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HLA ligandome analysis of Multiple Myeloma - Novel myeloma-associated antigens for peptide-based immunotherapy

Subject Area Hematology, Oncology
Immunology
Term from 2015 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 279879484
 
Final Report Year 2024

Final Report Abstract

Cancer immunotherapy has revolutionized the treatment of maligant diseases. The effectivity of these approaches is relying on functional tumor-specific immune cells, i.e. T cells as well as robustly and frequently presented antigen targets, namely tumor-associated HLA-presented peptides on the surface of tumor cells. Within this project we aimed to address these two central issues of effective T cell-based cancer immune control with the mid-term goal to develop novel peptidbased immunotherapies for cancer patient in particular patients suffering from multiple myeloma (MM). Identifying suitable tumor antigens is cruical for effective immunotherapy. We adresse this challenge developing a next-generation, high-throughput mass-spectrometry based immunopeptidome approaches which enables to directly identify and characterize the HLA-bound peptide antigens on from the cell surface of malignant cells. Using this unique pipeline we built a uniquely large HLA peptide database from malignant and benign tissue which enabled the subsequent characterization of a large panel of tumor antigens. Beyond high-frequent shared antigens from overexpressed self peptides as well as neoepitops from selected tumor-specific mutations, our approach enabled us to identify novel categories of tumor antigens. These comprise (i) neoepitopes from fusion transcripts (ii) HLA ligands derived from the intracellular domain of known MM-associated membrane antigens (iii) tumor antigens already expressed in premalignant disease stages that enable an early targeting of disease (iv) cryptic neoepitoes from noncanocial gene products as well as (v) cancer-drug-induced antigens as highly interesting targets for the development of combinatorial immunotherapy concepts. With regard to the second important requirement for effective T cell-based cancer immune control and immunotherapy development we characterized novel compounds that improve antigen-specific T cell response in particular in immunocompromised cancer patients including MM. Further, with the rise of the COVID-19 pandemic, we leveraged their unique expertise in T cell-activating cancer immunotherapies to address the threat of SARS-CoV-2, especially for our vulnerable tumor patients. In a highly competitive field, we conducted preclinical pioneer work to characterize the T cell epitopes of SARS-CoV-2 and elucidate the immunological mechanisms underlying protective immunity in healthy individuals as well as in cancer patients. In the latter, we could show that intensity and expandability of SARS-CoV-2 T cell responses were profoundly reduced, in particular in patients with hematological malignancies. Furthermore, the diversity of the SARS-CoV-2 T cell response was reduced in tumor patients and could be associated with a severe course of COVID-19 disease. On this basis, we developed the firstin-class peptide-based T cell activator CoVac-1 adjuvanted with our novel adjuvant XS15, which demonstrated safety and its ability to induce potent and long-lasting T cell immunity surpassing natural infection and mRNA-based vaccines within a first-in-human Phase I trial in healthy adults. Based on these promising results reported in a highly cited Nature paper, CoVac-1 is now evaluated in a Phase II trial in cancer patients with B-cell deficiency unable to mount a humoral immune response following standard vaccination. Even in this highly immunocompromised population, CoVac-1 induced strong and long-lasting T cell responses, confirming the potency of this adjuvant also for therapeutic cancer vaccines. These two first-in-human and first-in-cancer trials of XS15-adjuvanted peptide-based T cell activators paved the way for the subsequent fast-track development and clinical evaluation of therapeutic peptide-based cancer vaccines adjuvanted with XS15 with currently five ongoing clinical trials NCT0454684113, NCT0495446914, NCT04688385, NCT04842513, NCT05937295, NCT04842513, NCT06252584. Beyond the publication of our results in various high ranking scientific journals, we made our findings accessible and transparent to the general public, thus creating a broad understanding of the immunological processes and immunotherapy development. To this end new research finding are shared on our Social Media platforms (e.g. X (former Twitter) @LabWalz, Peptide-based Immunotherapy) and accompanied by a press release in laymen’s terms, which were uptaken by the national and international press (e.g. BBC, Daily Telegraph, Frankfurter Allgemeine Zeitung (FAZ), Agence France). Moreover, our research results are presented and discussed in podcasts and videos, to ensures that vital information reaches a broader audience, including patients and their families. The latter is exemplified by a YouTube educational video that we produced to introduce our research finding on the immune responses to SARS-CoV-2 in cancer patients published in Cancer Discovery 2021 to the general public that achieved more than 21.000 views so far.

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