نتائج البحث - "Brent A Hanks"

الوصف: Background Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017.Methods In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months.Results Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies.Conclusions This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority.Trial registration number NCT02267603.

وصف الملف: electronic resource

العلاقة: https://jitc.bmj.com/content/9/4/e002478.fullTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/73de26009f964e2780583bb59aad23b0Test

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النص الكامل

5

دورية أكاديمية

Assessing the utility of molecular diagnostic classification for cancers of unknown primary

المؤلفون: Elle C. Moore, Gerard C. Blobe, Nicholas C. DeVito, Brent A. Hanks, Michael R. Harrison, Christopher J. Hoimes, Jingquan Jia, Michael A. Morse, Parvathy Jayaprakasan, Andrew MacKelfresh, Hillary Mulder, Adam J. Hockenberry, Alia Zander, Martin C. Stumpe, Jackson Michuda, Kyle A. Beauchamp, Eric Perakslis, Timothy Taxter, Daniel J. George

المصدر: Cancer Medicine, Vol 12, Iss 19, Pp 19394-19405 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Background Roughly 5% of metastatic cancers present with uncertain origin, for which molecular classification could influence subsequent management; however, prior studies of molecular diagnostic classifiers have reported mixed results with regard to clinical impact. In this retrospective study, we evaluated the utility of a novel molecular diagnostic classifier by assessing theoretical changes in treatment and additional testing recommendations from oncologists before and after the review of classifier predictions. Methods We retrospectively analyzed de‐identified records from 289 patients with a consensus diagnosis of cancer of uncertain/unknown primary (CUP). Two (or three, if adjudication was required) independent oncologists separately reviewed patient clinical information to determine the course of treatment before they reviewed results from the molecular diagnostic classifier and subsequently evaluated whether the predicted diagnosis would alter their treatment plan. Results Results from the molecular diagnostic classifier changed the consensus oncologist‐reported treatment recommendations for 235 out of 289 patients (81.3%). At the level of individual oncologist reviews (n = 414), 64.7% (n = 268) of treatment recommendations were based on CUP guidelines prior to review of results from the molecular diagnostic classifier. After seeing classifier results, 98.1% (n = 207) of the reviews, where treatment was specified (n = 211), were guided by the tissue of origin‐specific guidelines. Overall, 89.9% of the 414 total reviews either expressed strong agreement (n = 242) or agreement (n = 130) that the molecular diagnostic classifier result increased confidence in selecting the most appropriate treatment regimen. Conclusions A retrospective review of CUP cases demonstrates that a novel molecular diagnostic classifier could affect treatment in the majority of patients, supporting its clinical utility. Further studies are needed to prospectively evaluate whether the use of molecular diagnostic classifiers ...

العلاقة: https://doi.org/10.1002/cam4.6532Test; https://doaj.org/toc/2045-7634Test; https://doaj.org/article/b59390dd42bb4274953a6323c81735b6Test

الإتاحة: https://doi.org/10.1002/cam4.6532Test
https://doaj.org/article/b59390dd42bb4274953a6323c81735b6Test

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النص الكامل

6

دورية أكاديمية

Editorial: Signaling pathways behind immune evasion and therapy resistance

المؤلفون: Elena Martin-Orozco, Lisheng Wang, Shilpak Chatterjee, Brent A. Hanks

المصدر: Frontiers in Immunology, Vol 13 (2022)

مصطلحات موضوعية: tumor immunity, PD-L1, cAMP, UPR, PDE4B, N6-methyladenosine, Immunologic diseases. Allergy, RC581-607

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2022.1104167/fullTest; https://doaj.org/toc/1664-3224Test; https://doaj.org/article/f33dc9a638954f2a9820acdbb5f7b936Test

الإتاحة: https://doi.org/10.3389/fimmu.2022.1104167Test
https://doaj.org/article/f33dc9a638954f2a9820acdbb5f7b936Test

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النص الكامل

7

The Enduring Effects of COVID for Cancer Care: Learning from Real-Life Clinical Practice

المؤلفون: Alex Broom, Leah Williams Veazey, Katherine Kenny, Imogen Harper, Michelle Peterie, Alexander Page, Nicole Cort, Jennifer Durling, Eric S. Lipp, Aaron C. Tan, Kyle M. Walsh, Brent A. Hanks, Margaret Johnson, Amanda E.D. Van Swearingen, Carey K. Anders, David M. Ashley, Mustafa Khasraw

المصدر: Clinical Cancer Research. 29:1670-1677

مصطلحات موضوعية: Cancer Research, Oncology

الوصف: For three years, COVID-19 has circulated among our communities and around the world, fundamentally changing social interactions, health care systems, and service delivery. For people living with (and receiving treatment for) cancer, pandemic conditions presented significant additional hurdles in an already unstable and shifting environment, including disrupted personal contact with care providers, interrupted access to clinical trials, distanced therapeutic encounters, multiple immune vulnerabilities, and new forms of financial precarity. In a 2020 perspective in this journal, we examined how COVID-19 was reshaping cancer care in the early stages of the pandemic and how these changes might endure into the future. Three years later, and in light of a series of interviews with patients and their caregivers from the United States and Australia conducted during the pandemic, we return to consider the potential legacy effects of the pandemic on cancer care. While some challenges to care provision and survivorship were unforeseen, others accentuated and amplified existing problems experienced by patients, caregivers, and health care providers. Both are likely to have enduring effects in the “post-pandemic” world, raising the importance of focusing on lessons that can be learned for the future.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::96b83faf23b6dae3f0915b751a837db9Test
https://doi.org/10.1158/1078-0432.ccr-23-0151Test

8

دورية أكاديمية

Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma

المؤلفون: Geoffrey T. Gibney, Omid Hamid, Jose Lutzky, Anthony J. Olszanski, Tara C. Mitchell, Thomas F. Gajewski, Bartosz Chmielowski, Brent A. Hanks, Yufan Zhao, Robert C. Newton, Janet Maleski, Lance Leopold, Jeffrey S. Weber

المصدر: Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-13 (2019)

مصطلحات موضوعية: Epacadostat, IDO1, Immune checkpoint inhibition, Ipilimumab, Melanoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889). Methods Only the phase 1, open-label portion of the study was conducted, per the sponsor’s decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies. Such decision was not related to the safety of epacadostat plus ipilimumab. Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg am, 25 mg pm]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks. Results Fifty patients received ≥1 dose of epacadostat. As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each). Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID). The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%). Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1. No objective response was seen in the 11 patients who received prior immunotherapy. Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID. Conclusions When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma. Trial registration ClinicalTrials.gov identifier, NCT01604889. Registration date, May 9, 2012, retrospectively registered.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s40425-019-0562-8Test; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/5099b0af01e64192a7b84fc9a960caa6Test

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النص الكامل

9

دورية أكاديمية

Overcoming Immunotherapy Resistance by Targeting the Tumor-Intrinsic NLRP3-HSP70 Signaling Axis

المؤلفون: Balamayooran Theivanthiran, Tarek Haykal, Linda Cao, Alisha Holtzhausen, Michael Plebanek, Nicholas C. DeVito, Brent A. Hanks

المصدر: Cancers; Volume 13; Issue 19; Pages: 4753

مصطلحات موضوعية: NLRP3 inflammasome, HSP70, adaptive immunotherapy resistance, granulocytic myeloid-derived suppressor cells

الوصف: The tumor-intrinsic NOD-like receptor family, pyrin-domain-containing-3 (NLRP3) inflammasome, plays an important role in regulating immunosuppressive myeloid cell populations in the tumor microenvironment (TME). While prior studies have described the activation of this inflammasome in driving pro-tumorigenic mechanisms, emerging data is now revealing the tumor NLRP3 inflammasome and the downstream release of heat shock protein-70 (HSP70) to regulate anti-tumor immunity and contribute to the development of adaptive resistance to anti-PD-1 immunotherapy. Genetic alterations that influence the activity of the NLRP3 signaling axis are likely to impact T cell-mediated tumor cell killing and may indicate which tumors rely on this pathway for immune escape. These studies suggest that the NLRP3 inflammasome and its secreted product, HSP70, represent promising pharmacologic targets for manipulating innate immune cell populations in the TME while enhancing responses to anti-PD-1 immunotherapy. Additional studies are needed to better understand tumor-specific regulatory mechanisms of NLRP3 to enable the development of tumor-selective pharmacologic strategies capable of augmenting responses to checkpoint inhibitor immunotherapy while minimizing unwanted off-target effects. The execution of upcoming clinical trials investigating this strategy to overcome anti-PD-1 resistance promises to provide novel insight into the role of this pathway in immuno-oncology.

وصف الملف: application/pdf

العلاقة: Cancer Immunology and Immunotherapy; https://dx.doi.org/10.3390/cancers13194753Test

الإتاحة: https://doi.org/10.3390/cancers13194753Test

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10

دورية أكاديمية

Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy

المؤلفون: Nicholas C. DeVito, Michael Sturdivant, Balamayooran Thievanthiran, Christine Xiao, Michael P. Plebanek, April K.S. Salama, Georgia M. Beasley, Alisha Holtzhausen, Veronica Novotny-Diermayr, John H. Strickler, Brent A. Hanks

المصدر: Cell Reports, Vol 35, Iss 5, Pp 109071- (2021)

مصطلحات موضوعية: Wnt-β-catenin pathway, anti-PD-1 resistance, dendritic cells, regulatory T cells, myeloid-deriver suppressor cells, indoleamine 2,3-dioxygenase, Biology (General), QH301-705.5

الوصف: Summary: While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration; however, activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.

العلاقة: http://www.sciencedirect.com/science/article/pii/S2211124721004022Test; https://doaj.org/toc/2211-1247Test; https://doaj.org/article/7d2f5f4e3fbf4817a9bfc19438eefb1bTest

الإتاحة: https://doi.org/10.1016/j.celrep.2021.109071Test
https://doaj.org/article/7d2f5f4e3fbf4817a9bfc19438eefb1bTest

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