Genomic Engineering of Immune Cells for Immunotherapy - NCCR MSE

Genomic Engineering of Immune Cells for Immunotherapy

Engineering immune cells by precise genome editing for applications in biotechnology and cellular immunotherapy.
Engineering immune cells by precise genome editing for applications in biotechnology and cellular immunotherapy.

This project uses state-of-the-art molecular and genomic editing platforms to engineer immune cells for applications in biotechnology and cellular immunotherapy.

Our ongoing projects are focused on applying molecular and genome editing tools to engineer various types of immune cells. The precise genomic exchange of highly similar immunogenomic genes has not been demonstrated before using genome-editing tools, thus a series of aims and milestones to advance this goal have been established. For example, in one of aims we are engineering mammalian cellular factories for protein production. In another aim we are using precise genome editing to improve cellular therapeutics for transplantation and cancer. We will combine our efforts with the network of NCCR researchers to push the boundaries of immunological systems engineering. 

Scientific Highlights

  • Plug-and-(dis)play mammalian cells. We have used precise genome editing to develop a platform for rapid generation of stable cell lines capable of surface expression and secretion of recombinant proteins. The simplicity of our plug-and-(dis)play platform is highlighted by the fact that it only requires a single transfection and screening step to generate stable cells. We envision these cell lines can be applied for generating recombinant protein reagents and therapeutics. 
  • Reprogramming MHC-specificity immune cells. We have established a proof-of-concept for MHC-allelic replacement, which could be used in the future for improving the donor-host matching, which is a major challenge in allogeneic cellular transplantations in cancer. We used genome editing methods to precisely exchange the MHC region of immune cells, which were then subsequently verified for functions immune activity. Our methods can be applied for the engineering of other immunogenomic regions, which would have value in cellular immunotherapy.


R. Castellanos-Rueda, R. B. Di Roberto, F. Bieberich, F. S. Schlatter, D. Palianina, O. T. P. Nguyen, E. Kapetanovic, H. Läubli, A. Hierlemann, N. Khanna, S. Reddy “speedingCARs: accelerating the engineering of CAR T cells by signaling domain shuffling and single-cell sequencing“ Nat. Commun. 2022. [DOI]
R. Vazquez-Lombardi, J. S. Jung, F. S. Schlatter, A. Mei, N. R. Mantuano, F. Bieberich, K. Hong, J. Kucharczyk, E. Kapetanovic, E. Aznauryan, C. R. Weber, A. Zippelius, H. Läubli, S. Reddy “High-throughput T cell receptor engineering by functional screening identifies candidates with enhanced potency and specificity“ Immunity 2022. [DOI]
S. Shui, P. Gainza, L. Scheller, C. Yang, Y. Kurumida, S. Rosset, S. Georgeon, R. B. Di Roberto, R. Castellanos-Rueda, S. ReddyB. Correia “A rational blueprint for the design of chemically-controlled protein switches“ Nat. Commun. 2021. [DOI]
R. B. Di Roberto, R. Castellanos-Rueda, S. Frey, D. Egli, R. Vazquez-Lombardi, E. Kapetanovic, J. Kucharczyk, S. Reddy “A Functional Screening Strategy for Engineering Chimeric Antigen Receptors with Reduced on-Target, Off-Tumor Activation“ Mol. Ther. 2020. [DOI]
T. Pesch, L. Bonati, W. Kelton, C. Parola, R. A. Ehling, L. Csepregi, D. Kitamura, S. Reddy “Molecular Design, Optimization, and Genomic Integration of Chimeric B Cell Receptors in Murine B Cells“ Front. Immunol. 2019. [DOI]
C. R. Weber, D. M. Mason, S. M. Meng, V. Greiff, W. J. Kelton, S. Reddy, C. Parola “High-throughput antibody engineering in mammalian cells by CRISPR/Cas9-mediated homology-directed mutagenesis“ Nucleic Acids Res. 2018, 46:7436-7449. [DOI]
S. Reddy “Reprogramming MHC specificity by CRISPR-Cas9-assisted cassette exchange“ Sci. Rep. 2017, 7:45775. [DOI]
M. Pogson, C. Parola, W. J. Kelton, P. Heuberger, S. Reddy “Immunogenomic engineering of a plug-and-(dis)play hybridoma platform“ Nat. Commun. 2016, 7:12535. [DOI]
Y. Cotelle, N. Chuard, S. Lascano, V. Lebrun, R. Wehlauch, N. Bohni, S. Lörcher, V. Postupalenko, S. Reddy, W. Meier, C. G. Palivan, K. Gademann, T. R. WardS. Matile “Interfacing Functional Systems“ Chimia 2016, 6:418. [DOI]
W. Kelton, T. PeschS. MatileS. Reddy “Surveying the Delivery Methods of CRISPR/Cas9 for ex vivo Mammalian Cell Engineering“ Chimia 2016, 6:439. [DOI]
M. Pogson, W. Kelton, S. Reddy “Microscale Technologies for High-Throughput Analysis of Immune Cells“ Microscale Technologies for Cell Engineering 2016:219-30. [DOI]
P. Muller, M. Kreuzaler, T. Khan, D. S. Thommen, K. Martin, K. Glatz, S. Savic, N. Harbeck, U. Nitz, O. Gluz, M. von Bergwelt-Baildon, H. Kreipe, S. Reddy, M. Christgen, A. Zippelius “Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade“ Sci. Transl. Med. 2015, 7:315ra188. [DOI]

Project Leader

Sai Reddy


Reddy group @D-BSSE