Final Report Summary - DENDRITOPHAGES (Therapeutic cancer vaccines)
The goal of cancer therapeutic cell vaccines is to prevent progression and tumour recurrence. Adoptive therapy in adjuvant settings complement classical anti-cancer treatments. In this technology, the patient's blood monocytes are transformed into effector monocyte-derived dendritic cells (dendritophages) which are activated to fight the patient's own disease. The therapeutic cell drug comprises dendritic cells loaded with cancer-specific antigens to activate the patient's immune system after re-injection.
Although still at an early stage of clinical development at the time, the concept of applying rationally designed cancer vaccines was considered to have the potential to change cancer treatment. Dendritic cells (DCs) as the principal regulators of immunity received special attention as a novel form of adjuvant for cancer immune therapy. An important issue in the design of a DC-based cancer vaccine concerns the decision to use immature or mature DCs.
Partners therefore developed a DC culture system designed to maximise IL-12 secretion by maturation with a bacterial membrane fraction (FMKP, P Fabre), or lipopolysaccharide (LPS), a potent bacterial endotoxin, and interferon gamma. Because IL-12 secretion from DC1 is limited to the first 24 hours after maturation, they applied DCs after maximal 6 hours of cultivation in the presence of FMKP or lipopolysaccharide (LPS) and interferon gamma as semi-mature actively IL-12 secreting type 1 DCs (smDC1).
Their strategy was supposed to polarise a type 1 immune response that supports cytolytic anti-tumour immunity, which had never before been attempted in a formalised clinical setting. Here they successfully delivered the first feasibility and safety data for this novel approach.
In vivo tracking of the DCs in humans according to different injection routes showed that accumulation of DCs in lymph nodes could be achieved after subcutaneous, intradermous or intranodal injections, but not after intravenous injection. Furthermore, partners developed efficient methods for generating large numbers of antigen-specific T cells by repetitive in vitro stimulation with defined peptide or protein loaded dendritic cells that may be used for functional analysis of tumour-associated antigen-specific CD8+ and CD4+ T lymphocytes. Immunomonitoring technologies, and mostly specific Enzyme-linked immunosorbent spots (ELISPOTs) could be standardised.
Standardised good manufacturing practice (GMP) procedures developed during the project were implemented in the new cell therapy production centres developed by the five partners (IDM, CCRI, ISS, Regen, Peter Mac) which at the time of writing had been successfully approved for four of them for clinical preparations by their respective regulatory authorities.
This complex project required many steps to proof the validity and safety of a dendritic cell vaccine optimised by the different partners. The very close collaboration in full confidence and friendly relations between the partners allowed timely exchanges of materials and information. They could determine the best approach for this vaccine, differentiation, maturation, tumour antigen loading. Large-scale manufacturing procedures in the right environment were produced in all centres. Partners could show that these DCs effectively migrate to lymph nodes after injection. Almost all project objectives were successfully achieved.
Although still at an early stage of clinical development at the time, the concept of applying rationally designed cancer vaccines was considered to have the potential to change cancer treatment. Dendritic cells (DCs) as the principal regulators of immunity received special attention as a novel form of adjuvant for cancer immune therapy. An important issue in the design of a DC-based cancer vaccine concerns the decision to use immature or mature DCs.
Partners therefore developed a DC culture system designed to maximise IL-12 secretion by maturation with a bacterial membrane fraction (FMKP, P Fabre), or lipopolysaccharide (LPS), a potent bacterial endotoxin, and interferon gamma. Because IL-12 secretion from DC1 is limited to the first 24 hours after maturation, they applied DCs after maximal 6 hours of cultivation in the presence of FMKP or lipopolysaccharide (LPS) and interferon gamma as semi-mature actively IL-12 secreting type 1 DCs (smDC1).
Their strategy was supposed to polarise a type 1 immune response that supports cytolytic anti-tumour immunity, which had never before been attempted in a formalised clinical setting. Here they successfully delivered the first feasibility and safety data for this novel approach.
In vivo tracking of the DCs in humans according to different injection routes showed that accumulation of DCs in lymph nodes could be achieved after subcutaneous, intradermous or intranodal injections, but not after intravenous injection. Furthermore, partners developed efficient methods for generating large numbers of antigen-specific T cells by repetitive in vitro stimulation with defined peptide or protein loaded dendritic cells that may be used for functional analysis of tumour-associated antigen-specific CD8+ and CD4+ T lymphocytes. Immunomonitoring technologies, and mostly specific Enzyme-linked immunosorbent spots (ELISPOTs) could be standardised.
Standardised good manufacturing practice (GMP) procedures developed during the project were implemented in the new cell therapy production centres developed by the five partners (IDM, CCRI, ISS, Regen, Peter Mac) which at the time of writing had been successfully approved for four of them for clinical preparations by their respective regulatory authorities.
This complex project required many steps to proof the validity and safety of a dendritic cell vaccine optimised by the different partners. The very close collaboration in full confidence and friendly relations between the partners allowed timely exchanges of materials and information. They could determine the best approach for this vaccine, differentiation, maturation, tumour antigen loading. Large-scale manufacturing procedures in the right environment were produced in all centres. Partners could show that these DCs effectively migrate to lymph nodes after injection. Almost all project objectives were successfully achieved.
