Primary objectives: we aim to investigate the feasibility of NK cell immunotherapy by evaluating the expression of activating and inhibitory NK cell receptor ligands on primary tumor cells. secondary objectives: we aim to evaluate the cytotoxic…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
if the BM sample is infiltrated by NBL cells, the expression of activating NK
cell receptor ligands on the tumor itself; such as MIC (MICA/B) and ULBP
(ULBP1-4) proteins and CD112-/ CD155 as well as the expression of HLA class I
(inhibitory liogand), CD54-/CD58 (adhesion) will be evaluated bij FACS analysis
using multiple markers.
NK cell sensitivity will be determined by labelling primary NBL cells with
51-Chromium or by chemo luminescent methods and adding resting and cytokine
actyivated NK cells. Furthermore, if NK cell cytotoxicity occurs, activating NK
cell receptors will be blocked by monocklonal antibodies (NKG2D, DNAM-1),
thereby allowing amnalysis of the activating signals involved. peripheral blood
samples of newly diagnosed, treated and during FU of HR NBL patients will allow
analysis of NK cell phenotype and function in these patients.
Phenotyping
The presence of a variety of lymphocyte subsets (e.g. standard T-cell subset,
dendritic cells, lineages of suppressor cells) has been described to be
associated with either response or failure of therapy in cancer patients,
including those treated with IL-2 or GM-CSF. For the present proposal we will
study the number and differentiation of each subset present in the HR NBL
patients in different stages of the disease/treatment regimen.
Immunophenotyping will be performed on biobanked peripheral blood and available
bone marrow aspirates using flow cytometry to visualize subsets of:
1. T cells (naïve, central/effector memory, resting or activated CD4, CD8 and
gamma/delta TCR)
2. Regulatory T cells (CD3/CD4/CD127/CD25/FoxP3)
3. T helper subsets (Th1, Th2, Th17, Th22)
4. B cells (naïve, memory, transitional, plasmablasts)
5. NK/NKT cells (CD16/CD56, CD3, Va24/Vb11)
6. DC/mono ((non-)classismal monocytesm, cDC and pDC)
7. Myeloid-derived (suppressor) cells and Tr1 cells
Secretome
Analyzing the profile of secreted cytokines, chemokines and growth factors
represents an integral part of immunomonitoring during immunotherapeutic
treatments. These biomarkers can distinguish diverse disease/response patterns
and identify surrogate markers of efficacy. Our home-made designed panel of
100+ markers include biomarkers for general inflammatory activation (e.g. IL-1,
IL-6, IL-18, TNF-a, sIL-2R etc.), Th cell skewing (e.g. IFN-g, IL-5, IL-13,
IL-17, IL-10), chemo attraction (full panel of CCL and CXCL), granulocyte
activation (e.g. elastase), etc. We will assess the dynamics of these markers
in time in each individual patient to study a profile of biomarkers that may be
diagnostic/prognostic for efficacy versus toxicity and that will be included in
immunomonitoring programs of future clinical trials.
Secondary outcome
N/A
Background summary
The defining characteristics of high risk (HR) NBL include an age of more than
one year, with regional or metastatic disease, unfavourable Shimada histology
or Myc-N amplification (NMA). Patients with HR NBL have a 5-year survival rate
of only 30-40%, even if there is a favourable response to initial therapy. For
the majority of patients with relapsed refractory solid tumors, there are
currently no further treatment options other than phase I/ II studies or
palliation. Therefore, we aim to explore the feasibility of adoptive
immunotherapy (AIT) as an additional treatment modality for this tumor, with a
focus on natural killer (NK) cells.
Study objective
Primary objectives: we aim to investigate the feasibility of NK cell
immunotherapy by evaluating the expression of activating and inhibitory NK cell
receptor ligands on primary tumor cells.
secondary objectives: we aim to evaluate the cytotoxic potential of
unstimulated and cytokine stimulated NK cells towards primary NBL tumor cells.
Cytotoxic activity of NK cells towards NBL cells in vitro and additional
stimulation methods (cytokines, irradiation, tumor manipulation). This will
encourage the development of novel AIT strategies as an additional treatment
for high risk or relapsed NBL next to conventional or other novel therapies
Study design
Prospective analysis, in newly diagnosed HR NBL patients, as well during
therapy and FU of bone marrow (BM) samples that are infiltrated with NBL cells
and immune cells (i.e. NK cells) obtained from blood, in order to perform
immunological analysis.
Study burden and risks
No additional burden, risks, the patients will undergo a bone amrrow aspirate
and bloods will be taken as a routine procedure in a newly diagnosed patient
(at diagnosis, during treatment and FU, max. 8 times). In this study additional
material will be taken during the same procedure: bone marrow 3-5 ml and blood
5-10 ml.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
High risk neuroblastoma, between 1 and 18 years at diagnosis
Neuroblastoma histological proven diagnosis
Informed consent
Initial staging of the tumor
No pregnancy
Exclusion criteria
Any prior anticancer treatment
Design
Recruitment
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 |
|---|---|
| CCMO | NL50762.018.14 |