A Preventive Vaccine for Lynch Syndrome?

Lynch syndrome (LS), or Hereditary nonpolyposis colorectal cancer (HNPCC), is the most common hereditary colorectal cancer that accounts for 3–5% of all colorectal cancers in the United States. The syndrome is one that is passed genetically from parent to child, and its early onset predisposes an individual to colorectal cancer and many other cancers, and can be disruptive to normal life.

As such, a preventive vaccine could not only reduce the risk of developing colorectal and other LS-associated cancers, but also improve quality of life for such individuals.

A clinical trial funded by the National Cancer Institute has begun investigating if the combination of adenovirus-based vaccines that include three tumor-associated antigens with an IL-15 superagonist can reduce the incidence of cancer in Lynch syndrome individuals.

The adenovirus vaccine combination, referred to as trivalent adenovirus-5 (Tri-Ad5), targets three components found in precancerous and cancer cells: brachyury, carcinoembryonic antigen (CEA) and mucin-1 (MUC1). These proteins are overexpressed in many cancers including colorectal cancer, and are useful diagnostic markers.

Like how other preventive vaccines work, the components are used to trigger an immune response and “train” memory T cells into recognizing precancerous and cancer cells that overexpress these antigens.

The IL-15 superagonist nogapendekin alfa inbakicept (N-803), or NAI, is a fusion protein that is designed to imitate the way interleukin 5 (IL-5) amplifies natural killer (NK) cell responses and antibody-dependent cellular cytotoxicity (ADCC), and increases IFNγ production in cells.

During the trial, participants will receive the vaccine through injections administered at weeks 0, 4, 8 and 52, and will undergo colonoscopies at weeks 52 and 104 to monitor the development of any colorectal neoplasms.

Recruitment is ongoing for this phase 2 clinical trial, and the study is expected to conclude in 2027.

The heterogeneous and multifactorial nature of colorectal cancer frequently requires different approaches to treatment that, at times, have limited effectiveness. While research into therapeutic vaccines have also been making steady headway, a preventive vaccine that nips the problem of Lynch syndrome in the bud could pave the way for similar approaches in preventing other colorectal cancer subtypes.