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

Abstract

There has been a rapid progress in developing genetically engineered T cells in recent years both in basic and clinical cancer studies. Chimeric antigen receptor (CAR)-T cells exert an immune response against various cancers, including the non-small-cell lung cancer (NSCLC). As novel agents of immunotherapy, CAR-T cells show great promise for NSCLC. However, targeting specific antigens in NSCLC with engineered CAR-T cells is complicated because of a lack of tumor-specific antigens, the immunosuppressive tumor microenvironment, low levels of infiltration of CAR-T cells into tumor tissue, and tumor antigen escape. Meanwhile, the clinical application of CAR-T cells remains limited due to the cases of on-target/off-tumor and neurological toxicity, as well as cytokine release syndrome. Hence, optimal CAR-T-cell design against NSCLC is urgently needed. In this review, we describe the basic structure and generation of CAR-T cells and summarize the common tumor-associated antigens targeted in clinical trials on CAR-T-cell therapy for NSCLC, as well as point out current challenges and novel strategies. Although many obstacles remain, the new/next generation of CARs show much promise. Taken together, research on CAR-T cells for the treatment of NSCLC is underway and has yielded promising preliminary results both in basic and pre-clinical medicine. More pre-clinical experiments and clinical trials are, therefore, warranted.

Keywords: CAR-T-cell therapy; Future perspective; Immunotherapy; Non-small-cell lung cancer; Tumor microenvironment.

Fig. 1

The structure and generation of chimeric antigen receptor (CAR)-T cells. a The CAR contains an extracellular antigen-binding domain, an extracellular spacer/hinge sequence motif, a transmembrane (TM) domain, and an intracellular signaling domain. The single-chain variable fragment (scFv) recognizes tumor-associated antigens (TAAs). The length of the spacer/hinge region can be adjusted to optimize the distance between CAR-T cells and targeted tumor cells for CAR signal transduction. The TM domain along with the spacer/hinge region, anchors the CAR to the cellular membrane. The signaling domain is an intracellular T-cell activation complex consisting of CD3ζ and many costimulatory molecules, which trigger antigen binding and modulate the downstream signaling cascade of T-cell activation. b In each new generation of CAR, signaling and applications are modified. The first generation of CARs included the scFv portion and the signaling endodomain of CD3ζ. The second generation of CARs added one costimulatory molecule (e.g., CD28, 4-1BB [CD137], and ICOS (inducible costimulator; CD278) to increase the persistence. The third generation of CARs contains CD3ζ and two costimulatory domains (e.g., CD28/ICOS and 4-1BB/OX-40/CD27). The fourth generation of CARs (also called TRUCKs) contains a nuclear factor of activated T cells (NFAT) domain, which induces a large amount of cytokines (e.g., IL-12). The fifth generation of CARs is based on the second generation, with the addition of a fragment of IL-2 receptor β (IL-2Rβ). The IL-2Rβ fragment can induce the production of Janus kinases (JAKs) and signal transducer and activator of transcription (STAT)-3/5 by mRNA transcription