1. Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma.
- Author
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Cebon JS, Gore M, Thompson JF, Davis ID, McArthur GA, Walpole E, Smithers M, Cerundolo V, Dunbar PR, MacGregor D, Fisher C, Millward M, Nathan P, Findlay MPN, Hersey P, Evans TRJ, Ottensmeier CH, Marsden J, Dalgleish AG, Corrie PG, Maria M, Brimble M, Williams G, Winkler S, Jackson HM, Endo-Munoz L, Tutuka CSA, Venhaus R, Old LJ, Haack D, Maraskovsky E, Behren A, and Chen W
- Subjects
- Adjuvants, Immunologic adverse effects, Antigens, Neoplasm genetics, Antigens, Neoplasm immunology, Biopsy, Cancer Vaccines adverse effects, Cancer Vaccines genetics, Cancer Vaccines immunology, Chemotherapy, Adjuvant adverse effects, Chemotherapy, Adjuvant methods, Cholesterol adverse effects, Dermatologic Surgical Procedures, Disease-Free Survival, Double-Blind Method, Drug Combinations, Female, Follow-Up Studies, Humans, Immunogenicity, Vaccine, Male, Melanoma diagnosis, Melanoma immunology, Melanoma mortality, Membrane Proteins genetics, Membrane Proteins immunology, Middle Aged, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local prevention & control, Neoplasm Staging, Phospholipids adverse effects, Saponins adverse effects, Skin pathology, Skin Neoplasms diagnosis, Skin Neoplasms immunology, Skin Neoplasms mortality, Adjuvants, Immunologic administration & dosage, Cancer Vaccines administration & dosage, Cholesterol administration & dosage, Melanoma therapy, Neoplasm Recurrence, Local epidemiology, Phospholipids administration & dosage, Saponins administration & dosage, Skin Neoplasms therapy
- Abstract
Background: To compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence., Methods: Participants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity., Results: The ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (pā¤0.0001) and NY-ESO-1-specific CD4
+ and CD8+ responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+ /Human Leukocyte Antigen (HLA) class I+ double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants., Conclusions: The vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse., Competing Interests: Competing interests: IDD, WC and JSC are coinventors on International Patent Application No: PCT/US2004/032147 ('In vivo efficacy of NY-ESO-1 plus adjuvant'). JFT has received honoraria for advisory board participation from Merck Sharpe Dohme Australia and Bristol-Myers Squibb Australia. He has also received honoraria and travel expenses from GSK and Provectus Inc. GAM has received research funding from Pfizer, Celgene and Ventana; acted as a consultant/advisor for Provectus; and received travel funding from Roche and Novartis. EW serves as consultant/advisor for Eli Lilly and Merck Serono, and has received travel funding from Roche. PN has received non-financial support from Novartis, as well as personal fees from Novartis and GlaxoSmithKline for advisory board participation. MPNF serves as consultant for, and has received travel funding from Sirtex. PGC has received payment for attending BMS advisory boards. RV declares stock or other ownership at Agenus, Dynavax and Soligenix. EM is an employee of, and holds stock in CSL Limited. ID is supported by an NHMRC Practitioner Fellowship (APP1102604). PRD is a founder and shareholder in SapVax which provides research funding to his laboratory., (© 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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