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A randomized controlled phase II clinical trial on mRNA electroporated autologous monocyte-derived dendritic cells (TriMixDC-MEL) as adjuvant treatment for stage III/IV melanoma patients who are disease-free following the resection of macrometastases

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Abstract

Background

Autologous monocyte-derived mRNA co-electroporated dendritic cells with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively activated TLR4 (caTLR4) (referred to as TriMixDC-MEL) have anti-tumor activity in advanced melanoma patients. We investigated the safety and activity of adjuvant TriMixDC-MEL in stage III/IV melanoma patients.

Materials and methods

Forty-one patients were randomly assigned to treatment with TriMixDC-MEL (n = 21) and standard follow-up (n = 20). “Cross-over” was allowed at the time of non-salvageable recurrence. The primary endpoint was the percentage of patients alive and disease-free at 1-year. For a subset of patients, (formalin-fixed paraffin-embedded), tumor tissue samples were available for mRNA expression profiling and PD-L1 immunohistochemical staining.

Results

Baseline characteristics were well balanced. One-year after randomization, 71% of patients in the study arm were alive and free of disease compared to 35% in the control arm. After a median follow-up of 53 months (range 3–67), 23 patients experienced a non-salvageable melanoma recurrence (TriMixDC-Mel arm n = 9 and control arm n = 14).The median time to non-salvageable recurrence was superior in the TriMixDC-MEL arm (median 8 months (range 1–6) vs. not reached; log-rank p 0.044). TriMixDC-MEL-related adverse events (AE) consisted of transient local skin reactions, flu-like symptoms and post-infusion chills. No grade ≥ 3 AE’s occurred. The mRNA expression profiling revealed four genes (STAT2, TPSAB1, CD9 and CSF2) as potential predictive biomarkers.

Conclusion

TriMixDC-MEL id/iv as adjuvant therapy is tolerable and may improve the 1-year disease-free survival rate. Combination of optimized autologous monocyte-derived DC-formulations warrants further investigation in combination with currently approved adjuvant therapy options.

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Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

%CV:

Percentage coefficient of variation

AJCC:

American Joint Committee on Cancer

AUC:

Area under the curve

CD40-L:

CD40 ligand

CLND:

Complete lymph node dissection

DC:

Dendritic cells

DMFS:

Distant metastasis free survival

FFPE:

Formalin-fixed paraffin-embedded

HKG:

Housekeeping genes

id:

Intradermal

iv:

Intravenous

OS:

Overall survival

RFS:

Recurrence-free survival

TCGA:

The Cancer Genome Atlas

TriMixDC-MEL:

Autologous monocyte-derived mRNA electroporated dendritic cells

WHO-PS:

World Health Organization performance status

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Acknowledgements

We thank the patients who participated in the study, their families and caregivers. We would also like to thank Katrien Van den Bossche for assisting us with the data management.

Funding

This study was funded by Rijksinstituut voor Ziekte- en Invaliditeitsverzekering Belgium.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090, Brussels, Belgium

    Yanina Jansen, Teofila Seremet & Bart Neyns

  2. Department of Medical Oncology, Universitair Ziekenhuis Gent (UZ Gent), Ghent, Belgium

    Vibeke Kruse & Lieve Brochez

  3. Laboratory of Molecular and Cellular Therapy and Dendritic Cell-bank, Vrije Universiteit Brussel, Brussels, Belgium

    Jurgen Corthals, Carlo Heirman & Kris Thielemans

  4. Histogenex NV, Antwerp, Belgium

    Kelly Schats, Pieter-Jan van Dam & Mark Kockx

Authors
  1. Yanina Jansen
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Contributions

YJ contributed to first draft, patient treatment, statistical analyses. VK contributed to patient treatment, revision of draft. JC contributed to manufacturing of study drug, revision of draft. KS contributed to analyses of samples, revision of draft, statistical analyses. TS contributed to patient treatment, revision of draft, statistical analyses. P-JVD contributed to analyses of samples, revision of draft, statistical analyses. CH contributed to manufacturing of study drug, revision of draft. LB contributed to patient treatment, revision of draft. MK contributed to analyses of samples, revision of draft, statistical analyses. KT contributed to concept of study, manufacturing of study drug, revision of draft, statistical analyses. BN contributed to concept of study, patient treatment, revision of draft, statistical analyses.

Corresponding author

Correspondence to Yanina Jansen.

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Conflict of interest

Yanina Jansen received travel grant support from BMS, MSD, Pfizer. Vibeke Kruse provided consultation, attended advisory boards, and/or provided lectures for: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen and Sanofi. My institution received honoraria for my contribution. Jurgen Corthals has no conflict of interest. Kelly Schats: KS is an employee of HistoGeneX NV which performs immunohistochemical and molecular testing for pharmaceutical companies as part of (pre-) clinical studies that evaluate new anticancer drugs. There is no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Pieter-Jan Van Dam4: PJ Van Dam is an employee of HistoGeneX NV which performs immunohistochemical and molecular testing for pharmaceutical companies as part of (pre-) clinical studies that evaluate new anticancer drugs. There is no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Teofila Seremet received congresses and advisory fees from Novartis and one preceptorship MSD. Carlo Heirman: CH is an inventor on patents related to TriMix and is employee of eTheRNA ImmunoTherapies and may therefore have a financial interest in the development of TriMix technologies. Lieve Brochez: Advisory Board Incyte 6/2017, Value-based health care project sponsored by Amgen. Mark Kockx: Mark Kockx is the CEO of HistoGeneX NV which performs immunohistochemical and molecular testing for pharmaceutical companies as part of (pre-) clinical studies that evaluate new anticancer drugs. There is no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Kris Thielemans: KT is an inventor on patents related to TriMix and DC technology and is consultant for eTheRNA ImmunoTherapies and may therefore has a financial interest in the development of TriMix technologies. Bart Neyns: Honoraria-Bristol-Myers Squibb; Merck Sharp & Dohme; Novartis; Roche. Consulting or Advisory Role-Bristol-Myers Squibb; Merck Sharp & Dohme; Novartis; Roche. Speakers’ Bureau-Novartis. Travel, Accommodations, Expenses-Amgen; Bristol-Myers Squibb; Merck Sharp & Dohme; Novartis; Roche.

Ethical approval and consent to participate

This trial was approved by the Institutional Ethics Committee of the UZ Brussel (ClinicalTrials.gov identifier: NCT01676779). All patients provided signed informed consent.

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Jansen, Y., Kruse, V., Corthals, J. et al. A randomized controlled phase II clinical trial on mRNA electroporated autologous monocyte-derived dendritic cells (TriMixDC-MEL) as adjuvant treatment for stage III/IV melanoma patients who are disease-free following the resection of macrometastases. Cancer Immunol Immunother 69, 2589–2598 (2020). https://doi.org/10.1007/s00262-020-02618-4

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