Prevention of cancer development in patients with Lynch syndrome

Evaluating more than 200 patients treated the past ten years with ex vivo generated tumor-antigen-loaded dendritic cells (DC), we found that this vaccination is safe and has limited side effects. Clinical responses measured in several patients directly coincided 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 immune-stimulatory 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 potentially 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 (i) tumor specific, because frameshift mutations only occur in tumor cells and their premalignant progenitor; (ii) 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, representing 10-15% of all colorectal cancers.
Currently, the clinical trial to show safety and feasibility of CEA/frameshift derived neopeptide loaded DC is being carried out, in patients with MSI-positive colorectal cancer and persons who are known to be carrier of a germline MMR-gene mutation with no signs of disease yet. This unique approach using the DC as a preventive vaccination had a lot of attention in the press: NOS news, ZonMw website and regional news ‘Omroep Gelderland’.