth J., additional, Neal, Frances, additional, Murray, Thomas V., additional, Toloczko, Aleksandra D., additional, Dall'Acqua, William, additional, Achour, Ikbel, additional, Freeman, Daniel J., additional, Wilkinson, Robert W., additional, and Mazor, Yariv, additional

Published
2021
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11. Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS Kinase and Core Components of the Hippo Pathway

Author

Toloczko, Aleksandra, primary, Guo, Fusheng, additional, Yuen, Hiu-Fung, additional, Wen, Qing, additional, Wood, Stephen A., additional, Ong, Yan Shan, additional, Chan, Pei Yi, additional, Shaik, Asfa Alli, additional, Gunaratne, Jayantha, additional, Dunne, Mark J., additional, Hong, Wanjin, additional, and Chan, Siew Wee, additional

Published
2017
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