LunX-CAR T Cells as a Targeted Therapy for Non-Small Cell Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) carries a high mortality, and efficacious therapy is lacking. Therapy using chimeric antigen receptor (CAR) T cells has been used efficaciously against hematologic malignancies, but the curative effect against solid tumors is not satisfactory. A lack of antigen targets is one of the main reasons for this limited efficacy. Previously, we showed that lung-specific X (LUNX; also known as BPIFA1, PLUNC, and SPLUNC1) is overexpressed in lung cancer cells. Here, we constructed a CAR-T-cell-based strategy to target LunX (CAR LunX T cells). CAR T cells were developed so that, upon specific recognition of LunX, they secreted cytokines and killed LunX-positive NSCLC cells. In vitro, CAR LunX T cells displayed enhanced toxicity toward NSCLC lines and production of cytokines and showed specific LunX-dependent recognition of NSCLC cells. Adoptive transfer of CAR LunX T cells induced regression of established metastatic lung cancer xenografts and prolonged survival. CAR LunX T cells could infiltrate into the tumor. Also, we constructed a patient-derived xenograft model of lung cancer. After therapy with CAR LunX T cells, tumor growth was suppressed, and survival was prolonged significantly. Together, our findings offer preclinical evidence of the immunotherapeutic targeting of LunX as a strategy to treat NSCLC.

Obstacles and Coping Strategies of CAR-T Cell Immunotherapy in Solid Tumors

“…Significant achievement of CAR-T cell immunotherapy in hematologic malignancies has promoted its application in the treatment of solid tumors. Therefore, several trials currently apply CAR-T against solid tumors, including glioblastoma ( 2 ), lung cancer ( 3 ), liver cancer ( 4 ), gastric cancer ( 5 ), renal cancer ( 6 ), prostate cancer ( 7 ), etc. Nevertheless, based on a meta-analysis on the efficacy of CAR-T in treating solid tumors, CAR-T cell immunotherapy produced a comprehensive response rate of 9% ( 8 ).…”

The Proposition of the Pulmonary Route as an Attractive Drug Delivery Approach of Nano-Based Immune Therapies and Cancer Vaccines to Treat Lung Tumors

“…It has been very successful in treating hematological malignancies but has been disappointing thus far in solid tumors due to lack of antigenic targets (Chen et al, 2019). The identification of some antigenic targets on lung cancers such as mesothelin, disialoganglioside (GD2), MUC 1, NY-ESO-1, human epidermal growth factor and epidermal growth factor receptor has begun research into testing the efficacy of CAR T-cells therapy in lung cancer (Hu et al, 2020). Currently, CAR T-cell therapy targeting the above mentioned antigens are in different stages of clinical trials as potential immunotherapy against thoracic malignancies (Kiesgen et al, 2018;Oliveres et al, 2018).…”

Chimeric antigen receptor (CAR)-T-cell therapy in non-small-cell lung cancer (NSCLC): current status and future perspectives

“…Anti-CD19 CAR-T cells are approved by the US Food and Drug Administration for the treatment of hematological B-cell malignancies, and clinical trials have yielded encouraging results [ 16 , 17 ]. Recent progress indicates that CAR-T-cell therapy is also a promising strategy for the treatment of NSCLC [ 18 , 19 ].…”