Next-generation immunotherapy: igniting new hope for lung cancer

Adoption of immunotherapy has completely transformed the treatment landscape of cancer. Patients with advanced cancer treated with immunotherapy may benefit from durable tumor response and long-term survival. The most widely used immunotherapy in solid tumors is anti-programmed-death (ligand) protein (PD-(L)1), which is now an integral part of non-small cell lung cancer (NSCLC) treatment irrespective of histological cell types and tumor stage. However, the vast majority of patients with advanced NSCLC treated with anti-PD-(L)1 still develop therapeutic resistance, and the prognosis after anti-PD-(L)1 resistance is poor. Resistance mechanisms to PD-1 blockade are often complex and encompass a combination of defects within the cancer-immunity cycle. These defects include failure in antigen presentation and T-cell priming, presence of co-inhibitory immune checkpoints, inability of immune cells to infiltrate the tumor, and presence of immunosuppressive tumor microenvironment. Recently, advances in drug design, genomic sequencing, and gene editing technologies have led to development of next-generation immunotherapies that may potentially overcome these resistance mechanisms. In this review, we will discuss the anti-PD-(L)1 resistance mechanism landscape in NSCLC and four novel modalities of immunotherapy in detail, namely novel immune checkpoint inhibitor and targeted therapy combinations, bispecific antibodies, cancer vaccine, and cell therapy. These novel therapeutics have all demonstrated early clinical data in NSCLC treatment and may work synergistically with each other to restore anticancer immunity. In addition, we share our perspectives on the future promises and challenges in the transformation of these novel immunotherapies to standard clinical care.