Staffan Holmberg-Thydén1,2, Inge Høgh Dufva3, Anne Ortved Gang1,4, Marie Fredslund Breinholt5, Lone Schejbel5, Mette Klarskov Andersen6, Mohammad Kadivar2, Inge Marie Svane4,7,8, Kirsten Grønbæk1,4,9, Sine Reker Hadrup10, Daniel El Fassi11,12. 1. Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark. 2. Experimental & Translational Immunology (XTI), Health Technology, T-Cells and Cancer, Technical University of Denmark, Lyngby, Denmark. 3. Department of Oncology and Palliative Care, Copenhagen University Hospital, Hillerød, Denmark. 4. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 5. Department of Pathology, Copenhagen University Hospital, Herlev, Denmark. 6. Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark. 7. National Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Denmark. 8. Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. 9. Biotech Research and Innovation Centre, BRIC, University of Copenhagen, Copenhagen, Denmark. 10. Experimental & Translational Immunology (XTI), Health Technology, T-Cells and Cancer, Technical University of Denmark, Lyngby, Denmark. sirha@dtu.dk. 11. Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark. daniel.el.fassi.01@regionh.dk. 12. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. daniel.el.fassi.01@regionh.dk.
Abstract
BACKGROUND: Standard care for patients with high-risk myelodysplastic syndrome (MDS) is hypomethylating agents such as azacitidine (AZA), which can induce expression of methylated tumor-associated antigens and therefore potentiate immunotherapeutic targeting. METHOD: In this phase 1 trial, we combined AZA with a therapeutic peptide vaccine targeting antigens encoded from NY-ESO-1, MAGE-A3, PRAME, and WT-1, which have previously been demonstrated to be upregulated by AZA treatment. RESULT: Five patients who had responded to AZA monotherapy were included in the study and treated with the vaccine. The combination therapy showed only few adverse events during the study period, whereof none classified as serious. However, no specific immune responses could be detected using intracellular cytokine staining or ELISpot assays. Minor changes in the phenotypic composition of immune cells and their expression of stimulatory and inhibitory markers were detected. All patients progressed to AML with a mean time to progression from inclusion (TTP) of 5.2 months (range 2.8 to 7.6). Mean survival was 18.1 months (range 10.9 to 30.6) from MDS diagnosis and 11.3 months (range 4.3 to 22.2) from inclusion. Sequencing of bone marrow showed clonal expansion of malignant cells, as well as appearance of novel mutations. CONCLUSION: The patients progressed to AML with an average time of only five months after initiating the combination therapy. This may be unrelated to the experimental treatment, but the trial was terminated early as there was no sign of clinical benefit or immunological response. Why the manuscript is especially interesting This study is the first to exploit the potential synergistic effects of combining a multi-peptide cancer vaccine with epigenetic therapy in MDS. Although our results are negative, they emphasize challenges to induce immune reactivity in patients with high-risk MDS.
BACKGROUND: Standard care for patients with high-risk myelodysplastic syndrome (MDS) is hypomethylating agents such as azacitidine (AZA), which can induce expression of methylated tumor-associated antigens and therefore potentiate immunotherapeutic targeting. METHOD: In this phase 1 trial, we combined AZA with a therapeutic peptide vaccine targeting antigens encoded from NY-ESO-1, MAGE-A3, PRAME, and WT-1, which have previously been demonstrated to be upregulated by AZA treatment. RESULT: Five patients who had responded to AZA monotherapy were included in the study and treated with the vaccine. The combination therapy showed only few adverse events during the study period, whereof none classified as serious. However, no specific immune responses could be detected using intracellular cytokine staining or ELISpot assays. Minor changes in the phenotypic composition of immune cells and their expression of stimulatory and inhibitory markers were detected. All patients progressed to AML with a mean time to progression from inclusion (TTP) of 5.2 months (range 2.8 to 7.6). Mean survival was 18.1 months (range 10.9 to 30.6) from MDS diagnosis and 11.3 months (range 4.3 to 22.2) from inclusion. Sequencing of bone marrow showed clonal expansion of malignant cells, as well as appearance of novel mutations. CONCLUSION: The patients progressed to AML with an average time of only five months after initiating the combination therapy. This may be unrelated to the experimental treatment, but the trial was terminated early as there was no sign of clinical benefit or immunological response. Why the manuscript is especially interesting This study is the first to exploit the potential synergistic effects of combining a multi-peptide cancer vaccine with epigenetic therapy in MDS. Although our results are negative, they emphasize challenges to induce immune reactivity in patients with high-risk MDS.
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