Multipeptide Vaccination Plus BTK Inhibition Shows Safety, Efficacy in CLL

Multipeptide T-cell activator iTAC-XS15-CLL01 plus TLR1/2 ligand XS15 was safe and conducive to durable, potent T-cell responses in patients with chronic lymphocytic leukemia (CLL) who were receiving Bruton tyrosine kinase (BTK) inhibitor–based regimens, according to data from a phase 1 trial (NCT04688385) published in Lancet Haematology.^1,2 

Data from the trial showed that among all patients who received the vaccine concurrently with BTK inhibitor–based regimens (n = 20), no treatment-emergent adverse effects (TEAEs) of grade 4 or higher were reported.¹ Common grade 1 or 2 TEAEs experienced by patients were granuloma (90%), erythema (85%), swelling (75%), influenza-like symptoms (45%), headache (10%), and hypertension (10%). Serious TEAEs included back pain, COVID-19, and atrial flutter. Rates for grades 1 to 2 were 0%, 15%, and 0%, respectively; corresponding rates for grade 3 were 5%, 0%, and 5%. Notably, other grade 3 TEAEs observed in patients included erythema (15%), granuloma (10%), ulceration (5%), lung infection (5%), and dental caries (5%).

Moreover, 84% of patients had achieved IFN-γ T-cell responses at the 6-month follow-up (end of study), whereas 20%, 63%, 84%, and 95% of patients did so at their first, second, and third injections of iTAC-XS15-CLL01 and 4 to 6 weeks after their third injection (end of treatment), respectively. Median spot counts at the first, second, and third injections, end of treatment, and end of study were 4, 28, 247, 445, and 918, respectively.

“In patients with CLL who were undergoing BTK inhibitor treatment, iTAC-CLL-XS15, a warehouse-based, personalized, multipeptide T-cell activator consisting of CLL-associated antigens, was safe and induced potent T-cell responses that lasted at least 6 months and were associated with decreases in the proportion of CLL cells,” lead study author Jonas Heitmann, MD, and coauthors wrote in the publication.

Heitmann is a senior physician and an internal medicine, hematology, and oncology specialist at Tübingen University Hospital in Germany.

How was the study evaluating multipeptide vaccines plus BTK inhibitors in CLL designed?

The single-center, open-label trial enrolled patients aged 18 years or older who were receiving treatment that included a BTK inhibitor and had an ECOG performance status of 2 or less. Patients were also required to have matching human leukocyte antigen (HLA-A*02, HLA-A*24, HLA-B*07) and to have achieved a partial remission or better with minimal residual disease positivity 6 to 8 months after BTK inhibitor initiation.

If patients had disease transformation, immune thrombocytopenia, autoimmune hemolysis, or preexisting autoimmune disease, or received prior immunosuppressive treatments unrelated to CLL except corticosteroids, they were not included in the trial.

Patients ultimately participated in 8 visits to the clinic for the trial, 1 of which was for baseline screening, 2 following BTK inhibitor therapy at 3 to 4 months and 6 to 8 months, and 3 to receive iTAC-XS15-CLL01. They then had end-of-treatment and end-of-study visits.

Frequency and severity of TEAEs and serious TEAEs, in addition to T-cell responses, were primary end points. Best overall response (BOR), MRD-negativity rate, and MRD reduction rate in peripheral blood and bone marrow were secondary end points.

Baseline characteristics revealed that patients had a median age of 56.5 years (range, 49.5-65.5) and were mostly male (70%). All patients in the trial were White; most had unmutated IGHV status (90%) and no TP53 mutations (90%). Prior BTK inhibitor treatments for patients consisted of ibrutinib (45%; Imbruvica), acalabrutinib (55%; Calquence), and zanubrutinib (5%; Brukinsa). All patients received their first and second doses of iTAC-XS15-CLL01, with fewer receiving their third dose (85%). All patients were in partial remission at baseline and had CLL International Working Group prognostic scores of 2 to 3 (45%), 4 to 6 (40%), and 7 to 10 (15%). Prior to receiving iTAC-XS15-CLL01, patients either had CLL cells in their peripheral blood or bone marrow, at rates of 44.6% (range, 17.4%-84.8%) and 43.9% (range, 26.5%-82.3%), respectively.

What were the additional data for iTAC-XS15-CLL01 following BTK inhibitors in CLL?

iTAC-XS15-CLL01–associated IFN-y T-cell responses were documented in 95% of patients (95% CI, 75.1%-99.9%). Four patients demonstrated low-frequency T-cell responses to the applied peptides: 3 to HLA class I peptides and 1 to HLA class II. Between the end-of-treatment and the end-of-study visits, T-cell responses to iTAC-XS15-CLL01 increased from 35% to 42%. T-cell responses targeting HLA class I peptides were mediated by CD8-positive, CD4-positive, and both CD4- and CD8-positive T cells in 43%, 29%, and 14% of evaluable patients, respectively.

“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,” Heitmann and coauthors wrote.

References

1. Heitmann J, 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. 2026;13(2):e74-e85. doi:10.1016/S2352-3026(25)00323-0
2. Personalized multi-peptide vaccination in CLL patients. ClinicalTrials.gov. Updated December 9, 2024. Accessed April 15, 2026. https://clinicaltrials.gov/study/NCT04688385