EGFR‐targeted CAR‐T cells are potent and specific in suppressing triple‐negative breast cancer both in vitro and in vivo

• Published in: Clinical & translational immunology Vol. 9; no. 5; pp. e01135 - n/a
• Main Authors: Xia, Lin, Zheng, Zao‐zao, Liu, Jun‐yi, Chen, Yu‐jie, Ding, Jian‐cheng, Xia, Ning‐shao, Luo, Wen‐xin, Liu, Wen
• Format: Journal Article
• Language: English
• Published: Australia John Wiley & Sons, Inc 01.05.2020; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; Antigens; Antitumor activity; Breast cancer; Cancer therapies; Caspase; Chimeric antigen receptors; chimeric antigen receptor‐modified T‐cell; Clinical trials; Cytokines; Cytotoxicity; Epidermal growth factor; epidermal growth factor receptor; Epidermal growth factor receptors; Epithelial cells; FADD protein; Flow cytometry; Genomes; Immunoglobulins; Immunotherapy; Invasiveness; Kinases; Lung cancer; Lymphocytes; Lymphocytes T; Original; Perforin; Ribonucleic acid; RNA; Sequence analysis; Signal transduction; triple‐negative breast cancer; Xenografts; γ-Interferon; triple‐negative breast cancer; epidermal growth factor receptor; immunotherapy; chimeric antigen receptor‐modified T‐cell
• ISSN: 2050-0068; 2050-0068
• DOI: 10.1002/cti2.1135

Objectives Triple‐negative breast cancer (TNBC) is well known for its strong invasiveness, rapid recurrence and poor prognosis. Immunotherapy, including chimeric antigen receptor‐modified T (CAR‐T) cells, has emerged as a promising tool to treat TNBC. The identification of a specific target tumor antigen and the design of an effective CAR are among the many challenges of CAR‐T therapy. Methods We reported that epidermal growth factor receptor (EGFR) is highly expressed in TNBC and consequently designed an optimal third generation of CAR targeting EGFR. The efficacy of primary T lymphocytes infected with EGFR CAR lentivirus (EGFR CAR‐T) against TNBC was evaluated both in vitro and in vivo. The signalling pathways activated in tumor and EGFR CAR‐T cells were revealed by RNA sequencing analysis. Results Third‐generation EGFR CAR‐T cells exerted potent and specific suppression of TNBC cell growth in vitro, whereas limited cytotoxicity was observed towards normal breast epithelial cells or oestrogen receptor‐positive breast cancer cells. This capability was further demonstrated in vivo in a xenograft mouse model, with minimal off‐tumor cytotoxicity. Mechanistically, in vitro stimulation with TNBC cells induced the expansion of naïve‐associated EGFR CAR‐T cells and enhanced their persistence. Furthermore, EGFR CAR‐T cells activated the interferon γ, granzyme–perforin–PARP and Fas–FADD–caspase signalling pathways in TNBC cells. Conclusion We demonstrate that EGFR is a relevant immunotherapeutic target in TNBC, and EGFR CAR‐T exhibits potent and specific antitumor activity against TNBC, suggesting the potential of this third‐generation EGFR CAR‐T as an immunotherapy tool to treat TNBC in the clinic. We demonstrated that epidermal growth factor receptor (EGFR) is an immunotherapeutic target in triple‐negative breast cancer (TNBC), and EGFR‐targeted chimeric antigen receptor‐modified T cells (EGFR CAR‐T) exhibited potent and specific antitumor activity towards TNBC in vitro and in vivo, which might serve as a promising immunotherapy tool to treat TNBC in clinic.