Cancer Preventive Vaccine Nous-209 for Lynch Syndrome Patients

PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of adenoviral tumor-specific neoantigen priming vaccine GAd-209-FSP (GAd20-209-FSPs) (1 prime) and MVA tumor-specific neoantigen boosting vaccine MVA-209-FSP (MVA-209-FSPs) (1 boost) vaccination when administered as a single agent (monotherapy) in participants with Lynch syndrome (LS). II. To evaluate the neoantigen-specific immunogenicity of GAd20-209-FSPs (1 prime) and MVA-209-FSPs (1 boost) vaccination when administered as a single agent (monotherapy) in participants with LS. III. To evaluate the neoantigen-specific immunogenicity of GAd20-209-FSP prime and MVA-209-FSP boost or MVA-209-FSP boost alone when administered to previously-vaccinated immunogenic participants with LS. IV. To evaluate the safety and tolerability of GAd20-209-FSP prime and MVA-209-FSP boost or MVA-209-FSP boost alone when administered to previously vaccinated immunogenic participants with LS. SECONDARY OBJECTIVES: I. To assess the effect of Nous-209 vaccination on T cell immune profile and T cell receptor (TCR) repertoire in the peripheral blood of participants with LS. II. To assess the effect of Nous-209 vaccination on TCR repertoire within histologically normal colorectal mucosal of participants with LS. III. To evaluate the effect of Nous-209 vaccination on tumor infiltrating lymphocyte (TIL) immune profile and TCR repertoire within colorectal adenomas in participants with LS. IV. To assess the cytotoxicity of matched T cells on participant-derived colorectal adenoma organoids following Nous-209 vaccination in participants with LS. V. To evaluate the effect of Nous-209 vaccination on the burden of colorectal adenomas/advanced neoplasia/carcinoma in participants with LS. VI. To assess the effect of Nous-209 vaccination on the burden of LS-related carcinomas in participants with LS. VII. To evaluate the effect of Nous-209 vaccination on cell free deoxyribonucleic acid (DNA) (cfDNA) mutation profiles and cfDNA burden in participants with LS. VIII. To correlate tobacco and alcohol consumption with the immune response to Nous-209 in trial participants. IX. To assess the mismatch repair (MMR) and/or microsatellite instability (MSI) status of polyps (and adjacent normal mucosa as control) detected in the baseline and end-of-the-study colonoscopy using different technologies such as immunohistochemistry, MSI analysis by polymerase chain reaction (PCR), or next-generation sequencing. OUTLINE: PART I: Patients receive GAd20-209-FSPs intramuscularly (IM) on day 1 and MVA-209-FSPs IM at week 8. Patients undergo endoscopy with biopsy during screening and follow up as well as blood sample collection on the trial. PART II: Eligible patients from Part I are randomized to 1 of 2 arms. ARM A: Patients receive GAd20-209-FSPs IM at week 52 and MVA-209-FSPs IM at week 60. Patients undergo endoscopy with biopsy as well as blood sample collection on the trial. ARM B: Patients receive MVA-209-FSPs IM at week 52. Patients undergo endoscopy with biopsy as well as blood sample collection on the trial. After completion of study treatment, patients are followed up at weeks 16, 24, 36, and 52.