Trial Information

Dendritic Cell Vaccination in Patients With Lynch Syndrome or Colorectal Cancer With MSI

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.