Trial in Progress: Phase I Trial Evaluating an Immunopeptidome-Defined Multi-Peptide Vaccine Against Acute Myeloid Leukemia Stem and Progenitor Cells

Acute myeloid leukemia (AML), the most common form of acute leukemia in adults, has a dismal prognosis with a 5-year survival rate of only 30%. The high mortality rate is mostly due to minimal residual disease (MRD)-driven relapse, making an elimination of persisting therapy-resistant leukemia progenitor/stem cells (LPCs) the main goal for novel therapeutic approaches.

The immunogenicity of AML which is documented by graft-versus leukemia effects after hematopoietic stem cell transplantation as well as the favorable immune effector-to-target cell ratios in the MRD setting suggest T cell-based immunotherapy as treatment option. To this end peptide-based cancer vaccines represent a promising low-side-effect approach aiming to induce a T cell response directed against human leukocyte antigen (HLA)-presented tumor antigens on malignant cells by therapeutic vaccination. However, the lack of suitable AML- and in particular LPC-specific antigens and cumbersome vaccination schedules due to ineffective adjuvants restrict broad applicability and efficacy of this approach in AML so far.

In preliminary studies of our group, a mass spectrometry-based analysis of the naturally presented immunopeptidome of a large cohort of primary enriched LSC and AML samples was performed and the resulting peptides compared with our benign immunopeptidome database to select antigens exclusively expressed on LSC/AML cells. Additionally, the AML/LSC immunopeptidomes were screened for naturally presented peptides derived from common AML-specific mutations (FLT3, NPM1, IDH2, etc.). The mutated and non-mutated AML/LSC antigens further showed de novo induction and spontaneous memory T cell responses in AML patients and healthy volunteers and their presentation as well as the corresponding memory T cell recognition was associated with improved disease outcome in AML patients (Nelde et al., Blood Cancer Discov, 2023).

Based on this work, we designed the broadly applicable, off-the shelf vaccine candidate AML-VAC-XS15 comprising immunopeptidome-defined mutated and non-mutated AML/LSC peptides. The vaccine comprises 2 mutated HLA class I-restricted peptides from the common AML-specific mutation in NPM1, and 7 HLA class II-restricted peptides, of which 6 are non-mutated high-frequent AML/LSC-associated antigens and one mutated peptide from the AML-specific mutation R140Q in IDH2. The peptide vaccine is adjuvanted with the novel toll like receptor (TLR) 1/2 ligand XS15 emulsified in montanide ISA 51 VG. XS15-adjuvanted peptide vaccines have already been evaluated in 5 clinical trials by our group, showing beneficial safety profile, the induction of strong and long-lasting T cell responses that exceed those of former peptide vaccines and mRNA vaccines, and first clinical efficacy (Heitmann et al, Nature, 2022; Heitmann et al, Nat Commun, 2023).

AML-VAC-XS15 is currently investigated in a Phase I open label clinical trial (NCT06252584, EU-CT: 2023-510316-39-00) for AML patients in complete cytological remission after first-line therapy, who may be MRD positive or negative. Concurrent low intensity or maintenance treatments, for example with hypomethylating agents or midostaurin, are permitted. Patients are vaccinated twice with an interval of 6 weeks. Depending on the following immune response, evaluated by interferon gamma enzyme-linked immunospot assay, a booster vaccination may be applied 3 months after the second vaccination. Patients will be followed-up over the course of 2 years.

The trial’s primary objectives are the assessment of immunogenicity, safety and toxicity of the vaccine, secondary objectives include a characterization of the vaccine-induced T cell responses and an assessment of preliminary clinical efficacy reflected in progression free and overall survival. With the aim of T cell mediated elimination of MRD, the prevention of relapse seems an achievable goal of this approach.