7 results on '"Aleksandra K. Olow"'
Search Results
2. Data from Reverse Translating Molecular Determinants of Anti–Programmed Death 1 Immunotherapy Response in Mouse Syngeneic Tumor Models
- Author
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Elaine M. Pinheiro, Terrill K. McClanahan, Brian J. Long, Svetlana Sadekova, Razvan Cristescu, Andrey Loboda, Derek Y. Chiang, Lily Y. Moy, Aleksandra K. Olow, Sarah Javaid, Heather A. Hirsch, Kimberly S. Kerr, Wendy M. Blumenschein, Manjiri Sathe, Michael Nebozhyn, Venkataraman Sriram, Jennifer H. Yearley, Hui Xiao, Lan Chen, Michael Caniga, Selvakumar Sukumar, Douglas C. Wilson, Louise Cadzow, Mingmei Cai, Yun Wang, Marlene C. Hinton, Douglas E. Linn, Eric S. Muise, and Peter Georgiev
- Abstract
Targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway with immunotherapy has revolutionized the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell–inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that can predict responsiveness to anti-PD-1/PD-L1 monotherapy in many tumor types. We analyzed the association between these biomarkers and the efficacy of PD-1 inhibitor in 11 commonly used preclinical syngeneic tumor mouse models using murinized rat anti-mouse PD-1 DX400 antibody muDX400, a surrogate for pembrolizumab. Response to muDX400 treatment was broadly classified into three categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune cell infiltration and activation in the tumor microenvironment of muDX400-responsive tumors. Baseline and on-treatment genomic analysis showed an association between TMB, murine T-cell–inflamed gene expression profile (murine-GEP), and response to muDX400 treatment. We extended our analysis to investigate a canonical set of cancer and immune biology-related gene signatures, including signatures of angiogenesis, myeloid-derived suppressor cells, and stromal/epithelial-to-mesenchymal transition/TGFβ biology previously shown to be inversely associated with the clinical efficacy of immune checkpoint blockade. Finally, we evaluated the association between murine-GEP and preclinical efficacy with standard-of-care chemotherapy or antiangiogenic agents that previously demonstrated promising clinical activity, in combination with muDX400. Our profiling studies begin to elucidate the underlying biological mechanisms of response and resistance to PD-1/PD-L1 blockade represented by these models, thereby providing insight into which models are most appropriate for the evaluation of orthogonal combination strategies.
- Published
- 2023
3. Supplementary Data from Reverse Translating Molecular Determinants of Anti–Programmed Death 1 Immunotherapy Response in Mouse Syngeneic Tumor Models
- Author
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Elaine M. Pinheiro, Terrill K. McClanahan, Brian J. Long, Svetlana Sadekova, Razvan Cristescu, Andrey Loboda, Derek Y. Chiang, Lily Y. Moy, Aleksandra K. Olow, Sarah Javaid, Heather A. Hirsch, Kimberly S. Kerr, Wendy M. Blumenschein, Manjiri Sathe, Michael Nebozhyn, Venkataraman Sriram, Jennifer H. Yearley, Hui Xiao, Lan Chen, Michael Caniga, Selvakumar Sukumar, Douglas C. Wilson, Louise Cadzow, Mingmei Cai, Yun Wang, Marlene C. Hinton, Douglas E. Linn, Eric S. Muise, and Peter Georgiev
- Abstract
Supplementary Data from Reverse Translating Molecular Determinants of Anti–Programmed Death 1 Immunotherapy Response in Mouse Syngeneic Tumor Models
- Published
- 2023
4. Reverse Translating Molecular Determinants of Anti–Programmed Death 1 Immunotherapy Response in Mouse Syngeneic Tumor Models
- Author
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Peter Georgiev, Eric S. Muise, Douglas E. Linn, Marlene C. Hinton, Yun Wang, Mingmei Cai, Louise Cadzow, Douglas C. Wilson, Selvakumar Sukumar, Michael Caniga, Lan Chen, Hui Xiao, Jennifer H. Yearley, Venkataraman Sriram, Michael Nebozhyn, Manjiri Sathe, Wendy M. Blumenschein, Kimberly S. Kerr, Heather A. Hirsch, Sarah Javaid, Aleksandra K. Olow, Lily Y. Moy, Derek Y. Chiang, Andrey Loboda, Razvan Cristescu, Svetlana Sadekova, Brian J. Long, Terrill K. McClanahan, and Elaine M. Pinheiro
- Subjects
Cancer Research ,Programmed Cell Death 1 Receptor ,B7-H1 Antigen ,Disease Models, Animal ,Mice ,Oncology ,Cell Line, Tumor ,Neoplasms ,Biomarkers, Tumor ,Tumor Microenvironment ,Animals ,Humans ,Immunotherapy ,Immune Checkpoint Inhibitors - Abstract
Targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway with immunotherapy has revolutionized the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell–inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that can predict responsiveness to anti-PD-1/PD-L1 monotherapy in many tumor types. We analyzed the association between these biomarkers and the efficacy of PD-1 inhibitor in 11 commonly used preclinical syngeneic tumor mouse models using murinized rat anti-mouse PD-1 DX400 antibody muDX400, a surrogate for pembrolizumab. Response to muDX400 treatment was broadly classified into three categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune cell infiltration and activation in the tumor microenvironment of muDX400-responsive tumors. Baseline and on-treatment genomic analysis showed an association between TMB, murine T-cell–inflamed gene expression profile (murine-GEP), and response to muDX400 treatment. We extended our analysis to investigate a canonical set of cancer and immune biology-related gene signatures, including signatures of angiogenesis, myeloid-derived suppressor cells, and stromal/epithelial-to-mesenchymal transition/TGFβ biology previously shown to be inversely associated with the clinical efficacy of immune checkpoint blockade. Finally, we evaluated the association between murine-GEP and preclinical efficacy with standard-of-care chemotherapy or antiangiogenic agents that previously demonstrated promising clinical activity, in combination with muDX400. Our profiling studies begin to elucidate the underlying biological mechanisms of response and resistance to PD-1/PD-L1 blockade represented by these models, thereby providing insight into which models are most appropriate for the evaluation of orthogonal combination strategies.
- Published
- 2022
5. Proteomic mapping of intercellular synaptic environments
- Author
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Tyler J, Bechtel, Jayde M, Bertoch, Aleksandra K, Olow, Margaret, Duich, Cory H, White, Tamara, Reyes-Robles, Olugbeminiyi O, Fadeyi, and Rob C, Oslund
- Subjects
Proteomics ,Programmed Cell Death 1 Receptor ,Ligands ,B7-H1 Antigen ,Catalysis - Abstract
Receptor-ligand interactions play essential signaling roles within intercellular contact regions. This is particularly important within the context of the immune synapse where protein communication at the surface of physically interacting T cells and antigen-presenting cells regulate downstream immune signaling responses. To identify protein microenvironments within immunological synapses, we combined a flavin-dependent photocatalytic labeling strategy with quantitative mass spectrometry-based proteomics. Using α-PD-L1 or α-PD-1 single-domain antibody (VHH)-based photocatalyst targeting modalities, we profiled protein microenvironments within the intercellular region of an immune synapse-forming co-culture system. In addition to enrichment of both PD-L1 and PD-1 with either targeting modality, we also observed enrichment of both known immune synapse residing receptor-ligand pairs and surface proteins, as well as previously unknown synapse residing proteins.
- Published
- 2022
6. Proteomic Mapping of Intercellular Synaptic Environments via Flavin-Dependent Photoredox Catalysis
- Author
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Tyler J. Bechtel, Jayde M. Bertoch, Aleksandra K. Olow, Margaret Duich, Cory H. White, Tamara Reyes-Robles, Olugbeminiyi O. Fadeyi, and Rob C. Oslund
- Abstract
Receptor-ligand interactions play essential signaling roles within intercellular contact regions. This is particularly important within the context of the immune synapse where protein communication at the surface of physically interacting T cells and antigen-presenting cells regulate downstream immune signaling responses. To identify protein microenvironments within immunological synapses, we combined a flavin-dependent photocatalytic labeling strategy with quantitative mass spectrometry-based proteomics. Using α-PD-L1 or α-PD-1 single-domain antibody (VHH)-based photocatalyst targeting modalities, we profiled protein microenvironments within the intercellular region of an immune synapse-forming co-culture system. In addition to enrichment of both PD-L1 and PD-1 with either targeting modality, we also observed enrichment of both known immune synapse residing receptor-ligand pairs and surface proteins, as well as previously unknown synapse residing proteins.
- Published
- 2022
7. Nanoscale Mapping of EGFR and c-MET Protein Environments on Lung Cancer Cell Surfaces via Therapeutic Antibody Photocatalyst Conjugates
- Author
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Tamara Reyes-Robles, Aleksandra K. Olow, Tyler J. Bechtel, Scott A. Lesley, Olugbeminiyi O. Fadeyi, and Rob C. Oslund
- Subjects
ErbB Receptors ,Lung Neoplasms ,Drug Resistance, Neoplasm ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Tumor Microenvironment ,Molecular Medicine ,Humans ,General Medicine ,Proto-Oncogene Proteins c-met ,Biochemistry ,Protein Kinase Inhibitors ,Cell Proliferation - Abstract
Receptor tyrosine kinases are involved in essential signaling roles that impact cell growth, differentiation, and proliferation. The overexpression or mutation of these proteins can lead to aberrant signaling that has been directly linked to a number of diseases including cancer cell formation and progression. This has led to intense clinical focus on modulating RTK activity through direct targeting of signaling activity or cell types harboring aberrant RTK behavior. In particular, epidermal growth factor receptor (EGFR) has attracted intense clinical attention due to the impact of inhibiting this RTK on tumor growth. However, mutations incurred through targeting EGFR have led to therapeutic resistance that involves not only direct mutations to the EGFR protein but also the involvement of other RTKs, such as c-MET, that can overcome therapeutic-based EGFR inhibition effects. This has, not surprisingly, led to co-targeting strategies of RTKs such as EGFR and c-MET to overcome resistance mechanisms. While the ability to co-target these proteins has led to success in the clinic, a more comprehensive understanding of their proximal environments, particularly in the context of therapeutic modalities, could further enhance both our understanding of their signaling biology and provide additional avenues for targeting these surface proteins. Thus, to investigate EGFR and c-MET protein microenvironments, we utilized our recently developed iridium photocatalyst-based microenvironment mapping technology to catalog EGFR and c-MET surface environments on non-small cell lung cancer cell lines. Through this approach, we enriched EGFR and c-MET from the cell surface and identified known EGFR and c-MET associators as well as previously unidentified proximal proteins.
- Published
- 2022
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