Abstract 3574: A Phase I trial of personalized multi-peptide vaccination in combination with the TLR1/2 ligand XS15 in CLL patients under Bruton-Tyrosin-Kinase-inhibitor based regimes - Preclinical development and study design

Abstract Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite the therapeutic success of novel small molecules (e.g. ibrutinib, idealisib and venetoclax), patients frequently experience disease relapse due to the persistence of minimal residual disease (MRD). Targeting the residual CLL cells by immunotherapy could further improve the depth and persistence of CLL remission. Here, we report on the preclinical development and clinical implementation of a phase I trial evaluating safety, immunogenicity and efficacy in terms of MRD response of a personalized multi-peptide vaccine adjuvanted with the novel toll-like receptor (TLR) 1/2 agonist XS15 emulsified in Montanide࣪ ISA51 VG (Rammensee et al. JIC 2019) in CLL patient receiving Bruton-Tyrosin-Kinase (BTK)-inhibitor based regimes (NCT04688385). So far, broad application of peptide vaccines in cancer patients is hampered by time- and cost-intensive design and the lack of neoepitopes from tumor-specific mutations, especially in low-mutational burden malignancies. To improve on these drawbacks, we developed an immunopeptidome-guided workflow for the design of tumor-associated off-the-shelf peptide warehouses for broadly applicable personalized therapeutics (Nelde et al., Front Immunol, 2021). For the trial reported here, comparative mass spectrometry-based immunopeptidome analyses of 61 CLL patient samples and a dataset of benign tissues samples (n = 351) enabled the identification of high-frequent non-mutated CLL-associated antigens for the most common HLA allotypes (HLA-A*02, -A*24, and -B*07). These antigens were proven to be recognized as T cell epitopes by pre-existing and de novo induced T cells in CLL patients and healthy volunteers, thereby enabling the selection of a 12-peptides panel comprising 9 HLA-class I (3 for each HLA allotype) and 3 HLA class II restricted high frequent CLL-exclusive T cell epitopes as warehouse for the personalized composition of study vaccine cocktails. Our meanwhile ongoing phase I trial recruits CLL patients eligible for treatment with BTK inhibitors. For those with matching HLA allotypes, a personalized peptide-cocktail is formulated comprising 6 CLL-associated peptides (3 HLA class I and 3 HLA class II peptides), selected from our warehouse based on individual immunopeptidome analysis, and 2 highly immunogenic HLA class II control peptides, one viral (human adenovirus C) and one tumor associated (Baculoviral IAP repeat-containing protein 5). Three doses of the vaccine are administered in a 4-weekly interval, after reduction of CLL-load by BTK inhibitors. So far, 10 CLL patients were included in the trial. The first vaccinations will be applied in November and December 2021 with first immunogenicity data expected in March 2022 and to be reported at the meeting. Citation Format: Maddalena Marconato, Annika Nelde, Yacine Maringer, Marcel Wacker, Marion Richter, Monika Denk, Helmut Salih, Jonas Heitmann, Juliane Sarah Walz. A Phase I trial of personalized multi-peptide vaccination in combination with the TLR1/2 ligand XS15 in CLL patients under Bruton-Tyrosin-Kinase-inhibitor based regimes - Preclinical development and study design [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 3574.