A frameshift peptide neoantigen-based vaccine for mismatch repair-deficient cancers: a phase I/IIa clinical trial
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 fr...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
September 2020
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| In: |
Clinical cancer research
Year: 2020, Volume: 26, Issue: 17, Pages: 4503-4510 |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-19-3517 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1158/1078-0432.CCR-19-3517 Verlag, lizenzpflichtig, Volltext: https://clincancerres.aacrjournals.org/content/26/17/4503 
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| Author Notes: | Matthias Kloor, Miriam Reuschenbach, Claudia Pauligk, Julia Karbach, Mohammad-Reza Rafiyan, Salah-Eddin Al-Batran, Mirjam Tariverdian, Elke Jäger, Magnus von Knebel Doeberitz |
| Summary: | 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. |
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| Item Description: | Gesehen am 03.12.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1557-3265 |
| DOI: | 10.1158/1078-0432.CCR-19-3517 |