A phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients.

Abstract

BACKGROUND:

Autologous monocyte-derived dendritic cells (DCs) electroporated with synthetic messenger RNA (mRNA) encoding a CD40 ligand, a constitutively active Toll-like receptor 4 and CD70, together with mRNA encoding fusion proteins of a human leukocyte antigen (HLA)-class II targeting signal (DC-LAMP) and a melanoma-associated antigen (MAA); either MAGE-A3, MAGE-C2, tyrosinase or gp100) (TriMixDC-MEL) are superiorly immunogenic.

PATIENTS AND METHODS:

In this phase IB clinical trial, 24 million viable DCs were administered by four biweekly combined intradermal (id) and intravenous (iv) administrations, and a fifth administration on week 16. The number of iv-administered DCs was escalated in four sequentially treated cohorts. Immune responses were assessed by analysis of antigen specificity of blood-derived T-cells and skin infiltrating lymphocytes (SKILs).

RESULTS:

Fifteen patients with pretreated advanced melanoma tolerated administration of TriMixDC-MEL well. Two patients achieved a complete response and two patients a partial response. All objective responders are progression-free after a follow-up of, respectively, 24+, 28+, 33+, and 34+ months. Post-therapy antigen-specific SKILs were documented in 6 of 12 patients, and antigen-specific CD8(+) T-cells were detected in the blood of 4 of 5 patients.

CONCLUSIONS:

Cellular immunotherapy with TriMixDC-MEL is safe and immunogenic. Antitumor activity with durable disease control is observed across the investigated iv-dose levels.

CLINICALTRIALSGOV IDENTIFIER:

NCT01066390.

• Authors: S Wilgenhof, A M T Van Nuffel, D Benteyn, J Corthals, C Aerts, C Heirman, I Van Riet, A Bonehill, K Thielemans, B Neyns
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 24 Issue 10 Pg. 2686-2693 (Oct 2013) ISSN: 1569-8041 [Electronic] England
• PMID: 23904461 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• CD27 Ligand
• Lysosomal-Associated Membrane Protein 3
• MAGEA3 protein, human
• MAGEC2 protein, human
• Neoplasm Proteins
• RNA, Messenger
• Recombinant Fusion Proteins
• TLR4 protein, human
• Toll-Like Receptor 4
• CD40 Ligand
• Monophenol Monooxygenase

Topics

• Adult
• Aged
• Antigens, Neoplasm (genetics, metabolism)
• CD27 Ligand (genetics, metabolism)
• CD40 Ligand (genetics, metabolism)
• CD8-Positive T-Lymphocytes (immunology)
• Cell- and Tissue-Based Therapy (methods)
• Dendritic Cells (cytology, immunology)
• Disease-Free Survival
• Electroporation
• Female
• Humans
• Immunotherapy (methods)
• Lysosomal-Associated Membrane Protein 3 (genetics, metabolism)
• Male
• Melanoma (therapy)
• Middle Aged
• Monophenol Monooxygenase (genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• RNA, Messenger (genetics)
• Recombinant Fusion Proteins (genetics, metabolism)
• Skin Neoplasms (therapy)
• Toll-Like Receptor 4 (genetics, metabolism)