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

Abstract

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 MMRdeficient 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.

The Peptide Vaccine of the Future

“…Owing to their true tumor specificity, neoepitopes are not affected by central or peripheral tolerance, which renders them ideal targets. The encouraging potential of neoantigen-based vaccination approaches was already investigated in preclinical and early-phase clinical trials assessing neoantigen-based peptide vaccines in several different cancer entities ( 11 , 12 , 13 , 14 ). Yet, substantial challenges remain in the effective identification of immunogenic and naturally presented neoepitopes derived from point mutations, insertion–deletions or frame-shift mutations.…”

Immunology of Lynch Syndrome

“…Frameshift peptide-specific effector T cell responses are detectable in the peripheral blood of both healthy LS patients without history of cancer and those with LS-CRC [44,[46][47][48]. In the evaluation of immune responses in these individuals, it was noted that the observed T cell responses were directed at 14 different FSP antigens with varying mutation frequencies predicted from human genome databases; it was discovered that the neoantigens derived from genes with high mutation frequencies that exhibit in vitro immunogenicity were common to both LS-CRC and sporadic MSI-CRC, demonstrating a "shared landscape" [44,49].…”

“…In the evaluation of immune responses in these individuals, it was noted that the observed T cell responses were directed at 14 different FSP antigens with varying mutation frequencies predicted from human genome databases; it was discovered that the neoantigens derived from genes with high mutation frequencies that exhibit in vitro immunogenicity were common to both LS-CRC and sporadic MSI-CRC, demonstrating a "shared landscape" [44,49]. Among these genes were HT001, AIM2, TAF1B, TGFβRII, and FSP06 [46,[50][51][52][53][54][55].…”

Perspectives on Immunotherapy of Metastatic Colorectal Cancer

“…However, only two patients (9%, two of 22 patients) achieved stable disease as best overall response. Among them, stable disease and stable CEA levels (≥7 months) was observed in a severely metastatic patient received extensive treatment ( 83 ).…”