CAR-T cell therapy for lung cancer: Potential and perspective

Abstract

Lung cancer is the highest incidence and mortality of all cancers around the world. In the present immunotherapy era, an increasing number of immunotherapeutic agents including monoclonal antibody-targeted drugs have been used in the clinical treatment of malignancy, but it still has many limitations. Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy, have not only been used successfully against hematological tumors, but have also opened up new avenues for immunotherapy of solid tumors, including lung cancer. However, targeting lung cancer-specific antigens using engineered CAR-T cells is complicated by the lack of proper tumor-specific antigens, an immunosuppressive tumor microenvironment, a low level of CAR-T cell infiltration into tumor tissues, along with off-target effect, etc. Simultaneously, the clinical application of CAR-T cells remains limited because of many challenges such as tumor lysis syndrome, neurotoxicity syndrome, and cytokine release syndrome. In this review, we outline the basic structure and generation characteristic of CAR-T cells and summarize the common tumor-associated antigens in clinical trials of CAR-T cell therapy for lung cancer, and point out the current challenges and new strategies, aiming to provide new ideas and approaches for the pre-clinical experiments and clinical trials of CAR-T cell therapy in lung cancer.

Keywords: chimeric antigen receptor-modified T cellsimmunotherapylung cancersolid tumortargeting specific antigens.

FIGURE 1

The structure of CAR. ICOS, inducible costimulatory; ScFv, single‐chain variable fragment; VH, heavy chain variable; VL, light chain variable

FIGURE 2

Different generations of CARs and development history. (a) The construction of 1st, 2nd, 3rd, 4th, and 5th generation CARs; (b) historic timeline of the development of CAR‐T cells. ALL, acute lymphocytic leukemia; CAR, chimeric antigen receptor; CTL‐019, tisagenlecleuel; EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; HC, hematological cancer; ide‐cel, idecabtagene vicleucel; JAK, Janus kinase; KTE‐X19, brexucabtagene autoleucel; LBCL, large B cell lymphoma; liso‐cel, lisocabtagene maraleucel; MCL, mantle cell lymphoma; NFATD, nuclear factor of activated T cells; NHL, non‐Hodgkin lymphoma; r/r, relapsed/refractory; STAT, signal transducer and activator of transcription