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Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8⁺ and CD4⁺ T-cell responses with multiple specificities including a novel DR7-restricted epitope.

ABSTRACT: Long synthetic peptides and CpG-containing oligodeoxynucleotides are promising components for cancer vaccines. In this phase I trial, 19 patients received a mean of 8 (range 1-12) monthly vaccines s.c. composed of the long synthetic NY-ESO-1_79-108 peptide and CpG-B (PF-3512676), emulsified in Montanide ISA-51. In 18/18 evaluable patients, vaccination induced antigen-specific CD8⁺ and CD4⁺ T-cell and antibody responses, starting early after initiation of immunotherapy and lasting at least one year. The T-cells responded antigen-specifically, with strong secretion of IFN? and TNF?, irrespective of patients' HLAs. The most immunogenic regions of the vaccine peptide were NY-ESO-1_89-102 for CD8⁺ and NY-ESO-1_83-99 for CD4⁺ T-cells. We discovered a novel and highly immunogenic epitope (HLA-DR7/NY-ESO-1_87-99); 7/7 HLA-DR7⁺ patients generated strong CD4⁺ T-cell responses, as detected directly ex vivo with fluorescent multimers. Thus, vaccination with the long synthetic NY-ESO-1_79-108 peptide combined with the strong immune adjuvant CpG-B induced integrated, robust and functional CD8⁺ and CD4⁺ T-cell responses in melanoma patients, supporting the further development of this immunotherapeutic approach.

SUBMITTER: Baumgaertner P

PROVIDER: S-EPMC5087303 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8+ and CD4+ T-cell responses with multiple specificities including a novel DR7-restricted epitope.

Baumgaertner P P Costa Nunes C C Cachot A A Maby-El Hajjami H H Cagnon L L Braun M M Derré L L Rivals J-P JP Rimoldi D D Gnjatic S S Abed Maillard S S Marcos Mondéjar P P Protti M P MP Romano E E Michielin O O Romero P P Speiser D E DE Jandus C C

Oncoimmunology 20160909 10

Long synthetic peptides and CpG-containing oligodeoxynucleotides are promising components for cancer vaccines. In this phase I trial, 19 patients received a mean of 8 (range 1-12) monthly vaccines s.c. composed of the long synthetic NY-ESO-179-108 peptide and CpG-B (PF-3512676), emulsified in Montanide ISA-51. In 18/18 evaluable patients, vaccination induced antigen-specific CD8+ and CD4+ T-cell and antibody responses, starting early after initiation of immunothe ...[more]

PMID: 27853637

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Project description:NY-ESO-1 or New York esophageal squamous cell carcinoma 1 is a well-known cancer-testis antigen (CTAs) with re-expression in numerous cancer types. Its ability to elicit spontaneous humoral and cellular immune responses, together with its restricted expression pattern, have rendered it a good candidate target for cancer immunotherapy. In this review, we provide background information on NY-ESO-1 expression and function in normal and cancerous tissues. Furthermore, NY-ESO-1-specific immune responses have been observed in various cancer types; however, their utility as biomarkers are not well determined. Finally, we describe the immune-based therapeutic options targeting NY-ESO-1 that are currently in clinical trial. We will highlight the recent advancements made in NY-ESO-1 cancer vaccines, adoptive T cell therapy, and combinatorial treatment with checkpoint inhibitors and will discuss the current trends for future NY-ESO-1 based immunotherapy. Cancer treatment has been revolutionized over the last few decades with immunotherapy emerging at the forefront. Immune-based interventions have shown promising results, providing a new treatment avenue for durable clinical responses in various cancer types. The majority of successful immunotherapy studies have been reported in liquid cancers, whereas these approaches have met many challenges in solid cancers. Effective immunotherapy in solid cancers is hampered by the complex, dynamic tumor microenvironment that modulates the extent and phenotype of the antitumor immune response. Furthermore, many solid tumor-associated antigens are not private but can be found in normal somatic tissues, resulting in minor to detrimental off-target toxicities. Therefore, there is an ongoing effort to identify tumor-specific antigens to target using various immune-based modalities. CTAs are considered good candidate targets for immunotherapy as they are characterized by a restricted expression in normal somatic tissues concomitant with a re-expression in solid epithelial cancers. Moreover, several CTAs have been found to induce a spontaneous immune response, NY-ESO-1 being the most immunogenic among the family members. Hence, this review will focus on NY-ESO-1 and discuss the past and current NY-ESO-1 targeted immunotherapeutic strategies.

Project description:Dendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs. Human anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, tumor necrosis factor and CD107a and by lysis of target tumor cells. CLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro. These data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.

Dataset Information

Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8⁺ and CD4⁺ T-cell responses with multiple specificities including a novel DR7-restricted epitope.

Publications

Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8<sup>+</sup> and CD4<sup>+</sup> T-cell responses with multiple specificities including a novel DR7-restricted epitope.

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