Next generation of immune checkpoint inhibitors and beyond

Abstract

The immune system is the core defense against cancer development and progression. Failure of the immune system to recognize and eliminate malignant cells plays an important role in the pathogenesis of cancer. Tumor cells evade immune recognition, in part, due to the immunosuppressive features of the tumor microenvironment. Immunotherapy augments the host immune system to generate an antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Molecules that block these pathways to enhance the host immunologic activity against tumors have been developed and become standard of care in the treatment of many malignancies. Only a small percentage of patients have meaningful responses to these treatments, however. New pathways and molecules are being explored in an attempt to improve responses and application of immune checkpoint inhibition therapy. In this review, we aim to elucidate these novel immune inhibitory pathways, potential therapeutic molecules that are under development, and outline particular advantages and challenges with the use of each one of them.

TIGIT Induces (CD3+) T Cell Dysfunction by Inhibiting Glucose Metabolism and its Reversal by TIGIT and/or PD-1 Blockade in Colorectal Cancer

“…To date, an increasing amount of studies have been conducted focusing on immune checkpoint targeting tumor microenvironment. One of the mechanisms of cancer immune escape is via the activation of immunosuppressive signaling pathways, among which, the PD-1/PD-L1 pathway and CTLA-4 pathway have been extensively studied [20] . The successful application of anti-PD-1 and anti-CTLA-4 antibodies in tumor therapy provides a promising opportunity for tumor immunotherapy.…”

The Tumor Microenvironment Factors That Promote Resistance to Immune Checkpoint Blockade Therapy

“…Apart from these immune checkpoints, drugs associated with inhibitory targets beyond traditional immune checkpoints which lead to indirect repercussions on T-cell effect are also being investigated as next generation inhibitors. This has been reviewed in detail elsewhere ( 92 ).…”

Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

“…For example, the combination of ICI with molecularly targeted agents, such as the vascular endothelial growth factor receptor (VEGFR) inhibitor bevacizumab or multi-tyrosine kinase inhibitors (e.g., axitinib or cabozantinib), has shown promising efficacy in recent trials [ 56 , 57 ]. The development of agents targeting novel immune checkpoint proteins (e.g., lymphocyte activating 3 (Lag3), T cell immunoglobulin and mucin domain-containing protein 3 (Tim3)) is also well underway and could be combined with existing ICIs [ 58 , 59 , 60 ].…”