Anti-PD-1/PD-L1 Therapy for Non-Small-Cell Lung Cancer: Toward Personalized Medicine and Combination Strategies

Abstract

Lung cancer remains a leading cause of cancer-related mortality worldwide with the poor prognosis. Encouragingly, immune checkpoint blockade targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has dramatically changed the landscape for treatments in patients with non-small-cell lung cancer (NSCLC). However, only a small proportion of NSCLC patients responded to monotherapy of anti-PD-1/PDL1 agents; together, the development of resistance to anti-PD-1/PD-L1 therapy that leads to failure of anti-PD-1/PD-L1 therapy has significantly limited a broad applicability of the findings in clinical practices. Nowadays, several companion diagnostic assays for PDL1 expression have been introduced for identifying patients who may benefit the immunotherapy. In addition, results from clinical trials explored combinatory therapeutic strategies with conventional and/or targeted therapy reported a higher efficacy with an acceptable safety profile in NSCLC treatments, as compared to the monotherapy of these agents alone. In this review article, we summarized several anti-PD-1/PD-L1 agents licensed for NSCLC treatment, with a focus on predictive biomarkers and companion diagnostic assays for identification of NSCLC patients for immunotherapy anti-PD-1/PDL1 antibodies. Of a great interest, potentials of the combinatory therapy of anti-PD-1/PDL1 therapy with a conventional or targeted therapy, or other immunotherapy such as CAR-T cell therapy were emphasized in the article.

Figure 1

Effect of PD-1/PD-L1 signaling on major signaling pathways and reprograming in T cells. Upon the stimulation of antigen, the MHC on the surface of APC could present antigens to the TCR and promote TCR/CD3 chains to phosphorylate, resulting in an activation and recruitment of Lck and Zap-70, which in turn lead to the phosphorylation of tyrosine motifs (ITAM) and initiation of the downstream signaling cascade of TCR. However, in the pathological state, the PD-1 bind to its ligand PD-L1 or PD-L2; the tyrosine phosphatase SHP-2 or SHP-1 can be recruited and bind to the ITSM sequence in the PD-1 cytoplasmic tail. An activation of PD-L/PD-L1 signaling PD-1 mediates the inhibition of the PI3K/Akt and Ras/MEK/Erk signaling pathway, resulting in the inhibition of T cell proliferation, protein synthesis, survival, and IL-2 production. APC: antigen-presenting cell; HLA: human leukocyte antigen; TCR: T cell receptor.

Figure 2

Illustrative image describing anti-PD-1/PD-L1 therapy combined with CAR-T cells. T cells are obtained and isolated from the patients. These T cells are transformed with chimeric antigen receptor (CAR) gene by lentiviruses. The CAR-T cells are expanded in vitro and finally infused back to patients. After the CAR-T cells transferred into patients, the CAR-T cells are able to recognize target gene-positive tumor cells. Meanwhile, CAR-T cells can secrete anti-PD-1/PD-L1 antibody and combine with foreign anti-PD-1/PD-L1 antibody to recognize and kill the tumor cells.