Non-pathogenic E. coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses

Shaobo Yang; Michal Sheffer; Isabel E Kaplan; Zongqi Wang; Mubin Tarannum; Khanhlinh Dinh; Yasmin Abdulhamid; Eden Bobilev; Roman Shapiro; Rebecca Porter; Robert Soiffer; Jerome Ritz; John Koreth; Yun Wei; Peiru Chen; Ke Zhang; Valeria Márquez-Pellegrin; Shanna Bonanno; Neel Joshi; Ming Guan; Mengdi Yang; Deng Li; Chiara Bellini; Fuguo Liu; Jianzhu Chen; Catherine J Wu; David Barbie; Jiahe Li; Rizwan Romee

doi:10.1038/s41587-024-02418-6

Non-pathogenic E. coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses

Nat Biotechnol. 2024 Oct 4. doi: 10.1038/s41587-024-02418-6. Online ahead of print.

Authors

Shaobo Yang^#^{1

2}, Michal Sheffer^#², Isabel E Kaplan², Zongqi Wang³, Mubin Tarannum², Khanhlinh Dinh², Yasmin Abdulhamid², Eden Bobilev², Roman Shapiro², Rebecca Porter², Robert Soiffer², Jerome Ritz², John Koreth², Yun Wei⁴, Peiru Chen⁴, Ke Zhang^{1

4}, Valeria Márquez-Pellegrin¹, Shanna Bonanno¹, Neel Joshi⁴, Ming Guan¹, Mengdi Yang¹, Deng Li¹, Chiara Bellini¹, Fuguo Liu², Jianzhu Chen⁵, Catherine J Wu², David Barbie², Jiahe Li⁶, Rizwan Romee⁷

Affiliations

¹ Department of Bioengineering, Northeastern University, Boston, MA, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA, USA.
⁵ Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. jiaheli@med.umich.edu.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. rizwan_romee@dfci.harvard.edu.

^# Contributed equally.

PMID: 39367093
DOI: 10.1038/s41587-024-02418-6

Abstract

The tumor microenvironment can inhibit the efficacy of cancer therapies through mechanisms such as poor trafficking and exhaustion of immune cells. Here, to address this challenge, we exploited the safety, tumor tropism and ease of genetic manipulation of non-pathogenic Escherichia coli (E. coli) to deliver key immune-activating cytokines to tumors via surface display on the outer membrane of E. coli K-12 DH5α. Non-pathogenic E. coli expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8⁺ T and natural killer (NK) cell-dependent immune responses and suppressed tumor progression in immune-competent colorectal carcinoma and melanoma mouse models. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting chimeric antigen receptor (CAR) NK cells and enhance their trafficking into tumors, which extended survival in an NK cell treatment-resistant mesothelioma xenograft model by enhancing TNF signaling and upregulating NK activation markers. Our live bacteria-based immunotherapeutic system safely and effectively induces potent anti-tumor responses in treatment-resistant solid tumors, motivating further evaluation of this approach in the clinic.