1. Comprehensive multiplexed autoantibody profiling of patients with advanced urothelial cancer.
- Author
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Ravi P, Freeman D, Thomas J, Ravi A, Mantia C, McGregor BA, Berchuck JE, Epstein I, Budde P, Ahangarian Abhari B, Rupieper E, Gajewski J, Schubert AS, Kilian AL, Bräutigam M, Zucht HD, and Sonpavde G
- Subjects
- Male, Humans, Aged, Antigens, Neoplasm, Membrane Proteins, Jumonji Domain-Containing Histone Demethylases, Autoantibodies, Carcinoma, Transitional Cell
- Abstract
Background: Comprehensive profiling of autoantibodies (AAbs) in metastatic urothelial cancer (mUC) has not been performed to date. This may aid in diagnosis of UC, uncover novel therapeutic targets in this disease as well as identify associations between AAbs and response and toxicity to systemic therapies., Methods: We used serum from patients with mUC collected prior to and after systemic therapy (immune checkpoint inhibitor (ICI) or platinum-based chemotherapy (PBC)) at Dana-Farber Cancer Institute. 38 age-matched and sex-matched healthy controls (HCs) from healthy blood donors were also evaluated. The SeroTag immuno-oncology discovery array (Oncimmune) was used, with quantification of the AAb reactivity toward 1132 antigens. Bound AAbs were detected using an anti-immunoglobulin G-specific detection antibody conjugated to the fluorescent reporter dye phycoerythrin. The AAb reactivity was reported as the median fluorescence intensity for each color and sample using a Luminex FlexMAP3D analyzer. Clinical outcomes of interest included radiographic response and development of immune-related adverse events (irAEs). Significance analysis of microarray was used to compare mUC versus HC and radiographic response. Associations with irAE were evaluated using a logistic regression model. P<0.05 was considered statistically significant., Results: 66 patients were included with a median age of 68 years; 54 patients (82%) received ICI and 12 patients (18%) received PBC. Compared with HCs, AAbs against the cancer/testis antigens (CTAG1B, CTAG2, MAGEB18), HSPA1A, TP53, KRAS, and FGFR3 were significantly elevated in patients with mUC. AAbs against BRCA2, TP53, and CTNBB1 were associated with response, and those against BICD2 and UACA were associated with resistance to ICI therapy. AAbs against MITF, CDH3, and KDM4A were associated with development of irAEs in patient who received an ICI. A higher variance in pre-to-post treatment fold change in AAb levels was seen in patients treated with ICI versus PBC and was associated with response to ICI., Conclusions: This is the first report of comprehensive AAb profiling of patients with mUC and identified key AAbs that were elevated in patients with mUC versus HCs as well as AAbs associated with therapeutic response to ICI. These findings are hypothesis generating and further mechanistic studies evaluating humoral immunity in UC are required., Competing Interests: Competing interests: PR: research funding (to institution) from Lilly, Bayer, and Telix and speaker’s fees from OncLive. BAM: consulting fees from BMS, Eisai, Exelixis, Gilead, Pfizer, and Seagen and research funding (to institution) from BMS, Exelixis, Pfizer, and Seagen. JEB: speaker honoraria from Guardant Health; consulting fees from Guardant Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo, and JucaBio; equity in Cityblock Health, Genome Medical, Oncotect, Precede, TracerDx, and Musculo; and filed an institutional patent on methods to detect neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis. GS: in advisory board of BMS, Genentech, EMD Serono, Merck, AstraZeneca, Sanofi, Seattle Genetics/Astellas, AstraZeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma, PrecisCa, and Primum; in consultant/scientific advisory board of Suba Therapeutics, Syapse, Servier, Merck, and Syncorp; received research support (to institution) from Sanofi, AstraZeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, and Jazz Therapeutics; received speaker's fees from Seagen, Gilead, Natera, Exelixis, Janssen, Bayer, and Aveo; received data safety monitoring committee honorarium from Mereo; received writing/editor fees from UpToDate, Practice Update, and Onviv; and spouse employed in Myriad. PB, BAA, ER, JG, AS-S, ALK, MB, and H-DZ are employees of Oncimmune., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
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