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A new study demonstrates that it is possible to vaccinate patients with MDS against a decitabine-induced antigen and that the level of induced expression is sufficient to trigger cytotoxicity in patient-derived vaccine-induced T cells.
It may be possible to vaccinate against induced NY-ESO-1 expression to produce an antigen-specific immune response in patients with high-risk myelodysplastic syndrome (MDS), according to a study by researchers at Roswell Park Comprehensive Cancer Center. They have found a new immunotherapy approach that may significantly benefit high-risk MDS patients who have limited options.
Currently, first-line therapy for MDS is azacitidine or decitabine. These two azanucleosides induce promoter demethylation and gene expression of the highly immunogenic tumor antigen NY-ESO-1. Study investigator Elizabeth Griffiths, MD, an associate professor of oncology and director of MDS at Roswell Park Comprehensive Cancer Center in Buffalo, New York, said the current study demonstrates that it is possible to vaccinate patients with MDS against a decitabine-induced antigen and that the level of induced expression is sufficient to trigger cytotoxicity in patient-derived vaccine-induced T cells.
Dr. Griffiths and colleagues previously demonstrated that acute myeloid leukemia patients receiving decitabine exhibit induction of NY-ESO-1 expression in circulating blasts. In the current study, the researchers enrolled nine MDS patients who received an HLA unrestricted NY-ESO-1 vaccine (CDX-1401 + poly-ICLC). The subjects received the vaccine in a non-overlapping schedule every 4 weeks in combination with standard-dose decitabine.
The analysis demonstrated induction of NY-ESO-1 expression in all seven patients who reached the end of the study. In addition, the study revealed that there were NY-ESO-1 specific CD4+ T-lymphocyte responses in six out of seven patients and CD8+ T-lymphocyte responses in four of the seven vaccinated patients.
“Not all the patients responded as well to the vaccine as we expected, and the presence of a particular immune cell called a CD141Hi dendritic cell appeared to be critical for response to our vaccine. Patients with MDS appear to have a defect in the production of this kind of cell, and we are currently exploring why there is a deficiency in this type of immune cell in patients with MDS and whether any treatments might improve the quantity or quality of these cells in MDS patients,” Dr. Griffiths told Cancer Network.
The researchers isolated myeloid cells expressing NY-ESO-1 from a patient at different time-points during decitabine therapy. They found these myeloid cells were capable of activating a cytotoxic response from autologous NY-ESO-1-specific T-lymphocytes. The team also found that the vaccine/decitabine combination led to a detectable population of CD141Hi conventional dendritic cells.
“Side effects were mostly those associated with the standard-of-care treatment for MDS (low blood counts, transfusions, neutropenic fevers) and with the underlying MDS diagnosis. Most patients who received the vaccine had local site reactions from the vaccine, as had been reported in patients with solid tumors who have received it previously,” said Dr. Griffiths.
The researchers now are planning a second phase I study combining NY-ESO-1 vaccine/decitabine with the PD-1 antibody nivolumab (Clinicaltrials.gov identifier: NCT03358719). “We hope to assess whether this combination can improve the response to our vaccine and safely produce anti-NY-ESO-1 immune responses in patients with MDS who are not eligible for bone marrow transplant,” said Dr. Griffiths.