Novel Multipeptide Agent Shows Potential in Early-Phase CLL Trial

Treatment with iTAC-XS15-CLL01, a novel warehouse-based multi-peptide T-cell activator combined with Toll-like receptor 1/2 ligand XS15, showed preliminary activity and safety in a small cohort of patients with chronic lymphocytic leukemia (CLL), according to data from a phase 1 trial (NCT04688385) published in The Lancet Haematology.¹

Peptide-specific IFN-γ T-cell responses occurred in 19 patients (95% CI, 75.1%-99.9%) who received iTAC-XS15-CLL01, with a higher induction of T-cell responses to CLL-related human leukocyte antigen (HLA) class II–restricted peptides from baseline to end of treatment vs class I–restricted peptides. Additionally, T-cell responses were sustained until the end-of-study visit among 84% of patients (n = 16/19), and the rate of T-cell responses to peptides of HLA class I and class II increased from 35% (n = 7/20) at the end of treatment to 42% (n = 8/19) at the end of the study.

All patients were alive at the end of the study, and none experienced progression of CLL. Reduced CLL cell populations vs baseline occurred in 90.0% (n = 18/20; 95% CI, 68.3%-98.8%) of patients, with a median decrease of 50.0% (IQR, 74.9%-21.9%) vs baseline. According to exploratory analyses, higher reduction rates were reported in those with CD4-positive T-cell responses or both CD4-positive and CD8-positive responses.

“This single-arm first-in-human trial was designed to prove safety and tolerability of iTAC-XS15-CLLO01, as well as immunogenicity, in patients with [CLL] under [Bruton’s tyrosine kinase (BTK) inhibitor] backbone regimens. The absence of a single-agent arm or placebo arm means that only preliminary data on the clinical activity of the T-cell activator were provided,” lead study author Jonas S. Heitmann, MD, from the Clinical Collaboration Unit Translational Immunology in the Department of Internal Medicine at University Hospital Tübingen; the Department of Peptide-based Immunotherapy of Institute of Immunology, University and University Hospital Tübingen; and Cluster of Excellence iFIT (EXC2180): Image-Guided and Functionally Instructed Tumor Therapies at University of Tübingen, wrote with coauthors.¹ “Nonetheless, the safety and immunogenicity data established by this trial show that iTAC-XS15-CLL01 is a promising therapeutic T-cell activator that warrants further evaluation, which will be addressed in an upcoming randomized trial.”

Developers engineered iTAC-XS15-CLL as a personalized multi-peptide-based T-cell activator-based on HLA allo-typing and immunopeptidome analysis of those with CLL. Selected peptides are combined with agonist XS1513 emulsified in Montanide ISA 51 VG, which facilitates the activation and maturation of antigen-presenting cells while preventing peptide degradation.

Investigators of the open-label phase 1 trial evaluated the immunogenicity, safety, and toxicity of iTAC-XS15-CLL01 among patients with CLL who were receiving BTK inhibitors as monotherapy or in combination with other agents. Patients who achieved a partial remission (PR) or better with leftover minimal residual disease (MRD) after 6 to 8 months of treatment with BTK inhibitors were assigned to receive 3 monthly doses of subcutaneous iTAC-XS15-CLL01, which included 300 μg of each peptide plus 50 μg of XS15 emulsified in Montanide ISA 51 VG.

The trial’s primary end points were the frequency and severity of adverse effects (AEs) and serious AEs (SAEs) as well as T-cell responses following the application of iTAC-XS15-CLL01. Secondary end points included duration of response, MRD negativity rate in peripheral blood and bone marrow, and reduction rate of MRD in peripheral blood and bone marrow.

Patients 18 years and older with documented CLL per International Workshop on CLL (iWCLL) guidelines and planned initiation of a regimen including ibrutinib (Imbruvica) as monotherapy or in combination with other agents were eligible for inclusion during the screening phase of the trial.² For the vaccination phase of the study, patients were eligible if they had ongoing ibrutinib therapy, a PR or better per iWCLL guidelines, MRD-positive status, and a negative COVID-19 testing result.

Of the 30 patients who underwent screening, 20 ultimately proceeded to treatment with iTAC-XS15-CLL01. Most patients were male (70%) and White (100%), with most having Rai stage II disease (55%), Binet stage B (65%), unmutated IGHV status (80%), no TP53 mutations (90%), a CLL-international prognostic index score of 2 or 3 (45%), and BTK inhibitor therapy with acalabrutinib (Calquence; 55%).

Investigators observed no treatment-related SAEs or grade 4 toxicities in the study. Most AEs occurred at a low grade and typically consisted of vaccination-site complications; grade 1/2 events included granuloma (90%), erythema (85%), and swelling (75%). Grade 3 treatment-emergent AEs included erythema (15%), granuloma (10%), atrial flutter (5%), dental caries (5%), lung infection (5%), ulceration (5%), and back pain (5%).

Data showed no deaths during the trial, and no patient discontinued the study due to treatment-related toxicity. Additionally, investigators reported no cytokine release syndrome higher than grade 1, immune effector cell-associated neurotoxicity syndrome, or any long-term immune-mediated medical condition by the final study visit for any patient.

References

1. Heitmann JS, Maringer Y, Jung S, et al. Personalised multipeptide-based T-cell activator for chronic lymphocytic leukaemia: an open-label, single-centre, phase 1 study. Lancet Haematol. Published online January 14, 2026. doi:10.1016/S2352-3026(25)00323-0
2. Personalized multi-peptide vaccination in CLL patients. ClinicalTrials.gov. Updated December 9, 2024. Accessed January 21, 2026. https://tinyurl.com/4fatbtba