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

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2020 Apr 23

PMID 32317292

Citations 16

Authors

Jonathan S Cebon

Martin Gore

John F Thompson

Ian D Davis

Grant A McArthur

Euan Walpole

Mark Smithers

Vincenzo Cerundolo

P Rod Dunbar

Duncan MacGregor

Cyril Fisher

Michael Millward

Paul Nathan

Michael P N Findlay

Peter Hersey

T R Jeffry Evans

Christian Hermann Ottensmeier

Jeremy Marsden

Angus G Dalgleish

Pippa G Corrie

Marples Maria

Margaret Brimble

Geoff Williams

Sintia Winkler

Heather M Jackson

Liliana Endo-Munoz

Candani S A Tutuka

Ralph Venhaus

Lloyd J Old

Dennis Haack

Eugene Maraskovsky

Andreas Behren

Weisan Chen

Affiliations

Soon will be listed here.

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 (p≤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.

Citing Articles

Intratumoral administration of mRNA COVID-19 vaccine delays melanoma growth in mice.

Boehm D, Landreth K, Kilic E, Lee K, Misra B, Bobbala S Sci Rep. 2025; 15(1):5337.

PMID: 39948424 PMC: 11825918. DOI: 10.1038/s41598-025-89930-0.

Multi-omics analysis of overexpressed tumor-associated proteins: gene expression, immunopeptide presentation, and antibody response in oropharyngeal squamous cell carcinoma, with a focus on cancer-testis antigens.

Kors T, Meier M, Muhlenbruch L, Betzler A, Oliveri F, Bens M Front Immunol. 2024; 15:1408173.

PMID: 39136024 PMC: 11317303. DOI: 10.3389/fimmu.2024.1408173.

Single-cell sequencing unveils extensive intratumoral heterogeneity of cancer/testis antigen expression in melanoma and lung cancer.

Traynor S, Jakobsen M, Green T, Komic H, Palarasah Y, Pedersen C J Immunother Cancer. 2024; 12(6).

PMID: 38886115 PMC: 11184195. DOI: 10.1136/jitc-2023-008759.

The quest for nanoparticle-powered vaccines in cancer immunotherapy.

Sun Z, Zhao H, Ma L, Shi Y, Ji M, Sun X J Nanobiotechnology. 2024; 22(1):61.

PMID: 38355548 PMC: 10865557. DOI: 10.1186/s12951-024-02311-z.

Cancer Vaccine Therapeutics: Limitations and Effectiveness-A Literature Review.

Kaczmarek M, Poznanska J, Fechner F, Michalska N, Paszkowska S, Napierala A Cells. 2023; 12(17).

PMID: 37681891 PMC: 10486481. DOI: 10.3390/cells12172159.

References

Nicholaou T, Chen W, Davis I, Jackson H, Dimopoulos N, Barrow C . Immunoediting and persistence of antigen-specific immunity in patients who have previously been vaccinated with NY-ESO-1 protein formulated in ISCOMATRIX™. Cancer Immunol Immunother. 2011; 60(11):1625-37. PMC: 11028944. DOI: 10.1007/s00262-011-1041-3. View

Jager E, Karbach J, Gnjatic S, Neumann A, Bender A, Valmori D . Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients. Proc Natl Acad Sci U S A. 2006; 103(39):14453-8. PMC: 1570182. DOI: 10.1073/pnas.0606512103. View

Valmori D, Dutoit V, Ayyoub M, Rimoldi D, Guillaume P, Lienard D . Simultaneous CD8+ T cell responses to multiple tumor antigen epitopes in a multipeptide melanoma vaccine. Cancer Immun. 2003; 3:15. View

Ennis F, Cruz J, Jameson J, Klein M, Burt D, Thipphawong J . Augmentation of human influenza A virus-specific cytotoxic T lymphocyte memory by influenza vaccine and adjuvanted carriers (ISCOMS). Virology. 1999; 259(2):256-61. DOI: 10.1006/viro.1999.9765. View

STOCKERT E, Jager E, Chen Y, Scanlan M, Gout I, Karbach J . A survey of the humoral immune response of cancer patients to a panel of human tumor antigens. J Exp Med. 1998; 187(8):1349-54. PMC: 2212223. DOI: 10.1084/jem.187.8.1349. View

Nicholaou T, Ebert L, Davis I, McArthur G, Jackson H, Dimopoulos N . Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma. Clin Cancer Res. 2009; 15(6):2166-73. DOI: 10.1158/1078-0432.CCR-08-2484. View

Shackleton M, Davis I, Hopkins W, Jackson H, Dimopoulos N, Tai T . The impact of imiquimod, a Toll-like receptor-7 ligand (TLR7L), on the immunogenicity of melanoma peptide vaccination with adjuvant Flt3 ligand. Cancer Immun. 2004; 4:9. View

Zeng G, Wang X, Robbins P, Rosenberg S, Wang R . CD4(+) T cell recognition of MHC class II-restricted epitopes from NY-ESO-1 presented by a prevalent HLA DP4 allele: association with NY-ESO-1 antibody production. Proc Natl Acad Sci U S A. 2001; 98(7):3964-9. PMC: 31162. DOI: 10.1073/pnas.061507398. View

Therasse P, Arbuck S, Eisenhauer E, Wanders J, Kaplan R, Rubinstein L . New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000; 92(3):205-16. DOI: 10.1093/jnci/92.3.205. View

10.

Dunn G, Old L, Schreiber R . The three Es of cancer immunoediting. Annu Rev Immunol. 2004; 22:329-60. DOI: 10.1146/annurev.immunol.22.012703.104803. View

11.

Hasegawa K, Noguchi Y, Koizumi F, Uenaka A, Tanaka M, Shimono M . In vitro stimulation of CD8 and CD4 T cells by dendritic cells loaded with a complex of cholesterol-bearing hydrophobized pullulan and NY-ESO-1 protein: Identification of a new HLA-DR15-binding CD4 T-cell epitope. Clin Cancer Res. 2006; 12(6):1921-7. DOI: 10.1158/1078-0432.CCR-05-1900. View

12.

Gnjatic S, Atanackovic D, Jager E, Matsuo M, Selvakumar A, Altorki N . Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc Natl Acad Sci U S A. 2003; 100(15):8862-7. PMC: 166404. DOI: 10.1073/pnas.1133324100. View

13.

Jackson H, Dimopoulos N, Chen Q, Luke T, Tai T, Maraskovsky E . A robust human T-cell culture method suitable for monitoring CD8+ and CD4+ T-cell responses from cancer clinical trial samples. J Immunol Methods. 2004; 291(1-2):51-62. DOI: 10.1016/j.jim.2004.04.017. View

14.

Jackson H, Dimopoulos N, Mifsud N, Tai T, Chen Q, Svobodova S . Striking immunodominance hierarchy of naturally occurring CD8+ and CD4+ T cell responses to tumor antigen NY-ESO-1. J Immunol. 2006; 176(10):5908-17. DOI: 10.4049/jimmunol.176.10.5908. View

15.

Jager E, Nagata Y, Gnjatic S, Wada H, STOCKERT E, Karbach J . Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. Proc Natl Acad Sci U S A. 2000; 97(9):4760-5. PMC: 18306. DOI: 10.1073/pnas.97.9.4760. View

16.

Bioley G, Dousset C, Yeh A, Dupont B, Bhardwaj N, Mears G . Vaccination with recombinant NY-ESO-1 protein elicits immunodominant HLA-DR52b-restricted CD4+ T cell responses with a conserved T cell receptor repertoire. Clin Cancer Res. 2009; 15(13):4467-74. DOI: 10.1158/1078-0432.CCR-09-0582. View

17.

Davis I, Chen W, Jackson H, Parente P, Shackleton M, Hopkins W . Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4(+) and CD8(+) T cell responses in humans. Proc Natl Acad Sci U S A. 2004; 101(29):10697-702. PMC: 489997. DOI: 10.1073/pnas.0403572101. View

18.

Sharma P, Bajorin D, Jungbluth A, Herr H, Old L, Gnjatic S . Immune responses detected in urothelial carcinoma patients after vaccination with NY-ESO-1 protein plus BCG and GM-CSF. J Immunother. 2008; 31(9):849-57. DOI: 10.1097/CJI.0b013e3181891574. View

19.

Klein O, Davis I, McArthur G, Chen L, Haydon A, Parente P . Low-dose cyclophosphamide enhances antigen-specific CD4(+) T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma. Cancer Immunol Immunother. 2015; 64(4):507-18. PMC: 11029160. DOI: 10.1007/s00262-015-1656-x. View

20.

Davis I, Chen Q, Morris L, Quirk J, Stanley M, Tavarnesi M . Blood dendritic cells generated with Flt3 ligand and CD40 ligand prime CD8+ T cells efficiently in cancer patients. J Immunother. 2006; 29(5):499-511. DOI: 10.1097/01.cji.0000211299.29632.8c. View