Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients

Bol, Kalijn F.; Figdor, Carl G.; Aarntzen, Erik H.J.G.; Welzen, Marieke E.B.; Rossum, Michelle M. van; Blokx, Willeke A.M.; Rakt, Mandy Wmm van de; Scharenborg, Nicole M.; Boer, Annemiek J. de; Pots, Jeanette M.; Nordkamp, Michel A. Olde; Oorschot, Tom Gm van; Mus, Roel; Croockewit, Sandra; Jacobs, Joannes F M; Schuler, Gerold; Neyns, Bart; Austyn, Jonathan M.; Punt, Cornelis J.A.; Schreibelt, Gerty; Vries, I. Jolanda M. de

doi:10.1080/2162402x.2015.1019197

Cited by 59 publications

(50 citation statements)

References 40 publications

(64 reference statements)

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“…DC in protocols 5 and 8B were matured with a cocktail of prophylactic vaccines including BCG vaccine SSI (4% v/v, Nederlands Vaccin Instituut, Bilthoven, the Netherlands), Typhim Vi (4% v/v, Sanofi Pasteur MSD, Brussels, Belgium), and Act-HIB (4% v/v, Aventis Pasteur, Brussels, Belgium), supplemented with PGE 2 (10 µg/mL) for 48 h (TLR-DC) 36 . In protocol 8A, DC were matured via electroporation with mRNA encoding CD40L, CD70, and constitutively active TLR4 32 . DC were pulsed with two gp100-derived peptides (gp100:154–162 and gp100:280–288) and a tyrosinase-derived peptide (tyrosinase:369–377) or electroporated with mRNA encoding gp100 or tyrosinase 37 .…”

Section: Methodsmentioning

confidence: 99%

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

et al. 2016

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Purpose: To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients.Experimental design: Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8+ T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines.Results: Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8+ T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154–162, gp100:280–288, and tyrosinase:369–377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154–162, gp100:280–288, and tyrosinase:369–377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively.Conclusions: DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response.

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Section: Methodsmentioning

confidence: 99%

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

et al. 2016

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“…In one published trial, patients with metastatic melanoma were treated with intranodally administered DCs electroporated with mRNA encoding the melanoma-associated antigens tyrosinase or gp100 and TriMix, which induced limited antitumour responses 144 .…”

Section: Mrna Cancer Vaccinesmentioning

confidence: 99%

mRNA vaccines — a new era in vaccinology

Pardi

Hogan

Porter

et al. 2018

Nat Rev Drug Discov

3,114

3,330

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mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use.

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“…Within the field of nucleic acid based vaccination, mRNA has now outcompeted plasmid DNA (pDNA) as the molecule of choice to deliver antigenic information due to its superior safety profile, its higher capacity to transfect nondividing cells, and its amenability to good manufacturing practice production . Over the past years, preclinical and clinical studies have highlighted the potential of antigen‐encoding mRNA to elicit T cell immunity upon intradermal and intranodal immunization. Nonetheless, these studies have also unmasked the limitations of naked mRNA vaccines and have emphasized the necessity to develop formulation strategies that can improve the potency of current mRNA vaccines.…”

Section: Introductionmentioning

confidence: 99%

Arginine‐Rich Peptide‐Based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide

Udhayakumar

Beuckelaer

McCaffrey

et al. 2017

Adv Healthcare Materials

134

107

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To date, the mRNA delivery field has been heavily dominated by lipid-based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell-penetrating peptide containing the amphipathic RALA motif to deliver antigen-encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH-dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5-methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine-rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.

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Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients

Cited by 59 publications

References 40 publications

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients

mRNA vaccines — a new era in vaccinology

Arginine‐Rich Peptide‐Based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide

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