Background: High level microsatellite instability (MSI-H) occurs in 15% of colorectal cancers as a consequence of DNA mismatch repair deficiency. MSI-H colorectal cancers are characterized by a dense immune cell infiltration. They are characteristic of the inherited HNPCC (hereditary non-polyposis colorectal cancer) or Lynch syndrome, but can also develop sporadically. DNA mismatch repair deficiency causes insertion or deletion mutations at coding microsatellites, which leads to the generation of frameshift peptide (FSP) antigens. FSP antigens are attractive targets for vaccination, because they are highly immunogenic shared antigens, which directly result from driver mutations in MSI-H cancers. To evaluate safety and immunological efficacy of FSP vaccination, we have initiated a clinical phase I/IIa vaccination trial (Micoryx). Methods: The protocol comprised 3 cycles of 4 subcutaneous applications of FSP antigens (frameshift variants of the coding microsatellite-containing genes AIM2, HT001, TAF1B) mixed with Montanide ISA-51 VG over a 6 month period. Inclusion criteria were history of colorectal cancer (UICC stage III or IV) who received standard chemotherapy. Phase I of the trial evaluated safety and toxicity as the primary endpoint (6 patients), phase IIa addressed the induction of cellular and humoral immune responses (16 patients). Results: No FSP antigen-associated severe adverse events have been observed. Significant induction of FSP-specific immune responses against one or more FSP antigens was observed in all patients vaccinated per protocol. Few patients had stage IV disease and were evaluable according to RECIST. One heavily pretreated patient with bulky metastases showed a stable disease and stable CEA levels over 7 months under the study treatment. Conclusions: Vaccination with FSPs is well tolerated and leads to the induction of humoral and cellular immune responses. FSP vaccination represents a promising novel approach for treatment of MSI-H colorectal cancer patients and for tumor prevention in Lynch syndrome, allowing the evaluation of the concept of preventive cancer vaccines in an ideal model scenario of a defined high-risk patient population. Clinical trial information: NCT01461148