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T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma.

ABSTRACT: The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptor in vitro, we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement and in vivo bioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma.

SUBMITTER: Singh N

PROVIDER: S-EPMC4760344 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma.

Singh Nathan N Kulikovskaya Irina I Barrett David M DM Binder-Scholl Gwendolyn G Jakobsen Bent B Martinez Daniel D Pawel Bruce B June Carl H CH Kalos Michael D MD Grupp Stephan A SA

Oncoimmunology 20150812 1

The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma s ...[more]

PMID: 26942053

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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.

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:BackgroundTumor-infiltrating CD8+ T cells are correlated with prolonged progression-free and overall survival in epithelial ovarian cancer (EOC). A significant fraction of EOC patients mount autoantibody responses to various tumor antigens, however the relationship between autoantibodies and tumor-infiltrating T cells has not been investigated in EOC or any other human cancer. We hypothesized that autoantibody and T cell responses may be correlated in EOC and directed toward the same antigens.Methodology and principal findingsWe obtained matched serum and tumor tissue from 35 patients with high-grade serous ovarian cancer. Serum samples were assessed by ELISA for autoantibodies to the common tumor antigen NY-ESO-1. Tumor tissue was examined by immunohistochemistry for expression of NY-ESO-1, various T cell markers (CD3, CD4, CD8, CD25, FoxP3, TIA-1 and Granzyme B) and other immunological markers (CD20, MHC class I and MHC class II). Lymphocytic infiltrates varied widely among tumors and included cells positive for CD3, CD8, TIA-1, CD25, FoxP3 and CD4. Twenty-six percent (9/35) of patients demonstrated serum IgG autoantibodies to NY-ESO-1, which were positively correlated with expression of NY-ESO-1 antigen by tumor cells (r = 0.57, p = 0.0004). Autoantibodies to NY-ESO-1 were associated with increased tumor-infiltrating CD8+, CD4+ and FoxP3+ cells. In an individual HLA-A2+ patient with autoantibodies to NY-ESO-1, CD8+ T cells isolated from solid tumor and ascites were reactive to NY-ESO-1 by IFN-gamma ELISPOT and MHC class I pentamer staining.Conclusion and significanceWe demonstrate that tumor-specific autoantibodies and tumor-infiltrating T cells are correlated in human cancer and can be directed against the same target antigen. This implies that autoantibodies may collaborate with tumor-infiltrating T cells to influence clinical outcomes in EOC. Furthermore, serological screening methods may prove useful for identifying clinically relevant T cell antigens for immunotherapy.

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T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma.

Publications

T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma.

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