Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma

Duaa O Khair; Heather Jane Bax; Silvia Mele; Silvia Crescioli; Giulia Pellizzari; Atousa Khiabany; Mano Nakamura; Robert John Harris; Elise French; Ricarda Melina Hoffmann; Iwan Philip Williams; Ka Ki Anthony Cheung; Benjamin Thair; Charlie T Beales; Emma Touizer; Adrian Wilhelm Signell; Nahrin L Tasnova; James Frederick Spicer; Debra Hannah Josephs; Jenny L. C. Geh; Alistair MacKenzie Ross; Ciaran Healy; Sophie Elinor Papa; Katie E. Lacy; Sophia N Karagiannis

doi:10.3389/fimmu.2019.00453

Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma

Duaa O Khair, Heather Jane Bax, Silvia Mele, Silvia Crescioli, Giulia Pellizzari, Atousa Khiabany, Mano Nakamura, Robert John Harris, Elise French, Ricarda Melina Hoffmann, Iwan Philip Williams, Ka Ki Anthony Cheung, Benjamin Thair, Charlie T Beales, Emma Touizer, Adrian Wilhelm Signell, Nahrin L Tasnova, James Frederick Spicer, Debra Hannah Josephs, Jenny L. C. GehAlistair MacKenzie Ross, Ciaran Healy, Sophie Elinor Papa, Katie E. Lacy, Sophia N Karagiannis

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Abstract

The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.

Original language	English
Article number	453
Journal	Frontiers in Immunology
Issue number	MAR
Early online date	19 Mar 2019
DOIs	https://doi.org/10.3389/fimmu.2019.00453
Publication status	Published - 19 Mar 2019

Keywords

Antibody engineering
CTLA-4
Checkpoint inhibitors
Combination immunotherapy
Immunooncology therapeutics
Melanoma
PD-1
PD-L1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Combining Immune Checkpoint_KHAIR_Accepted20February2019_GOLD VoRFinal published version, 2.16 MBLicence: CC BY

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Khair, D. O., Bax, H. J., Mele, S., Crescioli, S., Pellizzari, G., Khiabany, A., Nakamura, M., Harris, R. J., French, E., Hoffmann, R. M., Williams, I. P., Cheung, K. K. A., Thair, B., Beales, C. T., Touizer, E., Signell, A. W., Tasnova, N. L., Spicer, J. F., Josephs, D. H., ... Karagiannis, S. N. (2019). Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma. Frontiers in Immunology, (MAR), Article 453. https://doi.org/10.3389/fimmu.2019.00453

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title = "Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma",

abstract = "The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed. ",

keywords = "Antibody engineering, CTLA-4, Checkpoint inhibitors, Combination immunotherapy, Immunooncology therapeutics, Melanoma, PD-1, PD-L1",

author = "Khair, {Duaa O} and Bax, {Heather Jane} and Silvia Mele and Silvia Crescioli and Giulia Pellizzari and Atousa Khiabany and Mano Nakamura and Harris, {Robert John} and Elise French and Hoffmann, {Ricarda Melina} and Williams, {Iwan Philip} and Cheung, {Ka Ki Anthony} and Benjamin Thair and Beales, {Charlie T} and Emma Touizer and Signell, {Adrian Wilhelm} and Tasnova, {Nahrin L} and Spicer, {James Frederick} and Josephs, {Debra Hannah} and Geh, {Jenny L. C.} and {MacKenzie Ross}, Alistair and Ciaran Healy and Papa, {Sophie Elinor} and Lacy, {Katie E.} and Karagiannis, {Sophia N}",

year = "2019",

month = mar,

day = "19",

doi = "10.3389/fimmu.2019.00453",

language = "English",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media",

number = "MAR",

}

Khair, DO, Bax, HJ , Mele, S , Crescioli, S , Pellizzari, G, Khiabany, A, Nakamura, M , Harris, RJ, French, E, Hoffmann, RM , Williams, IP , Cheung, KKA, Thair, B, Beales, CT, Touizer, E, Signell, AW, Tasnova, NL, Spicer, JF , Josephs, DH, Geh, JLC, MacKenzie Ross, A, Healy, C, Papa, SE, Lacy, KE & Karagiannis, SN 2019, 'Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma', Frontiers in Immunology, no. MAR, 453. https://doi.org/10.3389/fimmu.2019.00453

TY - JOUR

T1 - Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma

AU - Khair, Duaa O

AU - Bax, Heather Jane

AU - Mele, Silvia

AU - Crescioli, Silvia

AU - Pellizzari, Giulia

AU - Khiabany, Atousa

AU - Nakamura, Mano

AU - Harris, Robert John

AU - French, Elise

AU - Hoffmann, Ricarda Melina

AU - Williams, Iwan Philip

AU - Cheung, Ka Ki Anthony

AU - Thair, Benjamin

AU - Beales, Charlie T

AU - Touizer, Emma

AU - Signell, Adrian Wilhelm

AU - Tasnova, Nahrin L

AU - Spicer, James Frederick

AU - Josephs, Debra Hannah

AU - Geh, Jenny L. C.

AU - MacKenzie Ross, Alistair

AU - Healy, Ciaran

AU - Papa, Sophie Elinor

AU - Lacy, Katie E.

AU - Karagiannis, Sophia N

PY - 2019/3/19

Y1 - 2019/3/19

N2 - The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.

AB - The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.

KW - Antibody engineering

KW - CTLA-4

KW - Checkpoint inhibitors

KW - Combination immunotherapy

KW - Immunooncology therapeutics

KW - Melanoma

KW - PD-1

KW - PD-L1

UR - http://www.scopus.com/inward/record.url?scp=85064197158&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2019.00453

DO - 10.3389/fimmu.2019.00453

M3 - Article

SN - 1664-3224

JO - Frontiers in Immunology

JF - Frontiers in Immunology

IS - MAR

M1 - 453

ER -

Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma

Abstract

Keywords

UN SDGs

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