دورية أكاديمية
أعرض في EDS

Co-expression patterns of chimeric antigen receptor (CAR)-T cell target antigens in primary and recurrent ovarian cancer.

التفاصيل البيبلوغرافية
العنوان: Co-expression patterns of chimeric antigen receptor (CAR)-T cell target antigens in primary and recurrent ovarian cancer.
المؤلفون: Banville AC; Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Wouters MCA; Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada., Oberg AL; Division of Biomedical Statistics & Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA., Goergen KM; Division of Biomedical Statistics & Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA., Maurer MJ; Division of Biomedical Statistics & Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA., Milne K; Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada., Ashkani J; Genome Sciences Centre, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada., Field E; Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada., Ghesquiere C; Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada., Jones SJM; Genome Sciences Centre, BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada., Block MS; Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA., Nelson BH; Deeley Research Centre, BC Cancer, Victoria, BC V8R 6V5, Canada; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8P 3E6, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada. Electronic address: bnelson@bccrc.ca.
المصدر: Gynecologic oncology [Gynecol Oncol] 2021 Feb; Vol. 160 (2), pp. 520-529. Date of Electronic Publication: 2020 Dec 17.
نوع المنشور: Journal Article; Observational Study; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Academic Press Country of Publication: United States NLM ID: 0365304 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-6859 (Electronic) Linking ISSN: 00908258 NLM ISO Abbreviation: Gynecol Oncol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: New York, Academic Press.
مواضيع طبية MeSH: Antigens, Neoplasm/*metabolism , Carcinoma, Ovarian Epithelial/*immunology , Immunotherapy, Adoptive/*methods , Neoplasm Recurrence, Local/*immunology , Ovarian Neoplasms/*immunology , Receptors, Chimeric Antigen/*metabolism, Antigens, Neoplasm/immunology ; CA-125 Antigen/immunology ; CA-125 Antigen/metabolism ; Carcinoma, Ovarian Epithelial/pathology ; Carcinoma, Ovarian Epithelial/therapy ; Female ; Folate Receptor 1/immunology ; Folate Receptor 1/metabolism ; GPI-Linked Proteins/immunology ; GPI-Linked Proteins/metabolism ; Gene Expression Profiling ; Humans ; Lymphocytes, Tumor-Infiltrating/immunology ; Membrane Proteins/immunology ; Membrane Proteins/metabolism ; Mesothelin ; Neoplasm Recurrence, Local/pathology ; Neoplasm Recurrence, Local/therapy ; Ovarian Neoplasms/pathology ; Ovarian Neoplasms/therapy ; Ovary/immunology ; Ovary/pathology ; Receptors, Chimeric Antigen/immunology
مستخلص: Objective: Chimeric antigen receptor (CAR)-T cell strategies ideally target a surface antigen that is exclusively and uniformly expressed by tumors; however, no such antigen is known for high-grade serous ovarian carcinoma (HGSC). A potential solution involves combinatorial antigen targeting with AND or OR logic-gating. Therefore, we investigated co-expression of CA125, Mesothelin (MSLN) and Folate Receptor alpha (FOLRA) on individual tumor cells in HGSC.
Methods: RNA expression of CA125, MSLN, and FOLR1 was assessed using TCGA (HGSC) and GTEx (healthy tissues) databases. Antigen expression profiles and CD3+, CD8+ and CD20+ tumor-infiltrating lymphocyte (TIL) patterns were assessed in primary and recurrent HGSC by multiplex immunofluorescence and immunohistochemistry.
Results: At the transcriptional level, each antigen was overexpressed in >90% of cases; however, MSLN and FOLR1 showed substantial expression in healthy tissues. At the protein level, CA125 was expressed by the highest proportion of cases and tumor cells per case, followed by MSLN and FOLRA. The most promising pairwise combination was CA125 and/or MSLN (OR gate), with 51.9% of cases containing ≥90% of tumor cells expressing one or both antigens. In contrast, only 5.8% of cases contained ≥90% of tumor cells co-expressing CA125 and MSLN (AND gate). Antigen expression patterns showed modest correlations with TIL. Recurrent tumors retained expression of all three antigens and showed increased TIL densities.
Conclusions: An OR-gated CAR-T cell strategy against CA125 and MSLN would target the majority of tumor cells in most cases. Antigen expression and T-cell infiltration patterns are favorable for this strategy in primary and recurrent disease.
Competing Interests: Declaration of Competing Interest MSB discloses involvement in clinical trials supported by the following companies: Merck, Marker Therapeutics, Transgene, Immune Design, Bristol-Myers Squib, Genentech, and Pharmacyclics. MM discloses involvement with the following companies: Celgene, Genentech, Kite Pharma, Morphosys, Nanostring, and Pfizer. BHN discloses involvement with Virogin Biotech, Akamara Therapeutics, IMV Technologies and Innovakine Therapuetics. None of these relationships influence or are influenced by the results presented in this study.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
معلومات مُعتمدة: MOP 142436 Canada CIHR; MFE 158087 Canada CIHR; P50 CA136393 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: Antigens; Chimeric antigen receptor (CAR)-T cell therapy; High-grade serous ovarian carcinoma; Immunotherapy; Ovarian cancer; Tumor-infiltrating lymphocytes
المشرفين على المادة: 0 (Antigens, Neoplasm)
0 (CA-125 Antigen)
0 (FOLR1 protein, human)
0 (Folate Receptor 1)
0 (GPI-Linked Proteins)
0 (MSLN protein, human)
0 (MUC16 protein, human)
0 (Membrane Proteins)
0 (Receptors, Chimeric Antigen)
J27WDC343N (Mesothelin)
تواريخ الأحداث: Date Created: 20201221 Date Completed: 20210630 Latest Revision: 20211204
رمز التحديث: 20221213
DOI: 10.1016/j.ygyno.2020.12.005
PMID: 33342620
قاعدة البيانات: MEDLINE
الوصف
تدمد:1095-6859
DOI:10.1016/j.ygyno.2020.12.005