30 results on '"Penny HL"'
Search Results
2. APWCA clinical rounds. The use of acticoat moisture control for the successful treatment of diabetic ulcers.
- Author
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Penny HL, Webster N, Sullivan R, Spinazzola J, Green A, and Faretta M
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- 2009
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3. APWCA clinical rounds. A multidisciplinary approach to a possible limb-threatening infection.
- Author
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Penny HL, Webster N, Sullivan R, and Spinazzola J
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- 2008
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4. Postaxial polydactyly with polymetatarsia. a case report
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Tozzi Ma and Penny Hl
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Postaxial polydactyly ,Male ,business.industry ,General Medicine ,Anatomy ,Toes ,Amputation, Surgical ,Metatarsus ,Pedigree ,Child, Preschool ,Medicine ,Humans ,Abnormalities, Multiple ,business - Published
- 1981
5. Postaxial polydactyly with polymetatarsia. a case report
- Author
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Tozzi, MA, primary and Penny, HL, primary
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- 1981
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6. Wound management on the leading edge: case presentations from APWCA.
- Author
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Penny HL, Webster N, and Spinazzola J
- Abstract
Here are some examples of different approaches to wound care [ABSTRACT FROM AUTHOR]
- Published
- 2007
7. A Phase I Study of Acapatamab, a Half-life Extended, PSMA-Targeting Bispecific T-cell Engager for Metastatic Castration-Resistant Prostate Cancer.
- Author
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Dorff T, Horvath LG, Autio K, Bernard-Tessier A, Rettig MB, Machiels JP, Bilen MA, Lolkema MP, Adra N, Rottey S, Greil R, Matsubara N, Tan DSW, Wong A, Uemura H, Lemech C, Meran J, Yu Y, Minocha M, McComb M, Penny HL, Gupta V, Hu X, Jurida G, Kouros-Mehr H, Janát-Amsbury MM, Eggert T, and Tran B
- Subjects
- Male, Humans, Prostate-Specific Antigen, Half-Life, Treatment Outcome, Androgen Receptor Antagonists therapeutic use, T-Lymphocytes metabolism, Prostatic Neoplasms, Castration-Resistant pathology, Antineoplastic Agents therapeutic use
- Abstract
Purpose: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC)., Patients and Methods: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed., Results: In all, 133 patients (dose exploration, n = 77; dose expansion, n = 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0-4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0-5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion., Conclusions: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity., (©2024 American Association for Cancer Research.)
- Published
- 2024
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8. Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study.
- Author
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Kelly WK, Danila DC, Lin CC, Lee JL, Matsubara N, Ward PJ, Armstrong AJ, Pook D, Kim M, Dorff TB, Fischer S, Lin YC, Horvath LG, Sumey C, Yang Z, Jurida G, Smith KM, Connarn JN, Penny HL, Stieglmaier J, and Appleman LJ
- Subjects
- Male, Humans, Immunotherapy, Treatment Outcome, Antigens, Neoplasm, Oxidoreductases therapeutic use, Prostate-Specific Antigen therapeutic use, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development., Significance: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5., (©2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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9. Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy.
- Author
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Penny HL, Hainline K, Theoharis N, Wu B, Brandl C, Webhofer C, McComb M, Wittemer-Rump S, Koca G, Stienen S, Bargou RC, Hummel HD, Loidl W, Grüllich C, Eggert T, Tran B, and Mytych DT
- Subjects
- Male, Humans, Root Cause Analysis, Prostate-Specific Antigen metabolism, Antibodies metabolism, Antigens, Surface metabolism, T-Lymphocytes, Prostate, Biological Products
- Abstract
Introduction: In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics., Methods: Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration., Results: Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm., Discussion: These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics., Competing Interests: All authors, except for NT, SW-R, GK, RB, H-DH, WL, CG, and BT, were/are employees of Amgen during the time this study and associated analyses were being conducted. SW-R and GK are employees of Bayer AG. Author WL was employed by Ordensklinikum Linz GmbH. RB is a patent holder for blinatumomab, from which he receives royalty payments, and has consulted for and received honoraria from Amgen, Cellex and Gemoab. H-DH has received travel, accommodations or other expenses from Johnson & Johnson, Boehringer Ingelheim, Amgen Inc. and Bristol Myers Squibb. WL has received honoraria from Accord and Novartis. BT has received a grant, consulting fees, and honoraria from Amgen Inc. NT was an employee of Labcorp Translational Biomarker Solutions at the time of this study and has no conflicts to disclose. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Bayer and Amgen. The funders were involved in the study design, collection, analysis, interpretation of results, the writing of this article and the decision to submit it for publication., (Copyright © 2023 Penny, Hainline, Theoharis, Wu, Brandl, Webhofer, McComb, Wittemer-Rump, Koca, Stienen, Bargou, Hummel, Loidl, Grüllich, Eggert, Tran and Mytych.)
- Published
- 2023
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10. Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma.
- Author
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Sieow JL, Penny HL, Gun SY, Tan LQ, Duan K, Yeong JPS, Pang A, Lim D, Toh HC, Lim TKH, Engleman E, Rotzschke O, Ng LG, Chen J, Tan SM, and Wong SC
- Subjects
- Humans, Animals, Mice, Neutrophils metabolism, Cell Line, Tumor, Mice, Knockout, Carcinogenesis, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Tumor Microenvironment genetics, Pancreatic Neoplasms, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal pathology
- Abstract
Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer.
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- 2023
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11. Are diabetic foot ulcers less harmful than other pressure ulcers?
- Author
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Penny HL
- Subjects
- Humans, Pressure, Diabetes Mellitus, Diabetic Foot therapy, Foot Ulcer, Pressure Ulcer therapy
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- 2022
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12. Immunogenicity assessment of bispecific antibody-based immunotherapy in oncology.
- Author
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Zhou Y, Penny HL, Kroenke MA, Bautista B, Hainline K, Chea LS, Parnes J, and Mytych DT
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- Humans, Immunologic Factors, Immunotherapy, Reproducibility of Results, Retrospective Studies, Antibodies, Bispecific therapeutic use
- Abstract
With increasing numbers of bispecific antibodies (BsAbs) and multispecific products entering the clinic, recent data highlight immunogenicity as an emerging challenge in the development of such novel biologics. This review focuses on the immunogenicity risk assessment (IgRA) of BsAb-based immunotherapies for cancer, highlighting several risk factors that need to be considered. These include the novel scaffolds consisting of bioengineered sequences, the potentially synergistic immunomodulating mechanisms of action (MOAs) from different domains of the BsAb, as well as several other product-related and patient-related factors. In addition, the clinical relevance of anti-drug antibodies (ADAs) against selected BsAbs developed as anticancer agents is reviewed and the advances in our knowledge of tools and strategies for immunogenicity prediction, monitoring, and mitigation are discussed. It is critical to implement a drug-specific IgRA during the early development stage to guide ADA monitoring and risk management strategies. This IgRA may include a combination of several assessment tools to identify drug-specific risks as well as a proactive risk mitigation approach for candidate or format selection during the preclinical stage. The IgRA is an on-going process throughout clinical development. IgRA during the clinical stage may bridge the gap between preclinical immunogenicity prediction and clinical immunogenicity, and retrospectively guide optimization efforts for next-generation BsAbs. This iterative process throughout development may improve the reliability of the IgRA and enable the implementation of effective risk mitigation strategies, laying the foundation for improved clinical success., Competing Interests: Competing interests: All authors are employees and shareholders of Amgen Inc., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2022
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13. Assay format diversity in pre-clinical immunogenicity risk assessment: Toward a possible harmonization of antigenicity assays.
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Ducret A, Ackaert C, Bessa J, Bunce C, Hickling T, Jawa V, Kroenke MA, Lamberth K, Manin A, Penny HL, Smith N, Terszowski G, Tourdot S, and Spindeldreher S
- Subjects
- Drug Evaluation, Preclinical, Humans, Risk Assessment, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Immunoconjugates adverse effects, Immunoconjugates immunology, Immunoconjugates therapeutic use
- Abstract
A major impediment to successful use of therapeutic protein drugs is their ability to induce anti-drug antibodies (ADA) that can alter treatment efficacy and safety in a significant number of patients. To this aim, in silico , in vitro, and in vivo tools have been developed to assess sequence and other liabilities contributing to ADA development at different stages of the immune response. However, variability exists between similar assays developed by different investigators due to the complexity of assays, a degree of uncertainty about the underlying science, and their intended use. The impact of protocol variations on the outcome of the assays, i.e., on the immunogenicity risk assigned to a given drug candidate, cannot always be precisely assessed. Here, the Non-Clinical Immunogenicity Risk Assessment working group of the European Immunogenicity Platform (EIP) reviews currently used assays and protocols and discusses feasibility and next steps toward harmonization and standardization.
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- 2022
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14. The high costs and inaccessibility of skin substitute therapies: an emerging alternative for hard-to-heal leg ulcer treatments in a post-pandemic environment.
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Penny HL and Galiano RD
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- Humans, Pandemics, Wound Healing, Leg Ulcer epidemiology, Leg Ulcer therapy, Skin, Artificial, Varicose Ulcer therapy
- Published
- 2021
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15. The quandary of DFU offloading: the need for updated standard of care and reimbursement guidelines.
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Penny HL
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- Humans, Wound Healing, Diabetic Foot, Standard of Care
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- 2021
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16. Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma.
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Penny HL, Sieow JL, Gun SY, Lau MC, Lee B, Tan J, Phua C, Toh F, Nga Y, Yeap WH, Janela B, Kumar D, Chen H, Yeong J, Kenkel JA, Pang A, Lim D, Toh HC, Hon TLK, Johnson CI, Khameneh HJ, Mortellaro A, Engleman EG, Rotzschke O, Ginhoux F, Abastado JP, Chen J, and Wong SC
- Subjects
- Adenocarcinoma immunology, Animals, Carcinoma, Pancreatic Ductal immunology, Cell Proliferation drug effects, Drug Resistance, Neoplasm drug effects, Glucose Transporter Type 1 metabolism, Humans, Hydroxybenzoates pharmacology, Inflammation pathology, Interleukin-1beta metabolism, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Macrophages drug effects, Mice, Inbred C57BL, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Pancreatic Neoplasms immunology, Survival Analysis, T-Lymphocytes, Cytotoxic drug effects, T-Lymphocytes, Cytotoxic immunology, Tumor Burden drug effects, Mice, Adenocarcinoma pathology, Carcinoma, Pancreatic Ductal pathology, Cytoprotection drug effects, Glycolysis drug effects, Macrophages metabolism, Pancreatic Neoplasms pathology
- Abstract
Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1β inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.
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- 2021
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17. Local IFNα enhances the anti-tumoral efficacy of systemic anti-PD1 to prevent tumor relapse.
- Author
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Guerin MV, Regnier F, Thoreau M, Vimeux L, Benard M, Dransart E, Penny HL, Johannes L, Trautmann A, and Bercovici N
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- Animals, Disease Models, Animal, Humans, Immunotherapy, Mice, Interferon-alpha metabolism, Neoplasms drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Background: Tumor relapse constitutes a major challenge for anti-tumoral treatments, including immunotherapies. Indeed, most cancer-related deaths occur during the tumor relapse phase., Methods: We designed a mouse model of tumor relapse in which mice transplanted with E7
+ TC1 tumor cells received a single therapeutic vaccination of STxB-E7+IFNα. Unlike the complete regression observed after two vaccinations, such a treatment induced a transient shrinkage of the tumor mass, followed by a rapid tumor outgrowth. To prevent this relapse, we tested the efficacy of a local administration of IFNα together with a systemic therapy with anti-PD1 Ab. The immune response was analyzed during both the tumor regression and relapse phases., Results: We show that, during the regression phase, tumors of mice treated with a single vaccination of STxB-E7 + IFNα harbor fewer activated CD8 T cells and monocytes than tumors doomed to fully regress after two vaccinations. In contrast, the systemic injection of an anti-PD1 Ab combined with the peri-tumoral injection of IFNα in this time frame promotes infiltration of activated CD8 T cells and myeloid cells, which, together, exert a high cytotoxicity in vitro against TC1 cells. Moreover, the IFNα and anti-PD1 Ab combination was found to be more efficient than IFNα or anti-PD1 used alone in preventing tumor relapse and was better able to prolong mice survival., Conclusions: Together, these results indicate that the local increase of IFNα in combination with an anti-PD1 therapy is an effective way to promote efficient and durable innate and adaptive immune responses preventing tumor relapse., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2020
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18. DFU offloading: we know what works, why don't we do it?
- Author
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Penny HL
- Subjects
- Humans, Medicare, United States, Wound Healing, Diabetic Foot therapy, Shoes
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- 2019
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19. Author Correction: Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8 + T cells.
- Author
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Fehlings M, Simoni Y, Penny HL, Becht E, Loh CY, Gubin MM, Ward JP, Wong SC, Schreiber RD, and Newell EW
- Abstract
The original version of this Article omitted a declaration from the competing interests statement, which should have included the following: 'R.D.S. is a cofounder, stock holder, and scientific advisory board member of Jounce Therapeutics and Neon Therapeutics, and a member of the scientific advisory boards of BioLegend, Constellation, Lytix, and NGM. He also received research funding from Janssen and Agios.'. This has now been corrected in both the PDF and HTML versions of the Article.
- Published
- 2018
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20. Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions.
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Evrard M, Kwok IWH, Chong SZ, Teng KWW, Becht E, Chen J, Sieow JL, Penny HL, Ching GC, Devi S, Adrover JM, Li JLY, Liong KH, Tan L, Poon Z, Foo S, Chua JW, Su IH, Balabanian K, Bachelerie F, Biswas SK, Larbi A, Hwang WYK, Madan V, Koeffler HP, Wong SC, Newell EW, Hidalgo A, Ginhoux F, and Ng LG
- Subjects
- Animals, Bone Marrow Cells immunology, CCAAT-Enhancer-Binding Proteins physiology, Cell Lineage, Cell Movement, Cell Proliferation, Cells, Cultured, Gene Expression Profiling, Humans, Mice, Neoplasms, Experimental immunology, Neutrophils immunology, Bone Marrow Cells physiology, Neutrophils physiology
- Abstract
Neutrophils are specialized innate cells that require constant replenishment from proliferative bone marrow (BM) precursors as a result of their short half-life. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined. Using mass cytometry (CyTOF) and cell-cycle-based analysis, we identified three neutrophil subsets within the BM: a committed proliferative neutrophil precursor (preNeu) which differentiates into non-proliferating immature neutrophils and mature neutrophils. Transcriptomic profiling and functional analysis revealed that preNeu require the C/EBPε transcription factor for their generation from the GMP, and their proliferative program is substituted by a gain of migratory and effector function as they mature. preNeus expand under microbial and tumoral stress, and immature neutrophils are recruited to the periphery of tumor-bearing mice. In summary, our study identifies specialized BM granulocytic populations that ensure supply under homeostasis and stress responses., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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21. Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8 + T cells.
- Author
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Fehlings M, Simoni Y, Penny HL, Becht E, Loh CY, Gubin MM, Ward JP, Wong SC, Schreiber RD, and Newell EW
- Subjects
- Animals, Antineoplastic Agents, Immunological pharmacology, CD8-Positive T-Lymphocytes drug effects, CTLA-4 Antigen antagonists & inhibitors, Immunophenotyping, Immunotherapy, Lymphocytes, Tumor-Infiltrating drug effects, Methylcholanthrene toxicity, Mice, Programmed Cell Death 1 Receptor antagonists & inhibitors, Sarcoma, Experimental chemically induced, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes immunology, Lymphocytes, Tumor-Infiltrating immunology, Sarcoma, Experimental immunology
- Abstract
The analysis of neoantigen-specific CD8
+ T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8+ T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice. High-dimensional phenotypic profiling reveals that antigen-specific, tumour-infiltrating T cells are highly heterogeneous. We further show that neoantigen-specific T cells display a different phenotypic profile in mice treated with anti-CTLA-4 or anti-PD-1 immunotherapy, whereas their peripheral counterparts are not affected by the treatments. Our results provide insights into the nature of neoantigen-specific T cells and the effects of checkpoint blockade immunotherapy.Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen-specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations.- Published
- 2017
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22. Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice.
- Author
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Penny HL, Prestwood TR, Bhattacharya N, Sun F, Kenkel JA, Davidson MG, Shen L, Zuniga LA, Seeley ES, Pai R, Choi O, Tolentino L, Wang J, Napoli JL, and Engleman EG
- Subjects
- Adenoma genetics, Adenoma metabolism, Adenoma pathology, Adenomatous Polyposis Coli complications, Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli metabolism, Adenomatous Polyposis Coli pathology, Animals, Cell Transformation, Neoplastic metabolism, Colorectal Neoplasms etiology, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Dendritic Cells immunology, Dendritic Cells metabolism, Enterocolitis drug therapy, Enterocolitis metabolism, Enterocolitis pathology, Humans, Mice, Phenotype, Th17 Cells immunology, Th17 Cells metabolism, Tretinoin metabolism, Tumor Burden, Vitamin A metabolism, Vitamin A Deficiency metabolism, Antineoplastic Agents pharmacology, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic genetics, Enterocolitis genetics, Genes, APC, Tretinoin pharmacology
- Abstract
Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APC
Min/+ mice, a model that recapitulates FAP in most respects. We also investigated the impact of intestinal RA repletion and depletion on tumorigenesis and inflammation in APCMin/+ mice. Tumors from both FAP patients and APCMin/+ mice displayed striking alterations in RA metabolism that resulted in reduced intestinal RA. APCMin/+ mice placed on a vitamin A-deficient diet exhibited further reductions in intestinal RA with concomitant increases in inflammation and tumor burden. Conversely, restoration of RA by pharmacologic blockade of the RA-catabolizing enzyme CYP26A1 attenuated inflammation and diminished tumor burden. To investigate the effect of RA deficiency on the gut immune system, we studied lamina propria dendritic cells (LPDC) because these cells play a central role in promoting tolerance. APCMin/+ LPDCs preferentially induced Th17 cells, but reverted to inducing Tregs following restoration of intestinal RA in vivo or direct treatment of LPDCs with RA in vitro These findings demonstrate the importance of intestinal RA deficiency in tumorigenesis and suggest that pharmacologic repletion of RA could reduce tumorigenesis in FAP patients. Cancer Immunol Res; 4(11); 917-26. ©2016 AACR., (©2016 American Association for Cancer Research.)- Published
- 2016
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23. Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer.
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Bhattacharya N, Yuan R, Prestwood TR, Penny HL, DiMaio MA, Reticker-Flynn NE, Krois CR, Kenkel JA, Pham TD, Carmi Y, Tolentino L, Choi O, Hulett R, Wang J, Winer DA, Napoli JL, and Engleman EG
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Carcinogenesis immunology, Colon immunology, Colon metabolism, Colorectal Neoplasms metabolism, Female, Humans, Mice, Mice, Inbred C57BL, Retinoic Acid 4-Hydroxylase metabolism, Signal Transduction immunology, Up-Regulation immunology, CD8-Positive T-Lymphocytes immunology, Colorectal Neoplasms immunology, Microbiota immunology, Tretinoin metabolism
- Abstract
Although all-trans-retinoic acid (atRA) is a key regulator of intestinal immunity, its role in colorectal cancer (CRC) is unknown. We found that mice with colitis-associated CRC had a marked deficiency in colonic atRA due to alterations in atRA metabolism mediated by microbiota-induced intestinal inflammation. Human ulcerative colitis (UC), UC-associated CRC, and sporadic CRC specimens have similar alterations in atRA metabolic enzymes, consistent with reduced colonic atRA. Inhibition of atRA signaling promoted tumorigenesis, whereas atRA supplementation reduced tumor burden. The benefit of atRA treatment was mediated by cytotoxic CD8(+) T cells, which were activated due to MHCI upregulation on tumor cells. Consistent with these findings, increased colonic expression of the atRA-catabolizing enzyme, CYP26A1, correlated with reduced frequencies of tumoral cytotoxic CD8(+) T cells and with worse disease prognosis in human CRC. These results reveal a mechanism by which microbiota drive colon carcinogenesis and highlight atRA metabolism as a therapeutic target for CRC., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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24. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma.
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Penny HL, Sieow JL, Adriani G, Yeap WH, See Chi Ee P, San Luis B, Lee B, Lee T, Mak SY, Ho YS, Lam KP, Ong CK, Huang RY, Ginhoux F, Rotzschke O, Kamm RD, and Wong SC
- Abstract
Patients with pancreatic ductal adenocarcinoma (PDAC) face a clinically intractable disease with poor survival rates, attributed to exceptionally high levels of metastasis. Epithelial-to-mesenchymal transition (EMT) is pronounced at inflammatory foci within the tumor; however, the immunological mechanisms promoting tumor dissemination remain unclear. It is well established that tumors exhibit the Warburg effect, a preferential use of glycolysis for energy production, even in the presence of oxygen, to support rapid growth. We hypothesized that the metabolic pathways utilized by tumor-infiltrating macrophages are altered in PDAC, conferring a pro-metastatic phenotype. We generated tumor-conditioned macrophages in vitro, in which human peripheral blood monocytes were cultured with conditioned media generated from normal pancreatic or PDAC cell lines to obtain steady-state and tumor-associated macrophages (TAMs), respectively. Compared with steady-state macrophages, TAMs promoted vascular network formation, augmented extravasation of tumor cells out of blood vessels, and induced higher levels of EMT. TAMs exhibited a pronounced glycolytic signature in a metabolic flux assay, corresponding with elevated glycolytic gene transcript levels. Inhibiting glycolysis in TAMs with a competitive inhibitor to Hexokinase II (HK2), 2-deoxyglucose (2DG), was sufficient to disrupt this pro-metastatic phenotype, reversing the observed increases in TAM-supported angiogenesis, extravasation, and EMT. Our results indicate a key role for metabolic reprogramming of tumor-infiltrating macrophages in PDAC metastasis, and highlight the therapeutic potential of using pharmacologics to modulate these metabolic pathways.
- Published
- 2016
- Full Text
- View/download PDF
25. Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid cells at the tumor site.
- Author
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Thoreau M, Penny HL, Tan K, Regnier F, Weiss JM, Lee B, Johannes L, Dransart E, Le Bon A, Abastado JP, Tartour E, Trautmann A, and Bercovici N
- Subjects
- Animals, Cell Communication immunology, Flow Cytometry, Fluorescent Antibody Technique, Mice, Mice, Inbred C57BL, Mice, Knockout, Transcriptome, CD8-Positive T-Lymphocytes immunology, Cancer Vaccines immunology, Lymphocytes, Tumor-Infiltrating immunology, Myeloid Cells immunology, Neoplasms, Experimental immunology
- Abstract
Most cancer immunotherapies under present investigation are based on the belief that cytotoxic T cells are the most important anti-tumoral immune cells, whereas intra-tumoral macrophages would rather play a pro-tumoral role. We have challenged this antagonistic point of view and searched for collaborative contributions by tumor-infiltrating T cells and macrophages, reminiscent of those observed in anti-infectious responses. We demonstrate that, in a model of therapeutic vaccination, cooperation between myeloid cells and T cells is indeed required for tumor rejection. Vaccination elicited an early rise of CD11b+ myeloid cells that preceded and conditioned the intra-tumoral accumulation of CD8+ T cells. Conversely, CD8+ T cells and IFNγ production activated myeloid cells were required for tumor regression. A 4-fold reduction of CD8+ T cell infiltrate in CXCR3KO mice did not prevent tumor regression, whereas a reduction of tumor-infiltrating myeloid cells significantly interfered with vaccine efficiency. We show that macrophages from regressing tumors can kill tumor cells in two ways: phagocytosis and TNFα release. Altogether, our data suggest new strategies to improve the efficiency of cancer immunotherapies, by promoting intra-tumoral cooperation between macrophages and T cells.
- Published
- 2015
- Full Text
- View/download PDF
26. Negative pressure wound therapy with Bio-Dome dressing technology in the treatment of complex wounds: a case series.
- Author
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Penny HL, Spinazzola J, Green A, Rifkah M, Faretta M, Youshaw D, Weaver A, and Zaki P
- Subjects
- Abscess therapy, Aged, Aged, 80 and over, Equipment Design, Female, Humans, Leg Injuries therapy, Male, Middle Aged, Pressure Ulcer therapy, Treatment Outcome, Negative-Pressure Wound Therapy instrumentation, Occlusive Dressings, Wound Healing physiology
- Abstract
The treatment of complex wounds is difficult and not always effective. Various treatment options are used with varying degrees of success. Negative pressure wound therapy (NPWT) is a cost-efficient and effective way to help treat these wounds. The use of a vacuum device applies the negative pressure to the site of the wound and promotes waste removal and increases circulation and tissue formation. While various NPWT systems are currently on the market, we utilised the ConvaTec Engenex® system with Bio-DomeTM technology; however, our case study is not intended to advocate the specific use of this system, but instead focuses on the use of NPWT as a viable option for wound healing. Each of the following case study patients presented with difficult-to-heal wounds that failed traditional therapeutic approaches. Through the use of NPWT, our patients saw major wound size reductions. Each patient exhibited at least a 94% reduction in wound area, wound volume or both.
- Published
- 2014
- Full Text
- View/download PDF
27. Selective case study describing the use of Apligraf on necrobiosis lipoidica associated with diabetes.
- Author
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Penny HL, Faretta M, Rifkah M, Weaver A, Swires A, and Spinazzola J
- Subjects
- Adolescent, Female, Humans, Collagen therapeutic use, Diabetes Mellitus, Type 1 complications, Necrobiosis Lipoidica etiology, Necrobiosis Lipoidica therapy
- Abstract
Necrobiosis lipoidica is a rare skin disease characterised by large, well-demarcated, symmetrical plaques with overlying telangiectasias and atrophic, fibrotic features. The disease is associated with diabetes mellitus (1 in 300 cases), but can also be linked to other diseases such as rheumatoid arthritis. Women are three times more likely to develop necrobiosis lipoidica compared to men. Ulcerations are the most serious type of complications in necrobiosis lipoidica, and they occur most frequently on the legs of patients. However, the aetiology of necrobiosis lipoidica still remains unclear. Although many studies have been conducted in order to determine necrobiosis lipoidica's pathophysiology, a clear and definite path to disease has not been recorded. In this case study, a patient with necrobiosis lipoidica that had been refractory to conventional therapy received treatment with Apligraf® bioengineered wound dressings. Apligraf was shown to be effective in managing the patient's multiple hard-to-heal wounds. It was more successful than previous therapies in achieving granulation tissue formation and wound volume reduction, in addition to being a more rapid form of treatment.
- Published
- 2014
- Full Text
- View/download PDF
28. The use of negative-pressure wound therapy with bio-dome dressing technology in the treatment of complex diabetic wounds.
- Author
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Penny HL, Dyson M, Spinazzola J, Green A, Faretta M, and Meloy G
- Subjects
- Adult, Combined Modality Therapy, Female, Humans, Male, Middle Aged, Occlusive Dressings, Treatment Outcome, Biological Dressings, Debridement, Diabetic Foot therapy, Negative-Pressure Wound Therapy methods, Wound Healing
- Published
- 2010
- Full Text
- View/download PDF
29. The use of acticoat moisture control for the successful treatment of diabetic ulcers.
- Author
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Penny HL, Webster N, Sullivan R, Spinazzola J, Green A, and Faretta M
- Subjects
- Aged, Anti-Bacterial Agents therapeutic use, Bandages, Diabetic Foot drug therapy, Diabetic Nephropathies complications, Diabetic Nephropathies therapy, Humans, Male, Middle Aged, Risk Factors, Wound Healing, Diabetes Mellitus, Type 2 complications, Diabetic Foot therapy, Polyesters, Polyethylenes
- Published
- 2009
- Full Text
- View/download PDF
30. A multidisciplinary approach to a possible limb-threatening infection.
- Author
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Penny HL, Webster N, Sullivan R, and Spinazzola J
- Subjects
- Combined Modality Therapy, Diabetic Foot drug therapy, Diabetic Foot surgery, Female, Humans, Middle Aged, Staphylococcal Infections drug therapy, Staphylococcal Infections surgery, Wound Infection drug therapy, Wound Infection surgery, Diabetic Foot therapy, Limb Salvage, Methicillin-Resistant Staphylococcus aureus, Patient Care Team, Staphylococcal Infections therapy, Wound Infection therapy
- Published
- 2008
- Full Text
- View/download PDF
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