Next generation immune-checkpoints for cancer therapy

Abstract

The discovery and clinical application of immune-checkpoint inhibitors has dramatically improved the treatments, outcomes and therapeutic concepts in multiple tumor settings. This breakthrough was mainly based on monoclonal antibodies blocking the inhibitory molecule CTLA-4 and or the PD-1/PD-L1 axis, with the aim of counteracting major tumor immune evasion mechanisms. Even acknowledging these important successes, not all the patients benefit from these treatments. Translational and clinical research efforts are ongoing to explore the potentialities of a new generation of immune-modulatory molecules to extend current clinical applications and contrast the unsolved issues of resistance and disease relapse that still affects a considerable rate of patients. New immune-checkpoints, with either stimulatory or inhibitory functions are emerging with key roles in regulating T cell response but also affecting other crucial effectors belonging to the innate immune response (e.g., natural killer). Their therapeutic exploitation, either alone or in strategical combinations, is providing important preclinical results, holding promises currently explored in initial clinical trials. The first results point toward favorable safety profiles with selective hints of activity in challenging settings. Important issues regarding the dose, schedule and rational combinations remain open and data from the clinical studies are needed. Here we provide an overview of the main emerging stimulatory or inhibitory immune-checkpoints exploitable in cancer treatment, briefly reporting their biological function, preclinical activity and preliminary clinical data.

Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

“…Nevertheless, in general, ICOS stimulation enhances T-cell activation, and its use has been proven to synergize with and potentiate the activity of CTLA-4 [ 167 , 168 ] as well as PD-1 inhibitors [ 169 ]. Further research is ongoing to explore the role of ICOS stimulation as a means of re-activating the immune response following treatment with checkpoint inhibitors [ 170 ].…”

Antibodies to watch in 2019

“…6 Tasuku Honjo and colleagues first described the programmed cell death 1 (PD-1) protein in 1992, 7 and James Allison and colleagues reported in 1996 8 that blocking CTLA-4's inhibitory effects improved immune responses directed toward tumor cells. Since then, the number of proteins known to function as either stimulatory or inhibitory checkpoints of the immune system has dramatically expanded, 9 and numerous antibody therapeutics targeting PD-1 (cemiplimab, nivolumab, pembrolizumab), the ligand for PD-1 (PD-L1; durvalumab, avelumab, atezolizumab) or CTLA-4 (ipilimumab) have been granted marketing approvals. Because these therapeutics act by enhancing the immune system response rather than targeting a tumor antigen, they are used to treat many types of cancers, including melanoma, nonsmall-cell lung cancer, renal cell cancer, urothelial carcinoma, hepatocellular cancer, gastric cancer, colorectal cancer, head and neck cancer, Merkel cell carcinoma and Hodgkin's lymphoma.…”

Echinococcus multilocularis vesicular fluid induces the expression of immune checkpoint proteins in vitro

“…For the past few years, immunotherapies against cancer have included the use of antibodies targeting immune checkpoint molecules such as CTLA‐4 (anti‐cytotoxic T lymphocyte‐associated protein‐4) or the PD‐1/PD‐L1 axis (anti‐programmed cell death protein‐1) 7 . This immune checkpoint blockade strategy has dramatically improved the treatment and patient outcome in multiple tumour settings 7,8 . The PD‐1/PD‐L1‐pathway, which inhibits lymphocytic proliferation in tumour development, 7 was shown to be overexpressed at the chronic stage of echinococcosis and to control AE development in mice 9,10 …”

“…Other new immune checkpoint targets are now being evaluated in preclinical tumour models and in clinical trials, such as the LAG‐3 (lymphocyte activation gene‐3) protein and TIM‐3 (T‐cell immunoglobulin and mucin domain‐containing‐3) protein 7,8 …”