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…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of the study is to investigate the toxicity of TLR-DC by
dose escalation of the number of cells.
Secondary outcome
The secondary objectives of the study are:
(a) The migratory capacity of the TLR-ligand matured DC.
(b) Activation of immune cells in vivo.
(c) The immunological response induced in melanoma patients vaccinated with
TLR-ligand matured DC loaded with mRNA encoding melanoma-associated tumor
antigens (gp100 and tyrosinase).
(d) The clinical efficacy of vaccination with TLR-ligand matured DC.
Background summary
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. 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-1β, IL-6, TNFα) 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 IFNγ and TNFα 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.
Study objective
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 immuniological effects of TLR-matured DC.
Study design
This study is an open label prospective exploratory intervention study.
Intervention
HLA-A2.1+ stage III and IV melanoma patients will be vaccinated with mature DC
loaded with mRNA encoding tumor-associated antigens gp100 and tyrosinase and
pulsed with KLH as an immune control. First, we will perform a dose-finding
study in 5 stage IV patients with DC matured in the presence of the vaccines
BCG, Typhim and Act-HIB (TLR-matured DC) (see Outline of study). If no toxicity
is observed, we will continue with the study and aim to randomly include 20
evaluable patients in arm A (TLR-matured DC) and 12 patients in arm B
(cytokine-matured DC). Furthermore, 5 stage III melanoma patients scheduled for
lymph node dissection will be vaccinated once before surgery and three times
thereafter. In these patients the immune activating potential in vivo of
TLR-matured DC will be studied. In all patients biopsies from DTH sites will be
investigated for the presence of specific anti-tumor immunity.
Study burden and risks
Based on the experience with our cytokine-matured DC and the studies performed
by Dr. Pawel Kalinski (PhD, MD) exploiting TLR-ligand matured DC, we expect
that the TLR-matured DC will be well tolerated. Common and expected side
effects of DC vaccination are usually mild and include flu-like symptoms and
local reaction at injection site, both CTC grade 1. Furthermore a few patients
showed allergic reactions (4 patients) and/or depigmentation of the skin (3
patients).
Aferesis is a safe procedure. Patients will have to visit our outpatient clinic
(aferese, vaccination 1-3, skin test), extra blood will be drawn (vaccination 2
and 3 and skin test) and 6 mm biopsies will be taken from skin tests.
Geert Grooteplein 26
6525 GA
NL
Geert Grooteplein 26
6525 GA
NL
Listed location countries
Age
Inclusion criteria
For both stage III and IV melanoma;- histologically documented evidence of melanoma;- stage III or IV melanoma according to the 2001 AJCC criteria;- HLA-A2.1 phenotype is required;- melanoma expressing gp100 (compulsory) and tyrosinase (non-compulsory);- WHO performance status 0-1 (Karnofsky 100-70%);- life expectancy >3 months;- age 18-70 years;- no clinical signs or symptoms of CNS metastases;- WBC >3.0×109/l, lymphocytes >0.8×109/l, platelets >100×109/l, ;serum crea-tinine <150 µmol/l, serum bilirubin <25 µmol/l;- normal serum LDH (<=450 U/l);- expected adequacy of follow-up;- no pregnant or lactating women;- written informed consent;For stage III melanoma;- interval since regional lymph node dissection is <2 months, or radical lymph node ;dissection is planned;For stage IV melanoma;- at least one unidimensional measurable target lesions according to RECIST, not previously irradiated, and limited tumor burden, according to the responsible physician
Exclusion criteria
- prior chemotherapy, immunotherapy or radiotherapy <4 weeks prior to planned ;vaccination or presence of treatment-related toxicity;- history of any second malignancy in the previous 5 years, with the exception of adequately treated basal cell carcinoma or carcinoma in situ of the cervix ;serious active infections, HbsAg or HIV positive or autoimmune diseases or organ allografts ;- concomitant use of immunosuppressive drugs;- known allergy to shell fish (since it contains KLH);- rapidly progressive disease;- any serious clinical condition that may interfere with the safe administration of DC
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-001973-14-NL |
| CCMO | NL22750.000.08 |