A frameshift peptide neoantigen-based vaccine for mismatch repair-deficient cancers

• Verfasst von: Kloor, Matthias [VerfasserIn]
• Verfasst von: Reuschenbach, Miriam [VerfasserIn]
• Verfasst von: Pauligk, Claudia [VerfasserIn]
• Verfasst von: Karbach, Julia [VerfasserIn]
• Verfasst von: Rafiyan, Mohammad-Reza [VerfasserIn]
• Verfasst von: Batran, Salah-Eddin al- [VerfasserIn]
• Verfasst von: Tariverdian, Mirjam [VerfasserIn]
• Verfasst von: Jäger, Elke [VerfasserIn]
• Verfasst von: Knebel Doeberitz, Magnus von [VerfasserIn]
• Titel: A frameshift peptide neoantigen-based vaccine for mismatch repair-deficient cancers
• Titelzusatz: a phase I/IIa clinical trial
• Verf.angabe: Matthias Kloor, Miriam Reuschenbach, Claudia Pauligk, Julia Karbach, Mohammad-Reza Rafiyan, Salah-Eddin Al-Batran, Mirjam Tariverdian, Elke Jäger, Magnus von Knebel Doeberitz
• E-Jahr: 2020
• Jahr: September 2020
• Umfang: 8 S.
• Fussnoten: Gesehen am 03.12.2020
• Titel Quelle: Enthalten in: Clinical cancer research
• Ort Quelle: Philadelphia, Pa. [u.a.] : AACR, 1995
• Jahr Quelle: 2020
• Band/Heft Quelle: 26(2020), 17, Seite 4503-4510
• ISSN Quelle: 1557-3265
• DOI: doi:10.1158/1078-0432.CCR-19-3517
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1741931029

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 MMR-deficient 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.