Clinical trial NCT01885702: Dendritic Cell Vaccination in Patients With Lynch Syndrome or Colorectal Cancer With MSI
Official title: Dendritic Cell Vaccination in Patients With Lynch Syndrome or Colorectal Cancer With MSI
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Colorectal Cancer
Keywords: Dendritic cell vaccination
MSI-high colorectal cancer (CRC)
Vaccines
Immunotherapy
CRC
Germline MMR-gene mutation without disease criteria of CRC
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2013-06-25
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Objectives:

In this Radboud University Nijmegen Medical Centre (RUNMC) initiated study our first objective is to investigate toxicity (safety and feasibility) of vaccination with frameshift-derived neoantigen-loaded DC of CRC patients with an MSI-positive CRC and persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet.

The secondary objectives of the study are:

* to demonstrate that peptide-loaded DC can induce or enhance an immune response to tumor-associated antigen CEA and specific frameshift-derived neoantigens in the study population.
* to study the pathological and clinical responses, e.g. disease-free survival, determined according to the standard protocol.

Study design:

This study is a phase I/II open-label study.

Study population:

Two groups of adults will be vaccinated:

Group I) CRC patients, who are known to carry a germline MMR-gene mutation and patients with an MSI-positive CRC and yet unknown or negative MMR-gene mutation status.

Group II) persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet. All participants need to be HLA-A2.1 positive.

Detailed description: Rationale of this study:

Ex vivo generated and tumor-antigen-loaded dendritic cells (DC) are currently used in clinical vaccination protocols in cancer patients. DC vaccines are safe, with minimal side effects. Evaluating more than 200 patients treated the past ten years we found that clinical responses measured in several patients directly coincide with specific cytotoxic T cell responses. The majority of studies investigated the therapeutic effects of DC vaccines in late-stage cancer patients with metastasis. In these (heavily) pretreated patients the immune system is compromised. Based on our observations that a specific immune response is indicative for a good clinical outcome we believe that the full potential of these immunostimulatory cells has to be exploited in high-risk patients with low tumor burden or in a precancerous state.

A good clinical model are carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes, such as patients with Lynch syndrome (also known as Hereditary Non-Polyposis Colorectal Cancer or HNPCC). These persons have a lifetime risk of 60-80% for colorectal cancer that has developed within a few years from a precancerous adenoma. The immune system is thought to be of potential great importance as the colorectal cancer in Lynch syndrome is characterized by a strong lymphocyte infiltration, even at the stage of adenomas. In affected cancer lesions, MMR dysfunction results in frameshift mutations at short, repetitive DNA sequences referred to as microsatellites. In coding regions these mutations destroy gene function and have been demonstrated to lead to the production of neopeptides. These neopeptides are: 1) tumor specific, because frameshift mutations only occur in tumor cells and their premalignant progenitors, 2) are very similar between patients, since the same genes are affected by the mismatch repair defect and 3) immunogenic, since cytotoxic T cells (CTL) and helper T cells could be induced in vitro from blood of patients with Lynch syndrome. Similar mechanisms occur in sporadic colon cancer with MMR dysfunction, which represents about 10-15% of all colorectal 2.

Objectives:

In this Radboud University Nijmegen Medical Centre (RUNMC) initiated study our first objective is to investigate toxicity (safety and feasibility) of vaccination with frameshift-derived neoantigen-loaded DC of CRC patients with an MSI-positive CRC and persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet.

The secondary objectives of the study are to demonstrate that peptide-loaded DC can induce or enhance an immune response to tumor-associated antigen CEA and specific frameshift-derived neoantigens in the study population. And we want to study the pathological and clinical responses, e.g. disease-free survival, determined according to the standard protocol.

Study design:

This study is a phase I/II open-label study.

Study population:

Two groups of adults will be vaccinated:

Group I) CRC patients, who are known to carry a germline MMR-gene mutation and patients with an MSI-positive CRC and yet unknown or negative MMR-gene mutation status.

Group II) persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet. All participants need to be HLA-A2.1 positive.

Main study endpoints:

The first objective of this study is to toxicity (safety and feasibility) of vaccination with frameshift-derived neoantigen-loaded DC. This will be measured by recording of the adverse events according to the Common Terminology Criteria for Adverse Events version 3.0.

The secondary objectives of the study are to demonstrate that peptide-loaded DC can induce or enhance an immune response to tumor-associated antigen CEA and specific frameshift-derived neoantigens in the study population. Immune responses will be assessed as:

* proliferative and humoral response to KLH
* cytokine production of KLH stimulated PBMC
* tumor antigen-specific T cell responses in peripheral blood
* tumor antigen-specific T cell responses in biopsies from DTH
* cytokine production of T cells in biopsies from DTH
* cytotoxicity of T cells in biopsies from DTH
* immunohistochemical characterization of DTH infiltrating lymphocytes

The pathological and clinical responses, e.g. disease-free survival, will be determined according to the standard protocol.

Eligibility criteria: Inclusion Criteria:

* histologically documented evidence of CRC (group I) and Lynch syndrome carrier without signs of disease (group II)
* HLA-A2.1 phenotype is required
* MSI high tumor
* WBC \>3.0 x 109/l, lymphocytes \>0.8 x 109/l, platelets \>100 x 109/l, serum crea¬tinine \<150 µmol/l, serum bilirubin \<25 µmol/l
* WHO performance status 0-1 (Karnofsky 100-70%)
* Age 18-75 years
* Expected adequacy of follow-up
* Written informed consent

Exclusion Criteria:

* History of malignancy in the past 5 years with the exception of adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix
* Serious active infections, HbsAg or HIV positive (test only in case of high risk or clinical suspicion)
* Autoimmune diseases or organ allografts
* Concomitant use of immunosuppressive drugs
* Known allergy to shell fish
* Pregnant or lactating women

Primary outcomes:
measure: Safety and feasibility of vaccination with frameshift-derived neoantigen-loaded DC of CRC patients
timeFrame: 5 years
Secondary outcomes:
measure: To evaluate whether peptide-loaded DC can induce or enhance an immune response to tumor-associated antigen CEA and specific frameshift-derived neoantigens in the study population
timeFrame: 5 years
measure: Pathological responses
timeFrame: 5 years
measure: Clinical responses, e.g. disease-free survival, determined according to the standard protocol.
timeFrame: 5 years
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Centre
state: Gelderland
Study officials:
affiliation: Radboud University Medical Center
name: Nicoline Hoogerbrugge-van der Linden, professor
role: STUDY_DIRECTOR
affiliation: Radboud University Medical Center
name: Jolanda IM de Vries, professor
role: PRINCIPAL_INVESTIGATOR
References: