Clinical Insights Into Novel Immune Checkpoint Inhibitors

Sang-Jun Ha,Jii Bum Lee,Hye Ryun Kim

doi:10.3389/fphar.2021.681320

Abstract

The success of immune checkpoint inhibitors (ICIs), notably anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) as well as inhibitors of CTLA-4, programmed death 1 (PD-1), and programmed death ligand-1 (PD-L1), has revolutionized treatment options for solid tumors. However, the lack of response to treatment, in terms of de novo or acquired resistance, and immune related adverse events (IRAE) remain as hurdles. One mechanisms to overcome the limitations of ICIs is to target other immune checkpoints associated with tumor microenvironment. Immune checkpoints such as lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7 homolog 3 protein (B7-H3), inducible T cell costimulatory (ICOS), and B and T lymphocyte attenuator (BTLA) are feasible and promising options for treating solid tumors, and clinical trials are currently under active investigation. This review aims to summarize the clinical aspects of the immune checkpoints and introduce novel agents targeting these checkpoints.

Highlights

Cancer cells have characteristics that allow diversification and sustenance of their neoplastic state (Hanahan and Weinberg, 2011)
Blocking cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and the interaction between programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) elicit activation of the host immune system through T cell responses (Pardoll, 2012). These findings have led to the development of immune checkpoint inhibitors (ICIs) to control one of the key mechanisms utilized by cancer cells (Pardoll, 2012)
This review provides an overview of the mechanisms and ongoing clinical trials on novel emerging immune checkpoints, including lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucindomain containing-3 (TIM-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7 homolog 3 protein (B7-H3), inducible T cell costimulatory (ICOS), and B and T lymphocyte attenuator (BTLA) (Chapoval et al, 2001; Monney et al, 2002; Yu et al, 2009; Paulos and June, 2010; Wang et al, 2011; Andrews et al, 2017; Marinelli et al, 2018)

Summary

BACKGROUND

Cancer cells have characteristics that allow diversification and sustenance of their neoplastic state (Hanahan and Weinberg, 2011). Phase 2 study including 72 patients treated with LAG-525, which is an IgG4 mAb for LAG-3, and spartalizumab (PDR001), an anti-PD-1, for advanced solid tumors and hematologic malignancies showed promising activity, especially in neuroendocrine tumors, small cell lung cancer (SCLC), and diffuse large B-cell lymphoma (DLBCL), with a clinical benefit rate at 24 weeks (CBR24) of 0.86, 0.27, and 0.804, respectively, meeting its primary endpoint (NCT03365791) (Uboha et al, 2019). MGD013 is a LAG-3 and PD-1 dual-affinity re-targeting (DART) protein; its safety, tolerability, DLT, MTD, PK/PD, and antitumor activity were analyzed in patients with unresectable and metastatic tumors in a phase 1 study (NCT03219268) (Luke et al, 2020). 1,2 Adjuvant 1,2 Stage II-IV 1 Advanced/metastatic 1 Stage III-IV 2 Advanced/metastatic 1 Advanced/metastatic 1,2 First, second line 2 Advanced/metastatic 2 Advanced/metastatic 2,3 Advanced/metastatic 2 Advanced/metastatic 1 Resectable

Recurrent

First line

Locally advanced or

Prior external beam

Findings

CONCLUSION