دورية أكاديمية
أعرض في EDS

Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer.

التفاصيل البيبلوغرافية
العنوان: Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer.
المؤلفون: Amit U; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.; Department of Radiation Oncology, Tel Aviv Medical Center, Tel Aviv 64239, Israel., Uslu U; Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104., Verginadis II; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Kim MM; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Motlagh SAO; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Diffenderfer ES; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Assenmacher CA; Department of Pathobiology, School of Veterinary Medicine, Comparative Pathology Core, University of Pennsylvania, Philadelphia, PA 19104., Bicher S; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Atoche SJ; Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104., Ben-Josef E; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Young RM; Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104., June CH; Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104.; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104., Koumenis C; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
المصدر: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jul 30; Vol. 121 (31), pp. e2403002121. Date of Electronic Publication: 2024 Jul 24.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : National Academy of Sciences
مواضيع طبية MeSH: Mesothelin* , Pancreatic Neoplasms*/therapy , Pancreatic Neoplasms*/immunology , Pancreatic Neoplasms*/radiotherapy , Pancreatic Neoplasms*/pathology , GPI-Linked Proteins*/metabolism , GPI-Linked Proteins*/immunology , Receptors, Chimeric Antigen*/immunology , Receptors, Chimeric Antigen*/metabolism , Immunotherapy, Adoptive*/methods , Tumor Microenvironment*/immunology , Carcinoma, Pancreatic Ductal*/therapy , Carcinoma, Pancreatic Ductal*/immunology , Carcinoma, Pancreatic Ductal*/radiotherapy , Carcinoma, Pancreatic Ductal*/pathology, Animals ; Mice ; Humans ; Cell Line, Tumor ; Proton Therapy/methods ; Combined Modality Therapy ; T-Lymphocytes/immunology ; Female
مستخلص: Pancreatic ductal adenocarcinoma (PDAC) represents a challenge in oncology, with limited treatment options for advanced-stage patients. Chimeric antigen receptor T cell (CAR T) therapy targeting mesothelin (MSLN) shows promise, but challenges such as the hostile immunosuppressive tumor microenvironment (TME) hinder its efficacy. This study explores the synergistic potential of combining proton radiation therapy (RT) with MSLN-targeting CAR T therapy in a syngeneic PDAC model. Proton RT significantly increased MSLN expression in tumor cells and caused a significant increase in CAR T cell infiltration into tumors. The combination therapy reshaped the immunosuppressive TME, promoting antitumorigenic M1 polarized macrophages and reducing myeloid-derived suppressor cells (MDSC). In a flank PDAC model, the combination therapy demonstrated superior attenuation of tumor growth and improved survival compared to individual treatments alone. In an orthotopic PDAC model treated with image-guided proton RT, tumor growth was significantly reduced in the combination group compared to the RT treatment alone. Further, the combination therapy induced an abscopal effect in a dual-flank tumor model, with increased serum interferon-γ levels and enhanced proliferation of extratumoral CAR T cells. In conclusion, combining proton RT with MSLN-targeting CAR T therapy proves effective in modulating the TME, enhancing CAR T cell trafficking, and exerting systemic antitumor effects. Thus, this combinatorial approach could present a promising strategy for improving outcomes in unresectable PDAC.
Competing Interests: Competing interests statement:R.M.Y. and C.H.J. are inventors of patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receive license revenue from such licenses. C.H.J. is an inventor on patents and/or patent applications licensed to Kite Pharma, Capstan Therapeutics. Dispatch Therapeutics and BlueWhale Bio. C.H.J. is a member of the scientific advisory boards of AC Immune, BluesphereBio, BlueWhale Bio, Cabaletta, Carisma, Cartography, Cellares, Celldex, Decheng, Poseida, Replay Bio, Verismo, ViTToria, and WIRB-Copernicus. No competing interests were declared by U.A., U.U., I.I.V., M.M.K., S.A.O.M., E.S.D., C.-A.A., S.B., S.J.A., E.B.-J., and C.K.
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معلومات مُعتمدة: P30 CA016520 United States CA NCI NIH HHS; S10 OD023465 United States OD NIH HHS; Postdoctoral training Tel Aviv Medical Center; Mildred-Scheel Postdoctoroal Fellowship Deutsche Krebshilfe (German Cancer Aid)
فهرسة مساهمة: Keywords: CAR T cells; pancreatic cancer; radiotherapy
المشرفين على المادة: J27WDC343N (Mesothelin)
0 (GPI-Linked Proteins)
0 (Receptors, Chimeric Antigen)
0 (Msln protein, mouse)
0 (MSLN protein, human)
تواريخ الأحداث: Date Created: 20240724 Date Completed: 20240725 Latest Revision: 20240804
رمز التحديث: 20240804
مُعرف محوري في PubMed: PMC11294999
DOI: 10.1073/pnas.2403002121
PMID: 39047033
قاعدة البيانات: MEDLINE
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.2403002121