Personalised multipeptide-based T-cell activator for chronic lymphocytic leukaemia: an open-label, single-centre, phase 1 study

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BACKGROUND: Therapeutic T-cell activation to induce tumour-specific immune responses promises sustainable cancer control. However, this treatment is not yet widely used because of the challenges of personalised drug design and a shortage of mutation-derived neoepitopes. This study aimed to evaluate the immunogenicity, safety, and toxicity of iTAC-XS15-CLL01, a personalised warehouse-based multipeptide T-cell activator combined with the Toll-like receptor 1/2 ligand XS15, in patients with chronic lymphocytic leukaemia who were undergoing Bruton's tyrosine kinase inhibitor (BTKi)-based regimes. METHODS: This open-label, single-centre, phase 1 study, conducted in Germany, enrolled patients aged 18 years or older who had chronic lymphocytic leukaemia with an Eastern Cooperative Oncology Group score of 2 or lower and were due to receive a BTKi-based regimen either as monotherapy or in combination (eg, with anti-CD20). The patients' HLA allotype had to match at least one of the corresponding HLA alleles of peptides included in the peptide warehouse. To begin treatment with iTAC-XS15-CLL01, patients had to have reached at least partial remission with remaining minimal residual disease after 6-8 months of BTKi therapy. iTAC-XS15-CLL01 comprised eight chronic lymphocytic leukaemia-specific peptides, selected for the individual patient from a peptide warehouse on the basis of HLA allotyping and immunopeptidomics. Participants received three monthly doses of iTAC-XS15-CLL01 (consisting of 300 μg of each peptide plus 50 μg XS15, emulsified in Montanide ISA 51 VG), injected subcutaneously. The primary endpoints were induction of a T-cell response after application of iTAC-XS15-CLL01 compared with baseline, as assessed with IFNγ ELISpot assays, and the frequency and severity of adverse events from the first application of iTAC-XS15-CLL01 to end of treatment. All analyses were done per protocol. This study was registered with ClinicalTrials.gov (NCT04688385) and is now closed. FINDINGS: Between Jan 21, 2021, and July 7, 2023, 30 patients with chronic lymphocytic leukaemia were screened, and 20 were recruited to enter the iTAC-XS15-CLL01 treatment phase and followed up for 6 months. All patients were of White ethnicity; six (30%) patients were female, and 14 (70%) were male. Median age was 56·5 years (IQR 49·5-65·5). The most common grade 3 adverse events were injection-site erythema (three [15%] of 20 patients), granuloma (two [10%] of 20), and ulceration (one [5%] of 20). There were no grade 4 adverse events, treatment-related serious adverse events, or deaths. T-cell responses targeting multiple peptides were induced in 19 (95% [95% CI 75·1-99·9]) of 20 patients at end of treatment and persisted in 16 (84%) of 19 at 6 months follow-up, with the intensity of responses increasing until end of study. INTERPRETATION: Our findings indicate that iTAC-XS15-CLL01 could be a potent immunotherapeutic agent in patients with chronic lymphocytic leukaemia and should be further evaluated in phase 2 trials. FUNDING: Medical Faculty, Tübingen University.

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