المؤلفون: Lim TL; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Pietrofesa RA; Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Arguiri E; Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Koumenis C; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Feigenberg S; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Simone CB 2nd; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Rengan R; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Cengel K; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Levin WP; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Christofidou-Solomidou M; Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Berman AT; Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

المصدر: Journal of alternative and complementary medicine (New York, N.Y.) [J Altern Complement Med] 2021 Oct; Vol. 27 (10), pp. 824-831. Date of Electronic Publication: 2021 Jun 23.

نوع المنشور: Clinical Trial, Phase II; Journal Article; Randomized Controlled Trial

بيانات الدورية: Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 9508124 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-7708 (Electronic) Linking ISSN: 10755535 NLM ISO Abbreviation: J Altern Complement Med Subsets: MEDLINE

مواضيع طبية MeSH: Carcinoma, Non-Small-Cell Lung*/drug therapy , Flax* , Lung Neoplasms*/drug therapy , Lung Neoplasms*/radiotherapy , Radiation Injuries*, Antineoplastic Combined Chemotherapy Protocols ; Chemoradiotherapy ; Combined Modality Therapy ; Humans

مستخلص: Background: Thoracic radiotherapy is complicated by acute radiation-induced adverse events such as radiation pneumonitis (RP) and radiation esophagitis (RE). Based on preclinical work and a randomized pilot trial from our laboratory, this single-arm phase II trial investigated administering flaxseed as a radioprotector in patients receiving definitive chemoradiation for nonsmall cell lung cancer (NSCLC). Methods: Between June 2015 and February 2018, 33 patients with locally advanced or metastatic NSCLC with planned definitive chemoradiation were enrolled. Finely-ground Linum usitatissimum L. (Linaceae; flaxseed or linseed) in 40-g packets were provided for daily consumption in any patient-desired formulation 1 week before radiotherapy and throughout radiotherapy as tolerated. The primary outcomes were overall adverse events, with particular focus on Grade ≥3 RP, and flaxseed tolerability. Adverse events were graded according to CTCAE v4.0. Results: Of the 33 patients enrolled, 5 patients (15%) did not receive chemoradiation, 4 (12%) withdrew promptly after enrollment, 4 (12%) did not return a flaxseed consumption log, and 1 patient had irritable bowel syndrome (3%). The remaining 19 patients (57%) had chemoradiation and flaxseed ingestion with a mean completion and standard deviation of the intended flaxseed course of 62% ± 8.3%. Nine (50%) of these 19 patients reported difficulties with flaxseed consumption, citing nausea, constipation, odynophagia, or poor taste or texture. One patient (5%), with unverifiable flaxseed consumption, developed Grade 3 RP. There were no cases of Grade 2 RP. Six patients (32%) developed Grade 2 RE, but no patients developed Grade ≥3 RE. Median overall and progression-free survival were 31 and 12 months, respectively. Conclusions: Despite the low incidence of acute radiation-induced complications reported, significant treatment-related gastrointestinal toxicities and subsequently low flaxseed tolerability inhibit accurate determination of flaxseed effect in patients receiving concurrent thoracic chemoradiation. Thus, further investigations should focus on optimizing flaxseed formulation for improved tolerability and evaluation. ClinicalTrials.gov ID: NCT02475330.

المؤلفون: Pierini S; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Mishra A; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Perales-Linares R; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Uribe-Herranz M; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Beghi S; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Giglio A; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Pustylnikov S; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Costabile F; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Rafail S; Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Amici A; School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Marche, Italy., Facciponte JG; Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Koumenis C; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Facciabene A; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA facciabe@pennmedicine.upenn.edu.; Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2021 Feb; Vol. 9 (2).

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural

بيانات الدورية: Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE

مواضيع طبية MeSH: Antigens, CD/*metabolism , Colorectal Neoplasms/*therapy , Immune Checkpoint Inhibitors/*administration & dosage , Lung Neoplasms/*therapy , Neoplasm Proteins/*metabolism , Vaccines, DNA/*administration & dosage, Adenoviridae/genetics ; Animals ; Cancer Vaccines/administration & dosage ; Cancer Vaccines/pharmacology ; Cell Line, Tumor ; Colorectal Neoplasms/diagnostic imaging ; Combined Modality Therapy ; Immune Checkpoint Inhibitors/pharmacology ; Lung Neoplasms/diagnostic imaging ; Mice ; Radiation Dose Hypofractionation ; Treatment Outcome ; Ultrasonography, Doppler ; Vaccines, DNA/pharmacology ; Xenograft Model Antitumor Assays

مستخلص: Background: Tumor endothelial marker 1 (TEM1) is a protein expressed in the tumor-associated endothelium and/or stroma of various types of cancer. We previously demonstrated that immunization with a plasmid-DNA vaccine targeting TEM1 reduced tumor progression in three murine cancer models. Radiation therapy (RT) is an established cancer modality used in more than 50% of patients with solid tumors. RT can induce tumor-associated vasculature injury, triggering immunogenic cell death and inhibition of the irradiated tumor and distant non-irradiated tumor growth (abscopal effect). Combination treatment of RT with TEM1 immunotherapy may complement and augment established immune checkpoint blockade.
Methods: Mice bearing bilateral subcutaneous CT26 colorectal or TC1 lung tumors were treated with a novel heterologous TEM1-based vaccine, in combination with RT, and anti-programmed death-ligand 1 (PD-L1) antibody or combinations of these therapies, tumor growth of irradiated and abscopal tumors was subsequently assessed. Analysis of tumor blood perfusion was evaluated by CD31 staining and Doppler ultrasound imaging. Immunophenotyping of peripheral and tumor-infiltrating immune cells as well as functional analysis was analyzed by flow cytometry, ELISpot assay and adoptive cell transfer (ACT) experiments.
Results: We demonstrate that addition of RT to heterologous TEM1 vaccination reduces progression of CT26 and TC1 irradiated and abscopal distant tumors as compared with either single treatment. Mechanistically, RT increased major histocompatibility complex class I molecule (MHCI) expression on endothelial cells and improved immune recognition of the endothelium by anti-TEM1 T cells with subsequent severe vascular damage as measured by reduced microvascular density and tumor blood perfusion. Heterologous TEM1 vaccine and RT combination therapy boosted tumor-associated antigen (TAA) cross-priming (ie, anti-gp70) and augmented programmed cell death protein 1 (PD-1)/PD-L1 signaling within CT26 tumor. Blocking the PD-1/PD-L1 axis in combination with dual therapy further increased the antitumor effect and gp70-specific immune responses. ACT experiments show that anti-gp70 T cells are required for the antitumor effects of the combination therapy.
Conclusion: Our findings describe novel cooperative mechanisms between heterologous TEM1 vaccination and RT, highlighting the pivotal role that TAA cross-priming plays for an effective antitumor strategy. Furthermore, we provide rationale for using heterologous TEM1 vaccination and RT as an add-on to immune checkpoint blockade as triple combination therapy into early-phase clinical trials.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

المؤلفون: Gui J; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Zahedi F; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Ortiz A; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Cho C; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Katlinski KV; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Alicea-Torres K; Immunology, Microenvironment, and Metastasis Program, Wistar Institute, Philadelphia, PA, USA., Li J; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Todd L; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Zhang H; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Beiting DP; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Sander C; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Kirkwood JM; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Snow BE; The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Wakeham AC; The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Mak TW; The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Diehl JA; Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Koumenis C; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Ryeom SW; Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Stanger BZ; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Puré E; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA., Gabrilovich DI; Immunology, Microenvironment, and Metastasis Program, Wistar Institute, Philadelphia, PA, USA., Fuchs SY; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. syfuchs@upenn.edu.

المصدر: Nature cancer [Nat Cancer] 2020 Jun; Vol. 1 (6), pp. 603-619. Date of Electronic Publication: 2020 May 25.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101761119 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2662-1347 (Electronic) Linking ISSN: 26621347 NLM ISO Abbreviation: Nat Cancer

مواضيع طبية MeSH: Lung Neoplasms*/pathology , Signal Transduction*, Fibroblasts/pathology ; Humans ; Lung/pathology ; Protein Kinases

مستخلص: Primary tumor-derived factors (TDFs) act upon normal cells to generate a pre-metastatic niche, which promotes colonization of target organs by disseminated malignant cells. Here we report that TDFs-induced activation of the p38α kinase in lung fibroblasts plays a critical role in the formation of a pre-metastatic niche in the lungs and subsequent pulmonary metastases. Activation of p38α led to inactivation of type I interferon signaling and stimulation of expression of fibroblast activation protein (FAP). FAP played a key role in remodeling of the extracellular matrix as well as inducing the expression of chemokines that enable lung infiltration by neutrophils. Increased activity of p38 in normal cells was associated with metastatic disease and poor prognosis in human melanoma patients whereas inactivation of p38 suppressed lung metastases. We discuss the p38α-driven mechanisms stimulating the metastatic processes and potential use of p38 inhibitors in adjuvant therapy of metastatic cancers.
Competing Interests: Competing Interests Statement The authors have declared that no conflict of interest exists

المؤلفون: Ortiz A; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Gui J; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Zahedi F; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Yu P; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Cho C; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Bhattacharya S; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Carbone CJ; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Yu Q; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Katlinski KV; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Katlinskaya YV; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Handa S; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Haas V; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Volk SW; Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Brice AK; Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Wals K; Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK., Matheson NJ; Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK., Antrobus R; Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK., Ludwig S; Departments of Pathology, Immunology, and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Otorhinolaryngology, University of Duisburg-Essen, Duisburg, Germany., Whiteside TL; Departments of Pathology, Immunology, and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Sander C; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Tarhini AA; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Kirkwood JM; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA., Lehner PJ; Department of Medicine, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK., Guo W; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA., Rui H; Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA., Minn AJ; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Koumenis C; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Diehl JA; Department of Biochemistry, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA., Fuchs SY; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: syfuchs@upenn.edu.

المصدر: Cancer cell [Cancer Cell] 2019 Jan 14; Vol. 35 (1), pp. 33-45.e6.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.

بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 101130617 Publication Model: Print Cited Medium: Internet ISSN: 1878-3686 (Electronic) Linking ISSN: 15356108 NLM ISO Abbreviation: Cancer Cell Subsets: MEDLINE

مواضيع طبية MeSH: Extracellular Vesicles/*metabolism , Lung Neoplasms/*secondary , Melanoma/*pathology , Receptor, Interferon alpha-beta/*metabolism , Steroid Hydroxylases/*metabolism, Animals ; Cell Line, Tumor ; Disease Progression ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Knockout Techniques ; Humans ; Interferons/pharmacology ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Melanoma/metabolism ; Mice ; Neoplasm Metastasis ; Oxysterols/metabolism ; Reserpine/administration & dosage ; Reserpine/pharmacology ; Steroid Hydroxylases/genetics ; THP-1 Cells

مستخلص: Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Low CH25H levels in leukocytes from melanoma patients correlated with poor prognosis. Mice incapable of downregulating the IFN receptor and Ch25h were resistant to TEV uptake, TEV-induced pre-metastatic niche, and melanoma lung metastases; however, ablation of Ch25h reversed these phenotypes. An anti-hypertensive drug, reserpine, suppressed TEV uptake and disrupted TEV-induced formation of the pre-metastatic niche and melanoma lung metastases. These results suggest the importance of CH25H in defense against education of normal cells by TEV and argue for the use of reserpine in adjuvant melanoma therapy.
(Copyright © 2018 Elsevier Inc. All rights reserved.)

المؤلفون: Maity A; Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, 19104-6072, USA. maity@uphs.upenn.edu, Koumenis C

المصدر: Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2010 Oct 01; Vol. 16 (19), pp. 4685-7. Date of Electronic Publication: 2010 Sep 21.

نوع المنشور: Comment; Journal Article

بيانات الدورية: Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE

مواضيع طبية MeSH: Tumor Microenvironment*, Lung Neoplasms/*metabolism , Lung Neoplasms/*pathology, Animals ; Cell Hypoxia ; Cell Line, Tumor ; Humans

مستخلص: Hypoxia is a clinically important component of the tumor microenvironment because it adversely affects progression, metastasis, response to chemoradiation therapy, and overall patient survival. Here, we describe how different animal tumor models of lung cancer can yield surprisingly different hypoxic profiles.
(©2010 AACR.)