Toll-like Receptor (TLR) Ligand Matured Dendritic Cell Vaccination 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 a dose escalation is
      performed and the primary objective is the safety of different doses of TLR-dendritic cell
      (TLR-DC). In part II TLR-DC vaccination will be compared with cytokine-matured DC vaccination
      and the primary objective of this part is the immunological response to TLR-DC vaccination,
      with toxicity and clinical efficacy being secondary objectives. These studies will provide
      important data on the safety and immunological effects of TLR-matured DC.

      Study design:

      This study is an open label prospective exploratory intervention study.

      Study population:

      The investigators' study population consists of HLA-A2.1 positive 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
      planned or 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. Thus far 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. We 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-1beta, IL-6, TNFalpha) 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. We 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 induced T cells secreting at least
           20-fold higher levels of the effector cytokines IFNalpha and TNFalpha as compared to DC
           matured in the absence of TLR ligands. In conclusion, these in vitro data demonstrate
           that TLR-ligand matured 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 a dose escalation is
           performed and the primary objective is the safety of different doses of TLR-DC. In part
           II TLR-DC vaccination will be compared with cytokine-matured DC vaccination and the
           primary objective of this part is the immunological response to TLR-DC vaccination, with
           toxicity and clinical efficacy being secondary objectives. These studies will provide
           important data on the safety and immunological effects of TLR-matured DC.

        3. Study design

           This study is an open label prospective exploratory intervention study.

        4. Study population

           Our study population consists of HLA-A2.1 positive 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 planned
           or 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 by dose
      escalation of DC numbers in part I, and to investigate immunological responses upon TLR-DC
      vaccination in part II of the study.

      Immunological responses are:

        1. The migratory capacity of the TLR-ligand matured DC in vivo.

        2. The activation of immune cells in vivo.

        3. The immunological response induced with TLR-ligand matured 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 vaccination
Intervention type(s): Biological
Intervention description(s): Autologous monocyte-derived dendritic cells electroporated with mRNA encoding gp100 and tyrosinase and matured with either cytokines or TLR ligands. Dendritic cells are vaccinated intradermal/intravenously 3 times with biweekly intervals every 6 months, if no signs of progression, for a total of 9 vaccinations.
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: dendritic cell vaccination; melanoma; toll like receptor ligands; vaccines