Double Guard Efficiency and Safety—Overcoming Resistance to Immunotherapy by Blocking or Stimulating Several Immune Checkpoints in Non-Small Cell Lung Cancer Patients

Abstract

Immunotherapy is one of the leading systemic therapies in non-small cell cancer (NSCLC) patients, but it is not effective in an important proportion of them due to primary or secondary resistance mechanisms. Clinicians do not have the tools to predict immunotherapy resistance, and thus, many patients still fail initial treatment. One of the scientific concepts to avoid resistance and/or offer the patient effective salvage second-line treatment is the dual immunologic checkpoint blockade. We aimed to review published and available data on combination immunotherapy in terms of mechanisms, efficacy, and safety data on many different dual blockades. We discussed the potential of combined CTLA-4 (Cytotoxic T Lymphocyte Antigen 4), PD-1 (Programmed Death 1) or PD-L1, TIGIT, LAG-3, TIM-3, macrophage leukocyte immunoglobulin-like receptor B2 (LILRB2/ILT4), S15-mediated immune suppression (SIGLEC-15), CD137, ICOS, and OX40 inhibitors in NSCLC treatment.