Abstract
Antibodies against programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the landscape of therapies for non-small cell lung carcinoma (NSCLC); however, the majority of patients do not respond to these agents. In addition, hyperprogressive disease (HPD) develops in a larger portion of NSCLC patients treated with PD-1/PD-L1 inhibitors than in patients treated with standard chemotherapy. The use of chimeric antigen receptor (CAR) T cells has been successful to treat blood cancers but not for solid tumors like NSCLC. In this work, we constructed CAR T cells that target PD-L1 and evaluated their efficacy in NSCLC with either high or low PD-L1 expression. PD-L1-CAR T cells exhibited antigen-specific activation, cytokine production, and cytotoxic activity against PD-L1high NSCLC cells and xenograft tumors. Furthermore, the addition of a subtherapeutic dose of local radiotherapy improved the efficacy of PD-L1-CAR T cells against PD-L1low NSCLC cells and tumors. Our findings indicate that PD-L1-CAR T cells represent a novel therapeutic strategy for patients with PD-L1-positive NSCLC, particularly for those who are susceptible to HPD.
Highlights
Lung cancer is the leading cause of cancer-related death in the world[1]
For PDL1-Chimeric antigen receptor (CAR) T cells, 28.5%, 3.9%, and 1.4% of them were positive for PD-1, PD-L1, and TIM3, respectively, on day 7
During PD-L1 CAR T cell expansion, the expression of PD-1 on these cells was higher at day 14 than that at day 7 (Fig. 1e, Supplementary Fig. 1b); there was no differences in fractions of central memory T cells (CD45RA−CD62L+, Tcm), stem cell-like memory T cells (CD45RA+CD62L+, Tscm), and effector memory T cells (CD45RA+CD62L−, Tem) between day 14 and day 7 (Fig. 1f, Supplementary Fig. 1c)
Summary
Lung cancer is the leading cause of cancer-related death in the world[1]. In the United States, approximately 234,000 lung cancer cases are diagnosed with 154,050 deaths annually[1,2]. 85% of patients with lung cancers have non-small cell lung carcinoma (NSCLC), and more than 40% of them are diagnosed with metastatic disease[1,3]. Significant progress in drug development against lung cancer has been made, the prognosis of lung cancer has not improved drastically over the past three decades[4]. Even with the current targeted therapies, most patients eventually experience disease relapse[5,6]. Immunotherapy is a promising therapeutic approach for patients with refractory cancers.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
