A Frameshift Peptide Neoantigen-Based Vaccine for Mismatch Repair-Deficient Cancers: A Phase I/IIa Clinical Trial

Clin Cancer Res. 2020 Sep 1;26(17):4503-4510. doi: 10.1158/1078-0432.CCR-19-3517. Epub 2020 Jun 15.


Purpose: DNA mismatch repair (MMR) deficiency is a hallmark of Lynch syndrome, the most common inherited cancer syndrome. MMR-deficient cancer cells accumulate numerous insertion/deletion mutations at microsatellites. Mutations of coding microsatellites (cMS) lead to the generation of immunogenic frameshift peptide (FSP) neoantigens. As the evolution of MMR-deficient cancers is triggered by mutations inactivating defined cMS-containing tumor suppressor genes, distinct FSP neoantigens are shared by most MMR-deficient cancers. To evaluate safety and immunogenicity of an FSP-based vaccine, we performed a clinical phase I/IIa trial (Micoryx).

Patients and methods: The trial comprised three cycles of four subcutaneous vaccinations (FSP neoantigens derived from mutant AIM2, HT001, TAF1B genes) mixed with Montanide ISA-51 VG over 6 months. Inclusion criteria were history of MMR-deficient colorectal cancer (UICC stage III or IV) and completion of chemotherapy. Phase I evaluated safety and toxicity as primary endpoint (six patients), phase IIa addressed cellular and humoral immune responses (16 patients).

Results: Vaccine-induced humoral and cellular immune responses were observed in all patients vaccinated per protocol. Three patients developed grade 2 local injection site reactions. No vaccination-induced severe adverse events occurred. One heavily pretreated patient with bulky metastases showed stable disease and stable CEA levels over 7 months.

Conclusions: FSP neoantigen vaccination is systemically well tolerated and consistently induces humoral and cellular immune responses, thus representing a promising novel approach for treatment and even prevention of MMR-deficient cancer.

Trial registration: ClinicalTrials.gov NCT01461148.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm / administration & dosage*
  • Antigens, Neoplasm / adverse effects
  • Antigens, Neoplasm / genetics
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / adverse effects
  • Cancer Vaccines / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / prevention & control*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / complications
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • Colorectal Neoplasms, Hereditary Nonpolyposis / immunology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / therapy*
  • DNA Mismatch Repair*
  • DNA-Binding Proteins / genetics
  • Female
  • Frameshift Mutation
  • Humans
  • Injections, Subcutaneous
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Pol1 Transcription Initiation Complex Proteins / genetics
  • Proteins / genetics
  • Vaccines, Subunit / administration & dosage
  • Vaccines, Subunit / adverse effects
  • Vaccines, Subunit / genetics


  • AIM2 protein, human
  • ASTE1 protein, human
  • Antigens, Neoplasm
  • Cancer Vaccines
  • DNA-Binding Proteins
  • Pol1 Transcription Initiation Complex Proteins
  • Proteins
  • TAF1B protein, human
  • Vaccines, Subunit

Associated data

  • ClinicalTrials.gov/NCT01461148
  • EudraCT/2011-000765-12