Study of expression of and immunity against neoantigens in patients with constitutional mismatch repair deficiency (CMMR-D) syndrome

CMMRD
In 1999, a recessive paediatric tumor predisposition syndrome called
Constitutional Mismatch Repair Deficiency (CMMR-D) syndrome was recognized.
CMMR-D syndrome is caused by homozygous or compound heterozygous germline
mutations in one of the DNA mismatch repair (MMR) genes. Mainly three types of
malignancy characterize this syndrome: gastrointestinal tract cancer,
haematological malignancies and brain tumors, which occur in childhood or
adolescence. If patients survive the first malignancy, they have a high chance
of developing a second or even a third malignancy. To date, patients with
CMMR-D are intensively screened but this does not guarantee the detection of
precancerous lesions or cancer at a curable stage. A preventive treatment
modality would therefore be a major step forward.
Due to germline mutations in MMR genes coding for proteins involved in repair
of nucleotide mismatches, truncated proteins with impaired function are formed.
These aberrant proteins can be recognized by the immune system and they might
be excellent targets for immunotherapy since only tumor cells express them.

DC vaccination
Dendritic cells (DCs) play a central role in the induction of immune responses.
During an infection, DCs become activated and migrate to the lymph nodes where
they stimulate specific killer T cells. Their decisive role in inducing
immunity formed the rationale for DC immunotherapy: DCs loaded with tumor
antigens are injected into cancer patients to stimulate T cells to eradicate
tumors. In experimental clinical studies, DC vaccination has led to effective
anti-tumor immune responses and increased survival in patients with melanoma.
In healthy Lynch syndrome carriers, who have only a mono-allelic mutation in
their DNA mismatch repair system, DC vaccination has led to induction of
neoantigen-specific T cells, without inducing serious side effects.

DC vaccination of CMMRD
In this study we want to develop a preventive treatment for children
with CMMRD. We aim to induce immune responses against neoantigens with DC
vaccines, to prevent the formation of new lesions. For this, we need more
knowledge of the presence of neoantigens and immune responses in tumors of
CMMRD patients. In this explorative study, we will make an inventory of
neoantigens expressed by different tumors of patients with CMMRD syndrome, to
select/identify possible target antigens for DC vaccination studies. In
addition, we will investigate the presence and specificity of pre-existing
immune responses against neoantigens in blood of CMMR-D patients. The results
of this study will be translated into the development of a preventive DC
vaccine for children with CMMRD in a follow-up study.

In this explorative study, we aim to:
• Analyze neoantigens expressed on different tumors of CMMR-D patients, to
identify possible target antigens for DC vaccination studies.
• Investigate the presence of pre-existing immune responses against neoantigens
in CMMR-D carriers.

This study is a single arm exploratory, multi-centre study

There are no additional risks to participation in this study other than that of
regular blood collection. The burden for the participants is minimal, as blood
collection for the study will take place during regular blood collection.