Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial

Driessche, Ann Van; Velde, Ann L.R. Van de; Nijs, Griet; Braeckman, Tessa; Stein, Barbara; Vries, Jolanda M De; Berneman, Zwi N.; Tendeloo, Viggo Van

doi:10.1080/14653240902960411

Cited by 97 publications

(63 citation statements)

References 47 publications

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“…16,17 Three different WT1 constructs were used to generate mRNA by in vitro transcription: construct 1 (WT1), encoding full-length WT1 16,17 ; construct 2 (WT1-DC-LAMP), incorporating a Sig-DC-LAMP major histocompatibility complex (MHC) class 2-skewing signal with deletion of the WT1 nuclear localization signal; and construct 3 (WT1-DC-LAMP-OPT), a codon-optimized version of construct 2 ( Figure 1; supplemental Table 1, available on the Blood Web site). 18 …”

Section: Vaccinationmentioning

confidence: 99%

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Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Anguille

Velde

Smits

et al. 2017

Blood

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169

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Key Points• WT1 mRNA-electroporated DCs can prevent or delay relapse in 43% of patients with AML in remission after chemotherapy.• OS compares favorably with the new survival data from the Swedish Acute Leukemia Registry and correlates with molecular and WT1-specific CD8 1 T-cell responses.Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P 5 .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age £65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8 1 T cells. Long-term OS was correlated with interferon-g 1 and tumor necrosis factor-a 1 WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8 1 T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8 1 T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224. (Blood. 2017;130(15):1713-1721

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Section: Vaccinationmentioning

confidence: 99%

“…To this end, we vaccinated 30 patients with AML in remission but at very high risk of relapse with autologous DCs loaded with the WT1 antigen by means of messenger RNA (mRNA) electroporation, a technique that allows for human leukocyte antigen (HLA) haplotype-independent, multiple-epitope antigen presentation to T cells. 15,16 …”

Section: Introductionmentioning

confidence: 99%

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Anguille

Velde

Smits

et al. 2017

Blood

Self Cite

169

146

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“…In this context, reference can be taken from the reports on clinical trials with non-replicating mRNA vaccines. These are often delivered as "dendritic cell vaccines" whereby the DCs have been transfected with the mRNA [8,[58][59][60][61][62][63][64], but mRNA vaccines have been employed for direct vaccination [62,64,65] and nanoparticulate delivery [59]. Such approaches were also applied in fields other than cancer vaccination [8,59], for example against HIV [58] and influenza [27].…”

Section: Nanoparticulate Vehicle Delivery Of Self-amplifying Rna To Dmentioning

confidence: 99%

Dendritic Cell Targets for Self-Replicating RNA Vaccines

McCullough

Milona²,

Démoulins³

et al. 2014

J Blood Lymph

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“…55 WT1 antigen IVT-mRNA was produced from pGEM4Z/WT1/A64 or purchased from CureVac. 8 Plasmids were linearized with SpeI (New England Biolabs, R0133S) and IVT was performed using a mMessage Machine T7 Ultra (Life Technologies, AM1345) as described previously. 56 The quantity and quality of mRNA were analyzed using a Bioanalyzer 2000 (Agilent).…”

Section: Isolation or Generationmentioning

confidence: 99%

“…[1][2][3][4] Nonetheless, recent studies suggest that DC vaccination may have a place in treating both hematological and other malignancies; particularly if applied after a reduction in tumor burden following surgical resection, chemotherapy, or hematopoietic-stem-cell transplantation, when tumor immunosuppression is at its lowest. [5][6][7] Recent trials in acute myeloid leukemia (AML) [8][9][10] and multiple myeloma 7 investigating monocyte derived dendritic cell (Mo-DC) vaccination, after induction chemotherapy and transplantation, have demonstrated objective clinical and immunological responses. To build on this, major improvements in the DC product are needed, first, to address limitations in DC performance and secondly, to make DC vaccination practical.…”

Section: Introductionmentioning

confidence: 99%

CMRF-56⁺blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

et al. 2016

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There are numerous transcriptional, proteomic and functional differences between monocyte-derived dendritic cells (Mo-DC) and primary blood dendritic cells (BDC). The CMRF-56 monoclonal antibody (mAb) recognizes a cell surface marker, which is upregulated on BDC following overnight culture. Given its unique ability to select a heterogeneous population of BDC, we engineered a human chimeric (h)CMRF-56 IgG4 mAb to isolate primary BDC for potential therapeutic vaccination. The ability to select multiple primary BDC subsets from patients and load them with in vitro transcribed (IVT) mRNA encoding tumor antigen might circumvent the issues limiting the efficacy of Mo-DC. After optimizing and validating the purification of hCMRF-56 C BDC, we showed that transfection of hCMRF-56 C BDC with mRNA resulted in efficient mRNA translation and antigen presentation by myeloid BDC subsets, while preserving superior DC functions compared to Mo-DC. Immune selected and transfected hCMRF-56 C BDC migrated very efficiently in vitro and as effectively as cytokine matured Mo-DC in vivo. Compared to Mo-DC, hCMRF-56 C BDC transfected with influenza matrix protein M1 displayed superior MHC peptide presentation and generated potent antigen specific CD8 C T-cell recall responses, while Wilms tumor 1 (WT1) transfected CMRF-56 C BDC generated effective primary autologous cytotoxic T-cell responses. The ability of the combined DC subsets within hCMRF-56 C BDC to present mRNA delivered tumor antigens merits phase I evaluation as a reproducible generic platform for the next generation of active DC immune therapies.

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Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial

Cited by 97 publications

References 47 publications

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Dendritic Cell Targets for Self-Replicating RNA Vaccines

CMRF-56⁺blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

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Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial

Cited by 97 publications

References 47 publications

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Dendritic Cell Targets for Self-Replicating RNA Vaccines

CMRF-56+blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

Contact Info

Product

Resources

About

CMRF-56⁺blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses