Single-step Antigen Loading and TLR Activation of Dendritic Cells in Melanoma Patients
Condition: Melanoma
MeSH terms: Melanoma
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Objectives: This is an exploratory study, consisting of two parts. In part I dose escalation
      is performed and the primary objective is the safety of different doses of TLR-DC and Trimix
      DC. In part II Trimix DC vaccination will be compared with TLR-DC vaccination and the primary
      objective of this part is the immunological response, with toxicity and clinical efficacy
      being secondary objectives. These studies will provide important data on the safety and
      immunological effects of TLR-DC and Trimix DC.

      Study design: Part I of this study is an open label dose escalation study. Part II of this
      study is an open label randomized phase II study.

      Study population: Our study population consists of melanoma patients, with proven expression
      of melanoma associated tumor antigens gp100 and tyrosinase. Melanoma patients with regional
      lymph node metastasis in whom a radical lymph node dissection is performed within 2 months of
      inclusion in this study (further referred to as stage III) and melanoma patients with
      measurable distant metastases (further referred to as stage IV) will be included.
    

Detailed description: 
      1. Rationale Immunotherapy applying ex vivo generated and tumor-antigen-loaded dendritic
           cells (DC) has now successfully been introduced in the clinic. A limited, but
           consistent, number of objective immunological and clinical responses have been observed.
           Thusfar it remains unclear why some patients respond and others not, but there is a
           general consensus that the current protocols applied to generate DC may not result in
           the induction of optimal Th1 responses. The investigators and others have demonstrated
           that DC maturation is one of the crucial factors, not only for effective DC migration
           but also to induce effective anti-tumor immune responses in cancer patients. Currently,
           the "golden standard" used to mature DC consists of a cocktail of pro-inflammatory
           cytokines (IL-1b, IL-6, TNFa) and prostaglandin E2 (PGE2). Recent mouse data
           demonstrated, however, that maturation of DC by solely pro-inflammatory cytokines
           yielded DC that supported T cell clonal expansion, but failed to efficiently direct
           effector T cell differentiation. Interestingly, DC matured in the presence of Toll like
           receptor (TLR) ligands were able to induce full T cell effector function and unleashed
           more potent immune responses. The investigators recently identified vaccines against
           infectious diseases that contain TLR ligands and are capable of inducing DC maturation.
           This knowledge provides a new application for these clinical applicable agents: clinical
           grade DC stimulators. A clinical grade DC maturation protocol is developed in which TLR
           ligands (preventive vaccines) and PGE2 are combined which resulted in the generation of
           mature DC that secrete high levels of the key cytokine IL-12. Moreover, these TLR-ligand
           matured DC (TLR-DC) induced T cells secreting at least 20-fold higher levels of the
           effector cytokines IFNa and TNFa as compared to DC matured in the absence of TLR
           ligands.

           In the group of Kris Thielemans and it was shown that the T-cell stimulatory capacity of
           peptide-pulsed DC can be greatly enhanced by providing them with three different
           molecular adjuvants through electroporation with mRNA encoding a so-called TriMix of
           CD40 ligand (CD40L), CD70, and a constitutively active form of TLR4 (caTLR4). The
           combination of CD40L and caTLR4 electroporation would mimic CD40 ligation and TLR4
           signaling of the DC and generates phenotypically mature, cytokine/chemokine-secreting
           DC, as has been shown for CD40 and TLR4 ligation through addition of soluble CD40L and
           lipopolysaccharide. On the other hand, the introduction of CD70 into the DC would
           provide a costimulatory signal to CD27+ naive T cells by inhibiting activated T cell
           apoptosis and by supporting T cell proliferation.

           In conclusion, these in vitro data demonstrate that both TLR-DC and Trimix DC are
           promising candidates to improve immunological and clinical responses in cancer
           immunotherapy.

        2. Objectives This is an exploratory study, consisting of two parts. In part I dose
           escalation is performed and the primary objective is the safety of different doses of
           TLR-DC and Trimix DC. In part II Trimix DC vaccination will be compared with TLR-DC
           vaccination and the primary objective of this part is the immunological response, with
           toxicity and clinical efficacy being secondary objectives. These studies will provide
           important data on the safety and immunological effects of TLR-DC and Trimix DC.

        3. Study design Part I of this study is an open label dose escalation study. Part II of
           this study is an open label randomized phase II study.

        4. Study population Our study population consists of melanoma patients, with proven
           expression of melanoma associated tumor antigens gp100 and tyrosinase. Melanoma patients
           with regional lymph node metastasis in whom a radical lymph node dissection is performed
           within 2 months of inclusion in this study (further referred to as stage III) and
           melanoma patients with measurable distant metastases (further referred to as stage IV)
           will be included.

        5. Main study endpoints The primary objectives of the study are to investigate the toxicity
           of TLR-DC and Trimix DC by dose escalation of DC numbers in part I, and to investigate
           immunological responses upon DC vaccination in part II of the study.

      Immunological responses are:

        1. The activation of immune cells in vivo.

        2. The immunological response induced with TLR-DC and Trimix DC loaded with mRNA encoding
           melanoma-associated tumor antigens (gp100 and tyrosinase).

      Safety and clinical efficacy are secondary objectives.
    

Intervention name(s): autologous dendritic cell vaccine; autologous dendritic cell vaccine
Intervention type(s): Biological; Biological
Intervention description(s): Autologous monocyte-derived dendritic cells electroporated with mRNA encoding gp100 and tyrosinase (for antigen loading), active TLR4 and CD70 (for activation). Dendritic cells are vaccinated intranodally 3 times with biweekly intervals every 6 months, if no signs of progression, for a total of 9 vaccinations; Autologous monocyte-derived dendritic cells electroporated with mRNA encoding gp100 and tyrosinase and matured with either cytokines or TLR ligands. Dendritic cells are vaccinated intranodally 3 times with biweekly intervals every 6 months, if no signs of progression, for a total of 9 vaccinations
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: dendritic cell vaccination; melanoma; toll like receptor ligands; mRNA electroporation; vaccines