To evaluate anti-tumor activity of T-cells in the GALT of patients with PDAC.
ID
Source
Brief title
Condition
- Exocrine pancreas conditions
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To identify tumour specific oncolytic activity of VA-GALT derived T cells in
patients with pancreatic cancer.
Secondary outcome
• To compare tumour specific antigens in plasma and tumor tissue of patients
with PDAC.
DNA sequencing will be used to identify mutant antigens, using the
Accel-Amplicon 56G Oncology Panel v2 (Swift Biosciences), compatible with the
Illumina HiSeq. If the tumor specific antigens in both plasma and tumor of the
same patient are comparable we could use the plasma results in the future for
peptide production.
• To identify the distinct immune gene expression signature in VAs from
patients with LAPC and (borderline) resectable PDAC compared to benign
controls.
To define the immune gene expression, we will use whole transcriptome RNA
sequencing, or the nCounter PanCancer Immune Profiling Panel (nanoString) that
includes 770 human genes. To validate abundance and location of the tumor
specific genes on the protein level, identified genes will be validated by
immunohistochemical staining of proteins in FFPE VA.. Proteins of interest are
selected based on differentially expressed genes from the RNA analyses..
• To compare peripheral blood T-cell and B cell receptor repertoires versus
lymphocytes of the VA in patients with PDAC.
Using the ImmunoSEQ Assay (Adaptive Biotechnologies) T cells and B cell
receptors will be sequenced using DNA from both PBMCs and from the of the VA
lymphocytes.
• To assess the VA microbiome we will collect fecal material of the resected
appendix and perform metagenomics shotgun sequencing (Illumina).
Background summary
The majority of pancreatic ductal adenocarcinoma (PDAC) patients are diagnosed
with advanced disease stage, for which surgical tumor removal has no impact on
survival. Development of novel therapeutic strategies is crucial to improve the
clinical outcome of patients with this devastating disease. PDAC is notorious
for an immune-suppressive tumor microenvironment, low numbers of intratumoral
cytotoxic T-cells which are often functionally exhausted and poor immune
checkpoint inhibitor response. We hypothesize that tumor antigens are presented
to naïve T-lymphocytes in lymph nodes and gut associated lymphoid tissue (GALT)
to induce differentiation to cytotoxic T cells (CTLs). Preclinical studies
performed in immune competent PDAC mouse models have shown that murine GALT may
be a potential source for pancreatic cancer specific CTLs. This study is
designed to investigate the molecular properties and anti-tumor cytolytic
function of T-cells isolated from the vermiform appendix (VA) of PDAC patients.
If the results of this study reveal that tumor reactive T-cells are present in
the GALT and capable of inducing PDAC cancer cell death, this research will
open up doors for therapeutic T cell transfer therapy and improvement of immune
therapy for PDAC.
Study objective
To evaluate anti-tumor activity of T-cells in the GALT of patients with PDAC.
Study design
Single center translational pilot study.
Intervention
Appendectomy during standard diagnostic laparoscopy or surgical resection in
all included patients. In addition, extra peripheral blood will be collected
for isolation of T cells and dendritic cells to be used in several laboratory
assays.
Study burden and risks
There are no extra benefits for the patients involved. The risks associated
with laparoscopic appendectomies (LA) for appendix sana are negligible. The
risk of complications from anesthesia or the introduction of laparoscopic
instrumentations in the abdomen will be shared, and thus not increase by the LA
procedure. The diagnostic laparoscopy will take 15 minutes longer, when the LA
is performed in addition to the diagnostic laparoscopy.
's-Gravendijkwal 230
Rotterdam 3015 CE
NL
's-Gravendijkwal 230
Rotterdam 3015 CE
NL
Listed location countries
Age
Inclusion criteria
• Age between 35 and 80 years.
• Histological or cytological confirmed pancreatic cancer (i.e. pancreatic
ductal adenocarcinoma).
• Planned diagnostic laparoscopy for LAPC or planned resection for
(borderline) resectable PDAC.
• Ability to undergo diagnostic laparoscopy and appendectomy.
• Written informed consent.
Exclusion criteria
• Previous appendectomy.
• Previous malignancy (excluding non-melanoma skin cancer), unless no evidence
of disease and diagnosed more than 5 years before diagnosis of pancreatic
cancer.
• Pregnancy.
• Serious concomitant systemic disorders that would compromise the safety of
the patient or his/her ability to complete the study, at the discretion of the
investigator.
• Use of immune suppressive medication in the past 3 months ( including TNF-α
antibody, azathioprine, mercaptopurine, methotrexaat, ciclosporin, adalimumab,
infliximab, or vedolizumab therapy).
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 | NL67371.078.18 |