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.

Keywords: B7-H3; BTLA; ICOS; LAG-3; TIGIT; TIM-3; VISTA; immune checkpoint.

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Clinical Insights Into Novel Immune Checkpoint Inhibitors

Jii Lee

Sang-Jun Ha

Hye Kim

^{Division of Hemato-oncology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, South Korea,}

^{Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea,}

^{Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, South Korea,}

Edited by:Claudia Cerella, Fondation de Recherche Cancer et Sang, Luxembourg

Reviewed by:Carmen Stecher, Medical University of Vienna, Austria

Salman M Toor, Hamad bin Khalifa University, Qatar

Reem Saleh, Qatar Biomedical Research Institute, Qatar

*Correspondence: Hye Ryun Kim, ca.shuy@glebon; Sang-Jun Ha, rk.ca.iesnoy@ahjs

This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

Edited by:Claudia Cerella, Fondation de Recherche Cancer et Sang, LuxembourgReviewed by:Carmen Stecher, Medical University of Vienna, Austria

Salman M Toor, Hamad bin Khalifa University, Qatar

Reem Saleh, Qatar Biomedical Research Institute, Qatar

This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

Received 2021 Mar 16; Accepted 2021 Apr 22.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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.

Keywords: immune checkpoint, LAG-3, TIGIT, TIM-3, B7-H3, VISTA, ICOS, BTLA

Abstract

Abbreviations: APC, antigen presenting cell; BTLA, B and T-lymphocyte attenuator; CAR-T, chimeric antigen receptor T cell; DART, dual-affinity re-targeting proteins; DCs, dendritic cells; Dies 1, differentiation of embryonic stem cells 1; HAVCR2, hepatitis A virus cellular receptor 2; HVEM, herpes-virus entry mediator; mAb, monoclonal antibody; ICOS, Inducible T cell costimulator; ICOSL, Inducible T cell costimulatory ligand; LAG-3, lymphocyte-associated gene 3; NK cells, natural killer cells; PD-1H, PD-1 homologue; PD-L1, programmed death-ligand 1; PtdSer, phosphatidyl serine; T regs, ceacam-1, carcinoembryonic antigen cell adhesion molecule 1; T regs, regulatory T cells; TIGIT, T cell immunoglobulin and ITIM domain; TIM-3, T-cell immunoglobulin and mucin domain-3; VISTA, V-domain immunoglobulin suppressor of T cell activation; VSIG-3, V-Set and Immunoglobulin domain containing 3; WUCAM, Washington University cell adhesion molecule.

Abbreviations: ADC, antibody drug conjugate; APC, antigen-presenting cell; BTLA, B and T-lymphocyte attenuator; CAR, chimeric antigen receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein; DART, dual-affinity re-targeting proteins; ICOS, inducible T-cell costimulator; LAG3, lymphocyte-associated gene 3; mAb, monoclonal antibody; PD-L1, programmed death-ligand 1; TIGIT, T cell immunoglobulin and ITIM domain; TIM, T-cell immunoglobulin and mucin domain-3; VISTA, V-domain immunoglobulin suppressor of T cell activation.

Abbreviations: AML, acute myeloid leukemia; anti-PD-1, anti-programmed death-1; BCLC, Barcelona Clinic Liver Stage; BTLA, B and T-lymphocyte attenuator; CML, chronic myelogenous leukemia; CNS, central nervous system; CRC, colorectal cancer; DART, dual-affinity re-targeting proteins; DLBCL, diffuse large B cell lymphoma; DSRCT, desmoplastic small round cell tumor; GBM, glioblastoma multiforme; GC, gastric cancer; GEJ, gastroesophageal junction cancer; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; ICOS, Inducible T cell costimulator; IDO1i, indoleamine 2,3-dioxygenase-1 inhibitor; IPSS-R, revised international prognostic scoring system; LAG3, lymphocyte-associated gene 3; MDM2, mouse double minute 2 homolog; MDS, myelodysplastic syndrome; MSI-H, microsatellite instability-high; MSS, microsatellite stable; NSCLC, non-small cell lung cancer; PEGPH20, pegylated recombinant human hyaluronidase; RCC, Renal cell carcinoma; rHuPH20, recombinant human hyaluronidase PH20 enzyme; SCLC, small cell lung carcinoma; TIGIT, T cell immunoglobulin and ITIM domain; TIM, T-cell immunoglobulin and mucin domain-3; TNBC, triple negative breast cancer; TNFRSF9, tumor necrosis factor receptor superfamily member 9; VEGF, vascular endothelial growth factor; VISTA, V-domain immunoglobulin suppressor of T cell activation.

Regimens: mFOLFOX, oxaliplatin 85mg/m^{intravenous (IV), leucovorin 400mg/m}^{IV, and fluorouracil 2400mg/m}^{IV over 4648h every 2weeks (Q2W) FOLFIRI, irinotecan 180mg/m}^{IV, leucovorin 400mg/m}^{IV, and 5-FU 2400mg/m}^{IV over 4648h (Q2W).}

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