First trial of a vaccine against the shared neoantigens of mismatch-repair-deficient cancers
A vaccine of three frameshift peptides shared by almost all microsatellite-unstable tumours was safe and induced immune responses in every patient with MSI colorectal cancer, opening the path to cancer interception vaccines for Lynch syndrome.
Mismatch-repair-deficient tumours accumulate insertion or deletion mutations in the same coding microsatellites, producing frameshift peptide (FSP) neoantigens that are shared across patients. This phase I/IIa trial vaccinated 22 patients with a history of MSI-high colorectal cancer with three FSP neoantigens (derived from AIM2, HT001 and TAF1B) with Montanide adjuvant.
The vaccine was well tolerated (injection-site reactions only) and induced humoral and cellular immune responses in all patients who completed the schedule. The study established that shared frameshift neoantigens are immunogenic in humans and are candidates for an off-the-shelf preventive vaccine in Lynch syndrome carriers.
It seeded the Nous-209 adenoviral vaccine (209 frameshift neoantigens) now in trials in Lynch carriers, and the NCI's Lynch interception programme.
- 22 patients enrolled; no vaccine-related serious adverse events
- Humoral and cellular responses to at least one frameshift peptide in all patients who completed the three-vaccination schedule
- Frameshift neoantigens targeted are present in the majority of MSI-high colorectal cancers regardless of patient
- The paper provided human proof of principle for a shared-antigen interception vaccine
Because Lynch syndrome tumours make the same abnormal proteins in almost every patient, a single vaccine could in principle be given to carriers before cancer develops. This small trial showed the concept is safe and immunogenic; whether it prevents cancer requires the randomised trials now being planned.
- Immune response, not cancer prevention, was the endpoint
- Patients had existing or prior cancers, not healthy carriers
- Peptide vaccines with Montanide elicit modest T-cell responses compared with viral-vector or mRNA platforms
- Efficacy trials in carriers need thousands of participants and years of follow-up
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Shares A randomised trial of a shared-antigen vaccine to prevent Lynch syndrome cancers, Off-the-shelf cancer vaccines, Neoantigen, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
- Key paperCAPP2: two years of aspirin cuts bowel cancer in Lynch syndrome by more than a third over 10 years
Shares Lynch syndrome, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Inherited risk is mostly unidentified, Endometrial cancer.
- IdeaGet every Lynch syndrome carrier onto the right dose of aspirin
Shares Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Inherited risk is mostly unidentified, Prevention we already have is not deployed, Colorectal cancer.
- TargetWRN helicase (MSI-high cancers)
Shares Lynch syndrome, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Endometrial cancer, Colorectal cancer.
- IdeaAutomatic germline testing for every cancer type where it changes care
Shares Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Inherited risk is mostly unidentified, Colorectal cancer.
- IdeaA therapeutic vaccine to clear cervical precancer without surgery
Shares Cancer interception vaccines for high-risk carriers, Prevention we already have is not deployed.
- PersonStefan Fröhling
Shares Heidelberg University Hospital / NCT / DKFZ, German Cancer Research Center (DKFZ).
- PersonAndreas von Deimling
Shares Heidelberg University Hospital / NCT / DKFZ, German Cancer Research Center (DKFZ).