Microsatellite-unstable (MSI) tumors often possess identical mutations between patients, encoding conserved frameshift peptide (FSP) neoantigens in tumor suppressor genes. Kloor et al. report a clinical trial of an FSP long peptide + Montanide vaccine in 22 previously treated patients with MSI colorectal cancer. The vaccine was well tolerated in the majority of patients. All patients demonstrated FSP-specific immunity after vaccination compared to 50% before, most commonly through antibody responses, followed by CD4+ and then CD8+ T cell responses. Of the 3 patients who had tumors prior to treatment, two experienced stable disease after treatment.
Contributed by Alex Najibi
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). EXPERIMENTAL DESIGN: The trial comprised 3 cycles of 4 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 (6 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 pre-treated 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.