Search

Your search keyword '"Alewine, Christine"' showing total 199 results
Start Over Author "Alewine, Christine"
199 results on '"Alewine, Christine"'

5. Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

Author

Hassan, Raffit, Morrow, Betsy, Thomas, Anish, Walsh, Tom, Lee, Ming K., Gulsuner, Suleyman, Gadiraju, Meghana, Panou, Vasiliki, Gao, Shaojian, Mian, Idrees, Khan, Javed, Raffeld, Mark, Patel, Snehal, Xi, Liqiang, Wei, Jun S., Hesdorffer, Mary, Zhang, Jingli, Calzone, Kathleen, Desai, Arpita, Padiernos, Emerson, Alewine, Christine, Schrump, David S., Steinberg, Seth M., Kindler, Hedy L., King, Mary-Claire, and Churpek, Jane E.

Published
2019

10. Tofacitinib to prevent anti-drug antibody formation against LMB-100 immunotoxin in patients with advanced mesothelin-expressing cancers.

Author

Skorupan, Nebojsa, Peer, Cody J., Xianyu Zhang, Hyoyoung Choo-Wosoba, Ahmad, Mehwish I., Min-Jung Lee, Shraddha Rastogi, Nahoko Sato, Yunkai Yu, Pegna, Guillaume Joe, Steinberg, Seth M., Kalsi, Shelley S., Liang Cao, Figg, William D., Trepel, Jane B., Pastan, Ira, FitzGerald, David, and Alewine, Christine

Subjects
CANCER patients, ANTIBODY formation, PANCREATIC intraepithelial neoplasia, T cells, EXOTOXIN
Abstract

Background: LMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies. Methods: A phase 1 trial testing LMB-100 and tofacitinib in patients with MSLNexpressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets. Results: The study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed. Discussion: Further testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings. [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

14. Supplementary Figure Legends from Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers

Author

Hagerty, Brendan, primary, O'Sullivan, T. Norene, primary, Zhang, Xianyu, primary, Collins, N. Keith, primary, Custer Lawrence, Wendi, primary, Bassel, Laura L., primary, Pate, Nathan, primary, Xu, Jian, primary, Guerin, Theresa M., primary, Kozlov, Serguei, primary, and Alewine, Christine, primary

Published
2023
Full Text
View/download PDF

15. Data from Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers

Author

Hagerty, Brendan, primary, O'Sullivan, T. Norene, primary, Zhang, Xianyu, primary, Collins, N. Keith, primary, Custer Lawrence, Wendi, primary, Bassel, Laura L., primary, Pate, Nathan, primary, Xu, Jian, primary, Guerin, Theresa M., primary, Kozlov, Serguei, primary, and Alewine, Christine, primary

Published
2023
Full Text
View/download PDF

16. Supplementary Figure 3 from Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers

Author

Hagerty, Brendan, primary, O'Sullivan, T. Norene, primary, Zhang, Xianyu, primary, Collins, N. Keith, primary, Custer Lawrence, Wendi, primary, Bassel, Laura L., primary, Pate, Nathan, primary, Xu, Jian, primary, Guerin, Theresa M., primary, Kozlov, Serguei, primary, and Alewine, Christine, primary

Published
2023
Full Text
View/download PDF

18. Supplementary Figure 1 from Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers

Author

Hagerty, Brendan, primary, O'Sullivan, T. Norene, primary, Zhang, Xianyu, primary, Collins, N. Keith, primary, Custer Lawrence, Wendi, primary, Bassel, Laura L., primary, Pate, Nathan, primary, Xu, Jian, primary, Guerin, Theresa M., primary, Kozlov, Serguei, primary, and Alewine, Christine, primary

Published
2023
Full Text
View/download PDF

24. Supplementary Figure 2 from Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers

Author

Hagerty, Brendan, primary, O'Sullivan, T. Norene, primary, Zhang, Xianyu, primary, Collins, N. Keith, primary, Custer Lawrence, Wendi, primary, Bassel, Laura L., primary, Pate, Nathan, primary, Xu, Jian, primary, Guerin, Theresa M., primary, Kozlov, Serguei, primary, and Alewine, Christine, primary

Published
2023
Full Text
View/download PDF

27. Supplemental Figure 2 from Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Author

Alewine, Christine, primary, Ahmad, Mehwish, primary, Peer, Cody J., primary, Hu, Zishuo I., primary, Lee, Min-Jung, primary, Yuno, Akira, primary, Kindrick, Jessica D., primary, Thomas, Anish, primary, Steinberg, Seth M., primary, Trepel, Jane B., primary, Figg, William D., primary, Hassan, Raffit, primary, and Pastan, Ira, primary

Published
2023
Full Text
View/download PDF

28. Supplemental Figure 1 from Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Author

Alewine, Christine, primary, Ahmad, Mehwish, primary, Peer, Cody J., primary, Hu, Zishuo I., primary, Lee, Min-Jung, primary, Yuno, Akira, primary, Kindrick, Jessica D., primary, Thomas, Anish, primary, Steinberg, Seth M., primary, Trepel, Jane B., primary, Figg, William D., primary, Hassan, Raffit, primary, and Pastan, Ira, primary

Published
2023
Full Text
View/download PDF

31. Supplemental Figure 3 from Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Author

Alewine, Christine, primary, Ahmad, Mehwish, primary, Peer, Cody J., primary, Hu, Zishuo I., primary, Lee, Min-Jung, primary, Yuno, Akira, primary, Kindrick, Jessica D., primary, Thomas, Anish, primary, Steinberg, Seth M., primary, Trepel, Jane B., primary, Figg, William D., primary, Hassan, Raffit, primary, and Pastan, Ira, primary

Published
2023
Full Text
View/download PDF

33. Supplementary Data from Phase I/II Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma

Author

Alewine, Christine, primary, Ahmad, Mehwish, primary, Peer, Cody J., primary, Hu, Zishuo I., primary, Lee, Min-Jung, primary, Yuno, Akira, primary, Kindrick, Jessica D., primary, Thomas, Anish, primary, Steinberg, Seth M., primary, Trepel, Jane B., primary, Figg, William D., primary, Hassan, Raffit, primary, and Pastan, Ira, primary

Published
2023
Full Text
View/download PDF

35. Systemic immune changes accompany combination treatment with immunotoxin LMB ‐100 and nab‐paclitaxel

Author

Pegna, Guillaume Joe, primary, Lee, Min‐Jung, additional, Peer, Cody J., additional, Ahmad, Mehwish I., additional, Venzon, David J., additional, Yu, Yunkai, additional, Yuno, Akira, additional, Steinberg, Seth M., additional, Cao, Liang, additional, Figg, William D., additional, Donahue, Renee N., additional, Hassan, Raffit, additional, Pastan, Ira, additional, Trepel, Jane B., additional, and Alewine, Christine, additional

Published
2022
Full Text
View/download PDF

42. Systemic immune changes accompany combination treatment with immunotoxin LMB‐100 and nab‐paclitaxel.

Author

Pegna, Guillaume Joe, Lee, Min‐Jung, Peer, Cody J., Ahmad, Mehwish I., Venzon, David J., Yu, Yunkai, Yuno, Akira, Steinberg, Seth M., Cao, Liang, Figg, William D., Donahue, Renee N., Hassan, Raffit, Pastan, Ira, Trepel, Jane B., and Alewine, Christine

Subjects
CAPILLARY leak syndrome, T cells, CD38 antigen, CD8 antigen, REGULATORY T cells
Abstract

LMB‐100 is a novel immune‐conjugate (immunotoxin) that targets mesothelin. A phase 1/2 clinical trial was conducted (NCT02810418) with primary objectives assessing the safety and efficacy of LMB‐100 ± nab‐paclitaxel. Participant blood samples were analyzed for changes in serum cytokines and circulating immune cell subsets associated with response or toxicity. On Arm A, participants (n = 20) received standard 30‐minute LMB‐100 infusion with nab‐paclitaxel. Although clinical efficacy was observed, the combination caused intolerable capillary leak syndrome (CLS), a major toxicity of unclear etiology that affects many immunotoxin drugs. Participants developing CLS experienced rapid elevations in IFNγ and IL‐8 compared to those without significant CLS, along with midcycle increases in Ki‐67‐ CD4 T cells that were CD38, HLA‐DR, or TIM3 positive. Additionally, a strong increase in activated CD4 and CD8 T cells and a concurrent decrease in Tregs were seen in the single Arm A patient achieving a partial response. In Arm B, administration of single agent LMB‐100 to participants (n = 20) as a long infusion given over 24–48 h was investigated based on pre‐clinical data that this format could reduce CLS. An optimal dose and schedule of long infusion LMB‐100 were identified, but no clinical efficacy was observed even in patients receiving LMB‐100 in combination with nab‐paclitaxel. Despite this, both Arm A and B participants experienced increases in specific subsets of proliferating CD4 and CD8 T cells following Cycle 1 treatment. In summary, LMB‐100 treatment causes systemic immune activation. Inflammatory and immune changes that accompany drug associated CLS were characterized for the first time. [ABSTRACT FROM AUTHOR]

Published
2023
Full Text
View/download PDF

45. Novel Humanized Mesothelin-Expressing Genetically Engineered Mouse Models Underscore Challenges in Delivery of Complex Therapeutics to Pancreatic Cancers

Author

Hagerty, Brendan, primary, O'Sullivan, T. Norene, additional, Zhang, Xianyu, additional, Collins, N. Keith, additional, Custer Lawrence, Wendi, additional, Bassel, Laura L., additional, Pate, Nathan, additional, Xu, Jian, additional, Guerin, Theresa M., additional, Kozlov, Serguei, additional, and Alewine, Christine, additional

Published
2021
Full Text
View/download PDF

46. Phase I Study of the Immunotoxin LMB-100 in Patients with Mesothelioma and Other Solid Tumors Expressing Mesothelin

Author

Hassan, Raffit, Alewine, Christine, Mian, Idrees, Spreafico, Anna, Siu, Lillian L., Gomez-Roca, Carlos, Delord, Jean-Pierre, Italiano, Antoine, Lassen, Ulrik, Soria, Jean-Charles, Bahleda, Rastilav, Thomas, Anish, Steinberg, Seth M., Peer, Cody J., Figg, William D., Niederfellner, Gerhard, Naegelen, Valérie Méresse, and Pastan, Ira

Subjects
Mesothelioma, Immunoconjugates, Immunotoxins, Mesothelin, Humans, Middle Aged, GPI-Linked Proteins, Article
Abstract

LMB-100 is an antibody-toxin conjugate with an antimesothelin Fab linked to a 24-kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first-in-human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin.Cohorts of 1 to 7 patients received intravenous LMB-100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21-day cycle.Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose-limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB-100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB-100 plasma concentrations were dose-dependent during cycle 1. The development of antidrug antibodies decreased LMB-100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3.The MTD for single-agent LMB-100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first-generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB-100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB-100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer.Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB-100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A. In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB-100, as well as the generation of antidrug antibodies. Ongoing phase 2 clinical trials are evaluating the combination of LMB-100 plus pembrolizumab in patients with treatment-refractory mesothelioma and non-small cell lung cancer.

Published
2020

48. Lin-7 targets the Kir 2.3 channel on the basolateral membrane via a L27 domain interaction with CASK

Author

Alewine, Christine, Kim, Bo-young, Hegde, Vandana, and Welling, Paul A.

Subjects
Calmodulin -- Health aspects, Calmodulin -- Research, Cell membranes -- Health aspects, Cell membranes -- Research, Protein kinases -- Health aspects, Protein kinases -- Research, Biological sciences
Abstract

Polarized expression of the Kir 2.3 channel in renal epithelial cells is influenced by the opposing activities of two different PDZ proteins. Mammalian Lin-7 (mLin-7) directly interacts with Kir 2.3 to coordinate basolateral membrane expression, whereas the tax interacting protein 1 (TIP-1), composed of a single PDZ domain, competes for interaction with mLin-7 and drives Kir 2.3 into the endocytic pathway. Here we show that the basolateral targeting function of mLin-7 depends on its L27 domain, which directs interaction with a cognate L27 domain in the basolateral membrane-anchoring protein, calcium/ calmodulin-dependent serine protein kinase (CASK). In MDCK cells, the expression of an mLin-7 mutant that lacks the L27 domain displaced Kir 2.3 from the mLin-7/CASK complex and caused the channel to accumulate into large intracellular vesicles that partially colocalized with Rab-11. Conversely, transplantation of the mLin-7 L27 domain to TIP-1 conferred CASK interaction and basolateral targeting of Kir 2.3. Expression of the CASK L27 domain redistributed endogenous mLin-7 to an intracellular compartment and caused Kir 2.3 to accumulate in subapical endosomes. Taken together, these data support a model whereby mLin-7 acts as a PDZ-to-L27 adapter, mediating indirect association of Kir 2.3 with a basolateral membrane scaffold and thereby stabilizing Kir 2.3 at the basolateral membrane. kidney; polarity; PDZ; scaffold; calcium/calmodulin-dependent serine protein kinase

Published
2007

49. Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

Author

Skorupan, Nebojsa, primary, Ahmad, Mehwish Iqra, additional, Pegna, Guillaume Joe, additional, Peer, Cody J., additional, Trepel, Jane B., additional, Lee, Min-Jung, additional, Lee, Sunmin, additional, Rastogi, Shraddha, additional, Sato, Nahoko, additional, Figg, William Douglas, additional, Hassan, Raffit, additional, FitzGerald, David JP, additional, Pastan, Ira, additional, and Alewine, Christine, additional

Published
2021
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results