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577 Engineered non-pathogenic synthetic biotic producing L-arginine synergize with PD-1-based cancer immunotherapy
  1. Fernando Canale1,
  2. Camilla Basso1,
  3. Ning Li2,
  4. Anna Sokolovska2,
  5. Michela Perotti1,
  6. Michael James2,
  7. Wenjie Jin1,
  8. Jean-Philippe Theurillat3,
  9. Daniel Leventhal2,
  10. Kip West2,
  11. Jose Lora2,
  12. Federica Sallusto1 and
  13. Roger Geiger1
  1. 1Institute for Research in Biomedicine, Bellinzona, Switzerland
  2. 2Synlogic Inc., Boston, MA, USA
  3. 3Institute for Oncology Reserach, Bellinzona, Switzerland


Background The availability of L-arginine in tumors is a key determinant of an efficient anti-tumor T cell response. Consequently, the elevation of typically low L-arginine levels within the tumor may greatly potentiate the anti-tumor responses of immune check point inhibitors, such as PD-L1 blocking antibodies. However, currently no means are available to locally increase intra-tumoral L-arginine levels.

Methods We used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumors and continuously converts ammonia, a metabolic waste product that accumulates in tumors, into L-arginine.

Results Colonization of tumors with these bacteria elevated intra-tumoral L-arginine concentrations, increased the amount of tumor-infiltrating T cells, and had striking synergistic effects with PD-L1 blocking antibodies in the clearance of tumors. The anti-tumor effect of the living therapeutic was mediated by L-arginine and was dependent on T cells.

Conclusions These results show that engineered microbial therapies enable metabolic modulation of the tumor microenvironment leading to enhanced efficacy of immunotherapies.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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