Immunotherapy has transformed the cancer treatment landscape leading to long-term responses. However, these strategies are effective in a limited number of patients and often lose their efficacy as the tumor progresses. Insufficient antigen presentation mediated by MHC downregulation and exclusion of functional antigen-presenting cells (APCs) from the tumor microenvironment (TME) are critical evasion mechanisms underlying lack of response to immunotherapy. Among APCs, conventional type 1 dendritic cells (cDC1s) in tumors are key drivers of efficient anti-tumor immunity and associate with better prognosis. We have previously demonstrated that overexpression of the transcription factors PU.1, IRF8 and BATF3 (PIB) drives cell fate reprogramming cancer cells into immunogenic antigen-presenting cDC1s able to mount anti-tumor immunity in immune-checkpoint inhibitor (ICI)-resistant models upon in-vivo transfer (1–3). To circumvent ex-vivo cell manipulation challenges, Asgard Therapeutics is developing AT-108, a novel immunotherapy based on de-novo recreation of cDC1s´ functional properties in tumor cells by in-vivo direct reprogramming.

Here, we hypothesize that cell fate reprogramming of tumor cells to cDC1 in vivo within the TME could force presentation of endogenous tumor neoantigens and induce durable and personalized anti-tumor immunity. The aims of this project are to investigate whether our gene therapy product AT-108 produces durable and systemic anti-tumoral responses in different cancer models and identify its mode of action. To do so, the PIB transcription factors are delivered intratumorally though adenoviral vectors into different ICI-resistant syngeneic tumor models to assess its efficiency as a monotherapy and in combination with ICIs. Flow cytometry, single-cell transcriptomic and immunoassays will be used to decipher how cDC1 reprogramming builds an effective anti-cancer.

Our goal is to generate an off-the-shelf cancer immunotherapy based on in-situ direct cDC1 reprogramming for aggressive tumors offering the advantages of precision cell therapy without complex ex vivo cell manipulation. Ultimately, our studies will pave the way to test AT-108 in first-in-human trials and bring for the first-time direct reprogramming into the clinic.

Published studies:

1.    F. F. Rosa, C. F. Pires, I. Kurochkin, A. G. Ferreira, A. M. Gomes, L. G. Palma, K. Shaiv, L. Solanas, C. Azenha, D. Papatsenko, O. Schulz, C. R. e Sousa, C.-F. F. Pereira, C. R. E. Sousa, C.-F. F. Pereira, Direct reprogramming of fibroblasts into antigen-presenting dendritic cells. Sci Immunol3, eaau4292 (2018).

2.    F. F. Rosa, C. F. Pires, I. Kurochkin, E. Halitzki, T. Zahan, N. Arh, O. Zimmermannová, A. G. Ferreira, H. Li, S. Karlsson, S. Scheding, C. F. Pereira, Single-cell transcriptional profiling informs efficient reprogramming of human somatic cells to cross-presenting dendritic cells. Sci Immunol7, 5539 (2022).

3.    O. Zimmermannova, A. G. Ferreira, E. Ascic, M. V. Santiago, I. Kurochkin, M. Hansen, Ö. Met, I. Caiado, I. E. Shapiro, J. Michaux, M. Humbert, D. Soto-Cabrera, H. Benonisson, R. Silvério-Alves, D. Gomez-Jimenez, C. Bernardo, M. Bauden, R. Andersson, M. Höglund, K. Miharada, Y. Nakamura, S. Hugues, L. Greiff, M. Lindstedt, F. F. Rosa, C. F. Pires, M. Bassani-Sternberg, I. M. Svane, C. F. Pereira, Restoring tumor immunogenicity with dendritic cell reprogramming. Sci Immunol8 (2023).