NY-ESO-1 Vaccination in Combination with Decitabine Induces Antigen-Specific T-lymphocyte Responses in Patients with Myelodysplastic Syndrome

Abstract

Treatment options are limited for patients with high-risk myelodysplastic syndrome (MDS). The azanucleosides, azacitidine and decitabine, are first-line therapy for MDS that induce promoter demethylation and gene expression of the highly immunogenic tumor antigen NY-ESO-1. We demonstrated that patients with acute myeloid leukemia (AML) receiving decitabine exhibit induction of NY-ESO-1 expression in circulating blasts. We hypothesized that vaccinating against NY-ESO-1 in patients with MDS receiving decitabine would capitalize upon induced NY-ESO-1 expression in malignant myeloid cells to provoke an NY-ESO-1-specific MDS-directed cytotoxic T-cell immune response. In a phase I study, 9 patients with MDS received an HLA-unrestricted NY-ESO-1 vaccine (CDX-1401 + poly-ICLC) in a nonoverlapping schedule every four weeks with standard-dose decitabine. Analysis of samples serially obtained from the 7 patients who reached the end of the study demonstrated induction of expression in 7 of 7 patients and NY-ESO-1-specific CD4 and CD8 T-lymphocyte responses in 6 of 7 and 4 of 7 of the vaccinated patients, respectively. Myeloid cells expressing NY-ESO-1, isolated from a patient at different time points during decitabine therapy, were capable of activating a cytotoxic response from autologous NY-ESO-1-specific T lymphocytes. Vaccine responses were associated with a detectable population of CD141 conventional dendritic cells, which are critical for the uptake of NY-ESO-1 vaccine and have a recognized role in antitumor immune responses. These data indicate that vaccination against induced NY-ESO-1 expression can produce an antigen-specific immune response in a relatively nonimmunogenic myeloid cancer and highlight the potential for induced antigen-directed immunotherapy in a group of patients with limited options. .

Epigenetic Regulation of CXCL12 Plays a Critical Role in Mediating Tumor Progression and the Immune Response In Osteosarcoma

“…Decitabine, also known as 5-aza-2 0 -deoxycytidine, is an FDA-approved hypomethylating agent that has shown a unique ability in facilitating an immune response against malignancies by elevating the expression of some given epitopes and consequently provided targets for specific immune attack (32,33), as well as its function in directly suppressing the proliferation of cancer cells (34,35). Epigenetic hypomethylating treatment has occupied a position in the treatment against leukemias (35,36), but its role in osteosarcoma treatment remains unclear.…”

Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes

“…CDX-1401,a vaccine featuring the fusion protein of CD205(DEC-205), a marker on dendritic cells, and cancer-testis antigen 1 (CTAG1 or NY-ESO-1), was shown to effectively induce cytotoxic response from T cells when examined ex vivo and has recently concluded phase I with no clinical outcomes reported to date. [81] Another vaccine target includes the PR1 peptide, an HLA-A2 restricted peptide on myeloid leukemia cells, Initially developed in 2008, the first phase I trial displayed both safety and efficacy of the PR1 vaccine. [82] Last year another phase I/II trial also demonstrated robust immune response (53% patients had at least doubled PR1-specific cytotoxic T cells (CTLs)) and objective clinical response (24% patients had complete, partial or hematological improvement) (NCT00004918).…”

Toll‐like receptor 7/8‐matured RNA‐transduced dendritic cells as post‐remission therapy in acute myeloid leukaemia: results of a phase I trial

“…[22][23][24][25] In the setting of myelodysplastic syndrome, the combination of vaccination against NY-ESO-1 and decitabine resulted in an increased antigen-specific immune response. 26 In our hands, the combination of next-generation DC vaccination with 5azacytidine resulted in a striking increase in local and systemic immune responses. This translated into a temporary MRD conversion in a single patient.…”