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Epigenetic therapy in combination with a multi-epitope cancer vaccine targeting shared tumor antigens for high-risk myelodysplastic syndrome - a phase I clinical trial

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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.

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Availability of data and material

Case report forms, trial master files, and experimental data are stored in accordance with EU regulation.

Code availability

R code for experimental statistical analysis is available upon request.

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Funding

Financial support to this study was provided by the Danish Cancer Society, grant no. R72-A4531 and R146-A9531-16-S2; Herlev-Gentofte hospital research grant and from an unrestricted research grant from Celgene inc.

Author information

Authors and Affiliations

  1. Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark

    Staffan Holmberg-Thydén, Anne Ortved Gang, Kirsten Grønbæk & Daniel El Fassi

  2. Experimental & Translational Immunology (XTI), Health Technology, T-Cells and Cancer, Technical University of Denmark, Lyngby, Denmark

    Staffan Holmberg-Thydén, Mohammad Kadivar & Sine Reker Hadrup

  3. Department of Oncology and Palliative Care, Copenhagen University Hospital, Hillerød, Denmark

    Inge Høgh Dufva

  4. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Anne Ortved Gang, Inge Marie Svane, Kirsten Grønbæk & Daniel El Fassi

  5. Department of Pathology, Copenhagen University Hospital, Herlev, Denmark

    Marie Fredslund Breinholt & Lone Schejbel

  6. Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark

    Mette Klarskov Andersen

  7. National Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Denmark

    Inge Marie Svane

  8. Department of Oncology, Copenhagen University Hospital, Herlev, Denmark

    Inge Marie Svane

  9. Biotech Research and Innovation Centre, BRIC, University of Copenhagen, Copenhagen, Denmark

    Kirsten Grønbæk

Authors
  1. Staffan Holmberg-Thydén
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  2. Inge Høgh Dufva
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  9. Kirsten Grønbæk
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  10. Sine Reker Hadrup
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Corresponding authors

Correspondence to Sine Reker Hadrup or Daniel El Fassi.

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Conflicts of interest

Celgene provided an unrestricted research grant for this clinical trial. They were allowed to read the final manuscript prior to publication but did not have any influence on the planning, conduction, or publishing of this clinical trial. There were no other conflicts of interest to report.

Ethics approval

The study was conducted in accordance with the Helsinki Declaration and ICH-GCP, and approved by the Danish Medicines Agency and the regional research ethics committee in Denmark. The trial is registered in the EU Clinical Trials Register (2014–002432-14) and clinicaltrials.gov (NCT02750995).

Consent to participate

Written informed consent was obtained from all patients in the clinical trial following oral and written information.

Consent for publication

All patients consented to the publication of anonymized data in scientific journals prior to receiving written and oral information hereof.

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Sine Reker Hadrup and Daniel El Fassi are shared senior authors.

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Holmberg-Thydén, S., Dufva, I.H., Gang, A.O. et al. Epigenetic therapy in combination with a multi-epitope cancer vaccine targeting shared tumor antigens for high-risk myelodysplastic syndrome - a phase I clinical trial. Cancer Immunol Immunother 71, 433–444 (2022). https://doi.org/10.1007/s00262-021-02993-6

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