Next generation of immune checkpoint therapy in cancer: New developments and challenges

Julian A. Marin-Acevedo, Bhagirathbhai Dholaria, Aixa E. Soyano, Keith L Knutson, Saranya Chumsri, Yanyan Lou

Research output: Contribution to journalReview article

97 Citations (Scopus)

Abstract

Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

Original languageEnglish (US)
Article number39
JournalJournal of Hematology and Oncology
Volume11
Issue number1
DOIs
StatePublished - Mar 15 2018

Fingerprint

CD274 Antigen
Neoplasms
Cytotoxic T-Lymphocytes
Programmed Cell Death 1 Receptor
Therapeutics
Self Tolerance
Phase II Clinical Trials
Clinical Trials, Phase I
Tumor Microenvironment
Pharmaceutical Preparations
Immunotherapy

Keywords

  • Cancer
  • Co-stimulatory pathways
  • Cytotoxic T lymphocytes
  • Immune checkpoint therapy
  • Immune evasion
  • Immunotherapy
  • Immunotherapy
  • Inhibitory pathways
  • Tumor microenvironment
  • Tumor microenvironment

ASJC Scopus subject areas

  • Hematology
  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Next generation of immune checkpoint therapy in cancer : New developments and challenges. / Marin-Acevedo, Julian A.; Dholaria, Bhagirathbhai; Soyano, Aixa E.; Knutson, Keith L; Chumsri, Saranya; Lou, Yanyan.

In: Journal of Hematology and Oncology, Vol. 11, No. 1, 39, 15.03.2018.

Research output: Contribution to journalReview article

@article{c98f08acdae74749b62b8876c9faedf2,
title = "Next generation of immune checkpoint therapy in cancer: New developments and challenges",
abstract = "Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.",
keywords = "Cancer, Co-stimulatory pathways, Cytotoxic T lymphocytes, Immune checkpoint therapy, Immune evasion, Immunotherapy, Immunotherapy, Inhibitory pathways, Tumor microenvironment, Tumor microenvironment",
author = "Marin-Acevedo, {Julian A.} and Bhagirathbhai Dholaria and Soyano, {Aixa E.} and Knutson, {Keith L} and Saranya Chumsri and Yanyan Lou",
year = "2018",
month = "3",
day = "15",
doi = "10.1186/s13045-018-0582-8",
language = "English (US)",
volume = "11",
journal = "Journal of Hematology and Oncology",
issn = "1756-8722",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Next generation of immune checkpoint therapy in cancer

T2 - New developments and challenges

AU - Marin-Acevedo, Julian A.

AU - Dholaria, Bhagirathbhai

AU - Soyano, Aixa E.

AU - Knutson, Keith L

AU - Chumsri, Saranya

AU - Lou, Yanyan

PY - 2018/3/15

Y1 - 2018/3/15

N2 - Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

AB - Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

KW - Cancer

KW - Co-stimulatory pathways

KW - Cytotoxic T lymphocytes

KW - Immune checkpoint therapy

KW - Immune evasion

KW - Immunotherapy

KW - Immunotherapy

KW - Inhibitory pathways

KW - Tumor microenvironment

KW - Tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85043773584&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043773584&partnerID=8YFLogxK

U2 - 10.1186/s13045-018-0582-8

DO - 10.1186/s13045-018-0582-8

M3 - Review article

C2 - 29544515

AN - SCOPUS:85043773584

VL - 11

JO - Journal of Hematology and Oncology

JF - Journal of Hematology and Oncology

SN - 1756-8722

IS - 1

M1 - 39

ER -