Prevention vaccines in clinical trials may help patients with rare, deadly childhood cancer syndrome

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Scientists at the Frederick National Laboratory for Cancer Research are studying vaccines designed to prevent cancers associated with Lynch syndrome and developing a biomarker panel to detect frameshift mutations and wanted to determine if the same approach can help patients with constitutional mismatch repair deficiency, CMMRD, a rare but devastating inherited cancer syndrome that affects very young children.

A meticulous search for the extremely rare patient samples led to research that shows some of the frameshift mutations in adult Lynch syndrome tumors are also found in CMMRD tumor specimens.

Yurong Song, Ph.D., team lead of the Cancer Immunoprevention Laboratory within the Vaccine, Immunity and Cancer Directorate, studies frameshift neoantigen-based cancer prevention vaccines on behalf of the National Cancer Institute’s Division of Cancer Prevention. Similar vaccines are now being tested in Lynch syndrome patients in clinical trials. 

Same inherited mutations cause two cancer syndromes: one relatively common among adults, the other rare, affecting very young children

Lynch and CMMRD are distinct cancer syndromes, yet both are caused by an inherited mutation in one of four genes: MLH1, MSH2, MSH6 or PMS2. These genes help repair DNA damage through a process called mismatch repair or MMR.

A single pathogenic mutation of a gene involved in MMR causes Lynch syndrome, a relatively common condition that puts people at greater risk for colon, uterine, ovarian and small bowel cancer. Most Lynch syndrome carriers develop these tumors in adulthood, although a rare subset of carriers develop cancer during childhood or young adulthood.

People who inherit mutations of the same genes involved in MMR from both parents have CMMRD. More than half of young patients with CMMRD develop brain tumors, blood cancers and other cancer types, with some occurring simultaneously or one after the other and resulting in death in the first two to three decades of life; 90 percent of patients develop cancer by age 18. Tumors start showing up in very early childhood. 

One out of 370 people is affected by Lynch syndrome. The incidence of CMMRD is about one in 1 million births though it is higher among children of parents who are blood relatives. It is estimated that one in 16 individuals of the Nunavik Inuit population in northern Quebec, Canada, is a carrier for PMS2, leading to a higher frequency of CMMRD.

With shared frameshift mutations, Lynch vaccine could benefit CMMRD patients 

To determine if CMMRD and pediatric Lynch patients might benefit from the vaccines under development for adult Lynch syndrome, scientists needed relevant patient tumor, blood and other samples. Song’s lab was tasked to identify collaborators to obtain human patient samples of CMMRD and pediatric Lynch syndrome for testing. 

As the CMMRD mutation is rare and associated cancers develop in children, patient samples are extremely difficult to come by. 

Song consulted the Frederick National Laboratory’s Biospecimen Research Group within the Clinical Research Directorate, whose expertise in procuring high-quality biospecimens including rare samples made them the ideal collaborators. The group connected Song with Yuriko Mori, M.D., Ph.D., an experienced researcher in Lynch syndrome and related cancers within the group, who knew exactly what Song was looking for.

Locating rare patient samples required deep dive search

Initial contact with a Canadian investigator who had experience with the Inuit population and inquiries to clinical research organizations in Canada produced no samples So, Mori put the Biospecimen Research Group's network and her investigative skills to work to locate the rare specimens:

• Began outreach to multiple biospecimen source sites within the group’s network which covers academia, industry, and nonprofit organizations.
• Conducted a literature search to identify any research institution that had published a case study or paper using a CMMRD sample.
• Checked in with disease-specific research networks and familial or pediatric cancer registries.
• Searched clinical trials focusing on pediatric cancers where investigators had participants undergo a whole genome sequencing, which may have led to an incidental finding of CMMRD.
• Leveraged any new contacts as gateways to further expand the network.

When identifying sources for samples for research, Mori said it’s generally more efficient to work with an organization that can provide multiple specimens. But with CMMRD, the team was lucky for an organization to have a single sample.

Once Mori identified a potential site, the next step was to invite them to collaborate. Song then laid out details of the project on a call, and it didn’t take long for potential collaborators at the sites to get excited.

“And when people get excited about the research, very often we can get collaboration,” Mori said. 

Of the 30 sites contacted, eight had relevant samples available and got on board. Following all required transfer agreements, they provided over 200 specimens from 12 CMMRD patients and 94 Lynch Syndrome patients (including 19 pediatric Lynch Syndrome cases) worldwide. Some wanted to continue the collaboration long term.

Song’s lab has sequenced and analyzed all the patient samples procured by Mori and is preparing a second manuscript based on the data. 

“By leveraging the diverse expertise and capabilities across the Frederick National Laboratory through extensive collaboration, such a project could be successfully completed,” Song said.