Abstract A006: Frameshift peptide neoantigens as vaccine targets in microsatellite-unstable cancers

Abstract

Abstract Background: Deficient DNA mismatch repair (MMR) boosts the accumulation of frameshift mutations in genes encompassing coding microsatellites (cMS). This results in translation of proteins with mutation-induced frameshift peptide (FSP) neoantigens rendering MMR-deficient microsatellite-unstable (MSI) cancers highly immunogenic. Patients with MSI cancers and healthy individuals affected by Lynch syndrome, an inherited prediposition for MSI cancers, develop specific immune responses against these neoantigens. MSI cancers are unique in tumor immunology, because they express a defined set of long neoantigens that result from functionally relevant driver mutations and therefore are shared by the majority of MSI cancers. Consequently, MSI cancers in Lynch syndrome are an ideal model to evaluate the concept of cancer vaccines, which, with the increasing knowledge about mutational antigens in a wide variety of cancer types, can potentially be applied to many human cancer types. We here report the results of a clinical phase I/IIa trial as the first step to translate this concept into the clinical application. Methods: The vaccination 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 MSI-H colorectal cancer (UICC stage III or IV) and completion of 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: Significant induction of FSP-specific immune responses against one or more FSP antigens was observed in all patients vaccinated per protocol. No vaccination-induced systematic severe adverse events occurred. 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 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. Note: This abstract was not presented at the conference. Citation Format: Magnus von Knebel Doeberitz, Matthias Kloor, Miriam Reuschenbach, Claudia Pauligk, Mohammad-Reza Rafiyan, Salah-Eddin Al Batran, Julia Karbach, Mirjam Tariverdian, Elke Jaeger. Frameshift peptide neoantigens as vaccine targets in microsatellite-unstable cancers [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A006.