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The Knut and Alice Wallenberg Foundation (KAW) awards the Pereira Lab a project grant to support “Neoantigen discovery with cellular reprogramming”

Our team was awarded with a KAW project grant that aims to use dendritic cell reprogramming for neoantigen identification, forwarding an alternative to boost the efficiency of current immunotherapies based on vaccines and neoantigen-specific T cell therapies.

Cancer is characterized by genetic and epigenetic alterations resulting in the production of tumor neoantigens. The restrictive expression of tumor neoantigens in tumor cells and not healthy tissue assigns them as ideal molecular targets for cancer vaccines and adoptive T cell therapies. Hence, neoantigen targeting immunotherapeutic strategies are personalized solutions to induce complete responses, while assuring minimal toxicity. However, they involve the efficient identification of neoantigens, currently performed by tumor tissue exome sequencing, transcriptional profiling, or mass-spectrometry analysis for MHC-I/II binding peptides (immunopeptidomics). Since tumor cells develop immune evasion mechanisms such as the downregulation of MHC-I, current strategies for identifying immunogenic neoantigens lack efficiency. This lack of efficiency establishes a pressing need for innovative methods to apply on neoantigen targeting immunotherapies.

In this project, we will begin by performing genomic, transcriptomic, and proteomic analysis of tumor evasion mechanisms and antigen presentation machinery in mouse and human patient-derived cancer cells. Then, we will reprogram tumor cells to type 1 conventional dendritic cells (cDC1) to force antigen presentation and prompt immunogenicity. We will identify tumor peptides present on MHC-I/II and validate neoantigens by immunogenicity assays to design cancer vaccines. Lastly, we will expand tumor antigen-specific T cells by co-culture with reprogrammed tumor cells, engineering effective adoptive T cells.

The proposal involves a consortium of four independent research groups (Filipe Pereira, Camila Consiglio, Janne Lehtiö, and Hanna Eriksson), affiliated to Lund University and Karolinska Institutet. Project members have joint expertise in cellular reprogramming, proteomics, immunology, and cancer research, with the potential to pioneer bench-to-bedside research that positively impacts human health. Our collaborations include Cristiana Pires and Fábio Rosa from Asgard Therapeutics, and Inge Marie Svane from CCIT-Herlev Hospital (Copenhagen University) and are crucial for the success of the project.

In summary, this project aims to employ dendritic cell reprogramming as a transformative platform for personalized cancer immunotherapies, taking the leap for new and effective neoantigen-based vaccines and T cell therapies.

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