Immunopeptidomics-Guided Warehouse Design for Peptide-Based Immunotherapy in Chronic Lymphocytic Leukemia

Abstract

Antigen-specific immunotherapies, in particular peptide vaccines, depend on the recognition of naturally presented antigens derived from mutated and unmutated gene products on human leukocyte antigens, and represent a promising low-side-effect concept for cancer treatment. So far, the broad application of peptide vaccines in cancer patients is hampered by challenges of time- and cost-intensive personalized vaccine design, and the lack of neoepitopes from tumor-specific mutations, especially in low-mutational burden malignancies. In this study, we developed an immunopeptidome-guided workflow for the design of tumor-associated off-the-shelf peptide warehouses for broadly applicable personalized therapeutics. Comparative mass spectrometry-based immunopeptidome analyses of primary chronic lymphocytic leukemia (CLL) samples, as representative example of low-mutational burden tumor entities, and a dataset of benign tissue samples enabled the identification of high-frequent non-mutated CLL-associated antigens. These antigens were further shown to be recognized by pre-existing and de novo induced T cells in CLL patients and healthy volunteers, and were evaluated as pre-manufactured warehouse for the construction of personalized multi-peptide vaccines in a first clinical trial for CLL (NCT04688385). This workflow for the design of peptide warehouses is easily transferable to other tumor entities and can provide the foundation for the development of broad personalized T cell-based immunotherapy approaches.

The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma

“…Jens Bauer 1,2,3 , Natalie Köhler 4,5 , Yacine Maringer 1,2,3 , Philip Bucher 3,6 , Tatjana Bilich 1,2,3 , Melissa Zwick 4,7 , Severin Dicks 7,8 , Annika Nelde 1,2,3 , Marissa Dubbelaar 1,2,3,9 , Jonas Scheid 1,2,9 , Marcel Wacker 1,2,3 , Jonas S. Heitmann 3,10 , Sarah Schroeder 1,2,11 , Jonas Rieth 1,2 , Monika Denk 1,2,12 , Marion Richter 1,2,12 , Reinhild Klein 13 , Irina Bonzheim 14 , Julia Luibrand 14 , Ursula Holzer 6 , Martin Ebinger 6 , Ines B. Brecht 6 , Michael Bitzer 3,12,15 , Article https://doi.org/10.1038/s41467-022-33746-3…”

“…T cell-based immunotherapies, comprising immune checkpoint inhibitors (ICIs), CAR-T cells, and bispecific T cell engager antibodies achieved a breakthrough in the treatment of malignant disease [1][2][3][4][5] , adoptive T cell transfer and vaccination strategies hold further promise [6][7][8][9][10] . However, these therapies, which rely on the rejection of cancer cells through recognition of tumor antigens and T cellmediated cytotoxicity are still only available and effective in small subsets of cancer patients and single tumor entities.…”

The Importance of Being Presented: Target Validation by Immunopeptidomics for Epitope-Specific Immunotherapies

“…HLA class I-mediated presentation of the selected epitopes was confirmed by immunopeptidomics ( 120 ). Utilizing a warehouse vaccine concept with 14 HLA class I and class II tumor-associated epitopes, iVAC-XS15-CLL01 is currently under clinical investigation for the treatment of chronic lymphocytic leukemia ( 121 ). The GAPVAC-101 trial investigated the combination of a warehouse vaccine and a fully personalized vaccine in glioblastoma patients and showed the induction of both CD8+ and CD4+ T cell responses ( 122 ).…”

Toll-like receptor-targeted anti-tumor therapies: Advances and challenges

“…It is noteworthy that Amplivant, the modified Pam3CSK4, can conjugate synthetic long peptides (SLPs) and elicit stronger DC and T cell stimulation in preclinical models compared to Pam3CSK4 ( 63 ). In 2021 the first-in-human phase I clinical trial NCT02821494 showed HPV16 E6 SLP-conjugated Amplivant induced robust HPV16-specific T cell immunity with good safety profile ( 187 ).XS15 is a TLR1/2 agonist, applied as an adjuvant to a multi-peptide vaccine scheme is in currently active phase I trial NCT04688385 ( 256 ).…”