This is an interventional study and the primary objective is the immunogenicity of combined pDC and myDC vaccination. The secondary objectives are the biodistribution, the safety, quality of life and overall survival.
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is the immunogenicity of single and combined pDC and mDC
vaccination.
Immunogenicity is defined as the antitumor immune response induced in stage III
melanoma patients. Therefore, immunomonitoring will be performed that includes:
1) Type I IFN gene expression in PBMC shortly after vaccination. The occurrence
of the type I IFN response in patients will be compared.
2) Proliferative, effector cytokine- and humoral responses to keyhole limpet
hemocyanin (KLH).The occurrence of the response will be compared.
3) Functional response and tetramer analysis of DTH-infiltrating T cells
against tumor peptides. The occurrence of the response will be compared.
Secondary outcome
The biodistribution, safety, quality of life and overall survival are secondary
objectives.
Biodistribution is:
(a) The migratory capacity of blood DC in vivo.
(b) The localization of injected blood DC in dissected lymph nodes.
Background summary
Melanoma is a highly malignant melanocyte-derived tumor. For patients with
resected high-risk primary melanoma and regional lymphnode metastases (stage
III), no standard systemic adjuvant treatment is available. We have explored
immunotherapy and have now vaccinated well over 300 melanoma patients with
monocyte-derived dendritic cell (moDC) vaccines and proved that DC therapy is
safe with minimal side effects. We observed that long lasting tumor specific T
cell-mediated immunological responses are clearly linked to increased
progression free- as well as overall- survival.
To date, most clinical trials use monocyte-derived DC (moDC) for DC
vaccination of cancer patients. We observed an increase in median survival in
stage III melanoma patients vaccinated with moDC in an adjuvant setting as
compared to carefully selected historical controls (64 vs 31 months, p=<0.02).
However, moDC may not be the optimal source of DC for DC-based vaccination
studies, due to extensive culture periods and compounds required to obtain
mature moDC. Since they do not require extensive culture periods, peripheral
blood-derived DC may be a good alternative. We recently completed a clinical
trial in stage IV melanoma patients using pDC. The results on both
immunological outcome as well as clinical outcome are promising. Additionally,
the first patients are vaccinated with blood-derived myeloid DC. In these
patients tumor-specific responses are observed as well. Taken together, we
demonstrated that it is feasible to use blood-derived pDC and myDC and that
these cells can be activated and loaded with peptides before injection into
melanoma patients. Based on in vitro data and preclinical studies, we
hypothesize that the combination of blood myDC and pDC may induce stronger
anti-tumor immune responses. The aim of this study is to investigate the
immunogenicity of combined pDC and myDC vaccination.
Study objective
This is an interventional study and the primary objective is the immunogenicity
of combined pDC and myDC vaccination. The secondary objectives are the
biodistribution, the safety, quality of life and overall survival.
Study design
This study is an interventional study.
Intervention
Stage lll melanoma patients will receive pDC (arm A, n=7), myDC (arm B, n=7) or
combined pDC/myDC (arm C, n=7). Subsequent vaccinations will be performed
according to the protocol: 2 biweekly vaccinations of intranodal injections
with pDc, myDC or the combination with pDC and myDC. After each vaccination we
will examine peripheral blood for proliferative and humoral KLH immune
responses. After the vaccinations, a DTH with peptide-loaded blood DC is
performed from which biopsies are taken for T cell analysis. lf patients remain
disease free, we will repeat this cycle with a 6 months interval up to a total
of three cycles. lf a tumor recurrence occurs a biopsy will be taken for
laboratory evaluation.
Study burden and risks
Based on the experience with the pDC and myDC vaccination separately, we expect
that the combined DC vaccine will be well tolerated. Common and expected side
effects of DC vaccination are usually mild and include flu-like symptoms, not
greater than CTCAE grade 1. During the skin test, a small amount of vaccine is
injected into the skin of the back, this may give a local reaction at the
injection site: redness, swelling and itching. Patient material (blood, lymph
nodes and skin and tumor biopsies) will be requested during the current study.
Geert Grooteplein 26
Nijmegen 6500HB
NL
Geert Grooteplein 26
Nijmegen 6500HB
NL
Listed location countries
Age
Inclusion criteria
- stage III melanoma according to the 2009 AJCC criteria
- cytological or histological documented evidence of stage III melanoma
- WHO performance status 0-1 (Karnofsky 100-70) (Appendix 1)
- life expectancy *3 months
- age 18-75 years
- WBC >3.0×109/l, lymphocytes >0.8×109/l, platelets >100×109/l,
serum creatinine <150 µmol/l, serum bilirubin <25 µmol/l
- normal serum LDH (*250 U/l)
- expected adequacy of follow-up
- no pregnant or lactating women
- written informed consent
Exclusion criteria
- irresectable stage III melanoma or stage IV melanoma
- any concurrent adjuvant therapy
- 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, known HbsAg or HIV positive, or autoimmune diseases or organ allografts
- concomitant use of oral immunosuppressive drugs
- known allergy to shell fish (since it contains KLH)
- any serious clinical condition that may interfere with the safe administration of DC or apheresis
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 | EUCTR2010-023757-11-NL |
| CCMO | NL49528.000.14 |