Abstract 4160: Promoting immunogenicity of synthetic long peptide vaccines based on in vivo IgG complex formation: Preclinical evaluation and clinical entry of the TET platform

Abstract

Abstract Vaccines based on synthetic long peptides, targeting immunogenic region(s) of tumor associated proteins, are becoming increasingly used in oncology. Synthetic long peptides require endogenous processing by antigen presenting cells to be presented to T cells, thus reducing the risk of antigen presentation by non-professional antigen presenting cells lacking co-stimulation receptors. The formulation and delivery strategies require further development as peptides degrade rapidly in vivo. Herein we make use of a novel targeting and adjuvant strategy to deliver peptides to antigen presenting cells. Tumor-derived peptides are coupled to a B cell epitope element (the MTTE sequence, a tetanus toxin-derived universal B cell epitope) which induce the formation of peptide-conjugate -complex formation in vivo. This strategy, further named the TET technology, makes use of pre-existing antibodies to improve the bioavailability, stability, and immunogenicity of tumor-derived peptide therapeutics. The TET technology is here used in TENDU, a first-in-class prostate cancer vaccine candidate. TENDU incorporates selected immunogenic prostate cancer epitopes derived from PAP and PSMA. The peptides are designed to include proteasome processing elements along with a unique TAP translocation element. To assess the design, a conjugate with a known DR4 epitope embedded in a longer peptide was evaluated for T cell priming in HLA-DR4 animals and displayed T cell expansion in response to a prime/boost vaccination. To ensure that prostate cancer patients respond with antibodies to the MTTE sequence after a tetanus toxoid (TTd) vaccination, both healthy controls and patients (age and gender matched) were vaccinated using a TTd-based vaccine regime. Anti-MTTE antibody titers were evaluated. Patients and HCs responded with increased IgG1 type antibodies against MTTE after TTd vaccination. Safety with regards to hypersensitivity in response to the vaccine platform was evaluated in rabbits and a human whole blood loop system without any identified adverse events. Based on preclinical data the no-observed-adverse-effect level (NOAEL) was set to 1440µg/dose. The vaccine is currently assessed in a First-in-Human clinical study (TENDU-101, 3+3 study design) in patients with relapse after a primary radical prostatectomy. No safety concerns were noted at the lowest dose level and the 400 µg dose cohort has been initiated with the first patient dosed with no reported adverse events. The study’s primary endpoints are safety and tolerability. Secondary endpoints involve cellular immune responses, systemic PSA and PAP levels along with dose level selection. In conclusion, TENDU, a first-in-class vaccine candidate is under clinical development evaluating safety and tolerability for the TET vaccine platform technology. Citation Format: Erika Fletcher, Iliana Kerzeli, Robert Cordfunke, Aikaterini Nasi, Gunilla Törnqvist, Robert Valentijn, Frida Lindqvist, Inken Dillmann, Martin Lord, Neanke Bouwman, Jacques Neefjes, Natasja Dolezal, Kees Franken, Stephanie McArdle, Murrium Ahmad, Silvia Johansson, Ferry Ossendorp, Michael Haggman, Wolfgang Lilleby, Gustav Ullenhag, Sam Ladjevardi, Justyna Jarblad, Jan Wouter Drijfhout, Sara Mangsbo. Promoting immunogenicity of synthetic long peptide vaccines based on in vivo IgG complex formation: Preclinical evaluation and clinical entry of the TET platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4160.