813MO - Phase I trial of a personalized multi-peptide vaccine combined with the TLR1/2 ligand XS15 under Bruton-Tyrosine-Kinase inhibitor (BTKi) treatment in chronic lymphocytic leukemia (CLL) patients

Background

Targeted substances, including BTKi, greatly improved prognosis in CLL. However, frequent disease relapses occur, due to remaining treatment resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD).

Methods

We here report on an open-label phase I clinical trial evaluating a personalized peptide vaccine in CLL patients under BTKi therapy (NCT04688385). The vaccine was compiled from a premanufactured warehouse of immunopeptidome-defined CLL-associated peptides (Nelde et al., Front Immunol. 2021) based on HLA allotype and individual CLL immunopeptidome, and with our TLR1/2 agonist XS15 emulsified in Montanide ISA 51 VG (iVAC-CLL-XS15). After achievement of at least partial remission (MRD-positive) under BTKi, iVAC-CLL-XS15 was applied three times. BTKi was continued through the trial until 6-month follow-up (FU). Primary endpoints were safety and immunogenicity, main secondary endpoints MRD negativity and reduction rate.

Results

20 patients (median age 59 years, male:female 2.3:1) were enrolled (75% BTKi 1^st and 25% 2^nd line; CLL IPI: 0% low, 47% interm, 37% high and 16% v. high). Vaccination was well tolerated and no treatment-related serious adverse events reported. Local granuloma formation at vaccination site was observed in all patients, enabling a local stimulation of CLL-specific T cells without relevant systemic inflammation. Vaccine-induced T cell responses were detected in all patients analyzed so far (100%, 17/17), targeting multiple vaccine peptides (50% CLL-associated HLA-class I and 88% HLA-class II epitopes). Vaccine-induced T cell responses persisted in all patients until FU and were mediated by multifunctional CD4⁺ and CD8⁺ T cells. Preliminary efficacy analyses showed MRD reduction (median 45%) in 87% (13/15) of patients from 1^st vaccination to FU with an association of vaccine-induced T cell response and MRD reduction in single patient analysis.

Conclusions

The beneficial safety profile, induction of profound, long-lasting CLL-specific T cell responses, and preliminary MRD efficacy data warrant further evaluation of iVAC-CLL-XS15 in an upcoming randomized Phase II trial.

Clinical trial identification

EudraCT: 2020-002367-65, NCT04688385.

Editorial acknowledgement

Legal entity responsible for the study

University Hospital Tuebingen.

Funding

AKF grant and Cluster of Excellence iFIT (EXC2180) of the University Tuebingen.

Disclosure

J.S. Heitmann: Financial Interests, Personal, Full or part-time Employment: Bicony Therapeutics GmbH. Y. Maringer: Financial Interests, Royalties, Yacine Maringer is listed as inventors on a patent related to the DNAJB1-PRKACA T cell epitopes and TCRs (Peptides and antigen binding proteins for use in immunotherapy against fibrolamellar HCC and other cancers, Application number: EP21214728.4): Patent. M. Marconato: Financial Interests, Ownership Interest, Maddalena Marconato, MD, is co-founder and shareholder of ATLyphe, a Pharmaceutical spinoff of the ETH and University of Zurich: ATLyphe. H.R. Salih: Financial Interests, Personal, Research Funding: ABL Bio, Synimmune, Novartis; Financial Interests, Personal, Advisory Role: Novartis, Pfizer, Philogen, Synimmune; Financial Interests, Personal, Royalties, Inventor on several patents in the field of cancer immunotherapy: Patents; Financial Interests, Personal, Other: Twyce GmbH. J.S. Walz: Financial Interests, Personal, Research Funding: GSK, Roche Pharma AG; Financial Interests, Personal, Royalties, Novel immunotherapy against several tumors of the blood, such as acute myeloid leukemia (AML), Application number: PCT/EP2015/060168, Novel immunotherapy against several tumors of the blood, in particular chronic lymphoid leukemia (CLL), Application number: PCT/EP2015/063566, Novel cell epitopes and combination of cell epitopes for use in the immunotherapy of myeloma and other cancers, Application number: PCT/EP2016/064317, Peptides and combination of peptides for use in immunotherapy against leukemias and other cancers, Application number: PCT/EP2018/059114, Peptides and combination thereof for use in the immunotherapy against cancers Application number: PCT/EP2018/059109, CoVac-1 peptide cocktail, Application number: PCT/EP 20 190 070.1, SARS-CoV-2 CD8+ und CD4+ T cell epitopes, Application number: PCT/EP 20 169 047.6, Peptides and antigen binding proteins for use in immunotherapy against fibrolamellar HCC and other cancers, Application number: EP 2121472: Patents; Financial Interests, Personal, Ownership Interest, Cofounder and Share holder: ViferaXS GmbH. All other authors have declared no conflicts of interest.