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Lentivirus-induced ‘Smart’ dendritic cells: Pharmacodynamics and GMP-compliant production for immunotherapy against TRP2-positive melanoma
- Source :
- Chan, L 2015, ' Lentivirus-induced 'Smart' dendritic cells : Pharmacodynamics and GMP-compliant production for immunotherapy against TRP2 positive melanoma ', Gene Therapy, vol. 22, pp. 707-720 . https://doi.org/10.1038/gt.2015.43, Gene Therapy
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- Monocyte-derived conventional dendritic cells (ConvDCs) loaded with melanoma antigens showed modest responses in clinical trials. Efficacy studies were hampered by difficulties in ConvDC manufacturing and low potency. Overcoming these issues, we demonstrated higher potency of lentiviral vector (LV)-programmed DCs. Monocytes were directly induced to self-differentiate into DCs (SmartDCTRP2) upon transduction with a tricistronic LV encoding for cytokines (granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-4 (IL-4)) and a melanoma antigen (tyrosinase-related protein 2 (TRP2)). Here, SmartDC-TRP2 generated with monocytes from five advanced melanoma patients were tested in autologous DC:T cell stimulation assays, validating the activation of functional TRP2-specific cytotoxic T lymphocytes (CTLs) for all patients. We described methods compliant to good manufacturing practices (GMP) to produce LV and SmartDC-TRP2. Feasibility of monocyte transduction in a bag system and cryopreservation following a 24-h standard operating procedure were achieved. After thawing, 50% of the initial monocyte input was recovered and SmartDC-TRP2 selfdifferentiated in vitro, showing uniform expression of DC markers, detectable LV copies and a polyclonal LV integration pattern not biased to oncogenic loci. GMP-grade SmartDC-TRP2 expanded TRP2-specific autologous CTLs in vitro. These results demonstrated asimpler GMP-compliant method of manufacturing an effective individualized DC vaccine. Such DC vaccine, when in combination with checkpoint inhibition therapies, might provide higher specificity against melanoma.
- Subjects :
- T cell
medicine.medical_treatment
Genetic Vectors
Biology
Cancer Vaccines
Viral vector
Genetics
medicine
Humans
Cytotoxic T cell
Melanoma
Molecular Biology
Melanoma-associated antigen
Monocyte
Lentivirus
Membrane Proteins
Dendritic Cells
Immunotherapy
medicine.disease
Peptide Fragments
HEK293 Cells
medicine.anatomical_structure
Granulocyte macrophage colony-stimulating factor
Immunology
Molecular Medicine
Original Article
T-Lymphocytes, Cytotoxic
medicine.drug
Subjects
Details
- ISSN :
- 14765462 and 09697128
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Gene Therapy
- Accession number :
- edsair.doi.dedup.....bb8da118b9831cb41d51e9a6cd777e41