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Monoclonal Antibodies to CTLA-4 with Focus on Ipilimumab

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Interaction of Immune and Cancer Cells

Part of the book series: Experientia Supplementum ((EXS,volume 113))

Abstract

The immune checkpoint cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 or CD152) is a negative regulator of T-cell-mediated immune responses which plays a critical role in suppressing autoimmunity and maintaining immune homeostasis. Because of its inhibitory activity on T cells, CTLA-4 has been investigated as a drug target to induce immunostimulation, blocking the interaction with its ligands. The antitumor effects mediated by CTLA-4 blockade have been attributed to a sustained active immune response against cancer cells, due to the release of a brake on T cell activation. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human anti-CTLA-4 IgG1κ monoclonal antibody (mAb) that represents the first immune checkpoint inhibitor approved as monotherapy by FDA and EMA in 2011 for the treatment of unresectable/metastatic melanoma. In 2015, FDA also granted approval to ipilimumab monotherapy as adjuvant treatment of stage III melanoma to reduce the risk of tumour recurrence. The subsequent approved indications of ipilimumab for metastatic melanoma, regardless of BRAF mutational status, and other advanced/metastatic solid tumours always involve its use in association with the anti-programmed cell death protein 1 (PD-1) mAb nivolumab. Currently, ipilimumab is evaluated in ongoing clinical trials for refractory/advanced solid tumours mainly in combination with additional immunostimulating agents.

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Abbreviations

APC:

antigen-presenting cells

CTLA-4 :

cytotoxic T-lymphocyte antigen-4

dMMR :

mismatch repair deficiency

EMA :

European Medicines Agency

FDA :

Food and Drug Administration

FoxP3 :

transcription factor forkhead box protein P3

GM-CSF :

granulocyte-macrophage colony-stimulating factor

HRQL :

health-related quality of life

ICOS :

inducible co-stimulator

IDO :

indoleamine 2,3 deoxygenase

IL :

interleukin

irAEs :

immune-related adverse effects

irRC :

immune-related criteria

LAT :

linker for activation of T cells

mAb :

monoclonal antibody

MHC :

major histocompatibility complex

MSI-H :

microsatellite instability high

MSI-L :

microsatellite instability low

MSS :

microsatellite stability

mWHO :

modified World Health Organization

NIBIT :

Italian Network of Tumour Biotherapy

NSCLC :

non–small-cell lung cancer

OS :

overall survival

PD-1 :

programmed cell death protein 1

PFS :

progression-free survival

PI3K :

phosphatidylinositol 3-kinase

PKC :

protein kinase C

PLC :

phospholipase C

PP2A :

serine-threonine protein phosphatase 2A

RECIST :

Response Evaluation Criteria in Solid Tumours

REMS :

Risk Evaluation and Mitigation Strategy

SCLC :

small-cell lung cancer

SHP2:

src homology 2 domain-containing tyrosine phosphatase 2

TCR :

T cell receptor

Tregs :

regulatory T cells.

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  1. Pharmacology Section, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

    Grazia Graziani & Lucio Tentori

  2. Section of Pharmacology, Department of Healthcare Surveillance and Bioethics, Catholic University Medical School, Catholic University of the Sacred Heart, Rome, Italy

    Lucia Lisi & Pierluigi Navarra

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  1. Grazia Graziani
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  2. Lucia Lisi
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  1. Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland

    Magdalena Klink

  2. Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland

    Izabela Szulc-Kielbik

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Graziani, G., Lisi, L., Tentori, L., Navarra, P. (2022). Monoclonal Antibodies to CTLA-4 with Focus on Ipilimumab. In: Klink, M., Szulc-Kielbik, I. (eds) Interaction of Immune and Cancer Cells. Experientia Supplementum, vol 113. Springer, Cham. https://doi.org/10.1007/978-3-030-91311-3_10

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