Clinical development of targeted and immune based anti-cancer therapies

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Abstract

Cancer is currently the second leading cause of death globally and is expected to be responsible for approximately 9.6 million deaths in 2018. With an unprecedented understanding of the molecular pathways that drive the development and progression of human cancers, novel targeted therapies have become an exciting new development for anti-cancer medicine. These targeted therapies, also known as biologic therapies, have become a major modality of medical treatment, by acting to block the growth of cancer cells by specifically targeting molecules required for cell growth and tumorigenesis. Due to their specificity, these new therapies are expected to have better efficacy and limited adverse side effects when compared with other treatment options, including hormonal and cytotoxic therapies. In this review, we explore the clinical development, successes and challenges facing targeted anti-cancer therapies, including both small molecule inhibitors and antibody targeted therapies. Herein, we introduce targeted therapies to epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), BRAF, and the inhibitors of the T-cell mediated immune response, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1)/ PD-1 ligand (PD-1 L).

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Most cited references 221

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The blockade of immune checkpoints in cancer immunotherapy.

Drew M Pardoll (2012)

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

Y Iwai, M. Ishida, Y. Tanaka … (2002)

PD-1 is a receptor of the Ig superfamily that negatively regulates T cell antigen receptor signaling by interacting with the specific ligands (PD-L) and is suggested to play a role in the maintenance of self-tolerance. In the present study, we examined possible roles of the PD-1/PD-L system in tumor immunity. Transgenic expression of PD-L1, one of the PD-L, in P815 tumor cells rendered them less susceptible to the specific T cell antigen receptor-mediated lysis by cytotoxic T cells in vitro, and markedly enhanced their tumorigenesis and invasiveness in vivo in the syngeneic hosts as compared with the parental tumor cells that lacked endogenous PD-L. Both effects could be reversed by anti-PD-L1 Ab. Survey of murine tumor lines revealed that all of the myeloma cell lines examined naturally expressed PD-L1. Growth of the myeloma cells in normal syngeneic mice was inhibited significantly albeit transiently by the administration of anti-PD-L1 Ab in vivo and was suppressed completely in the syngeneic PD-1-deficient mice. These results suggest that the expression of PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses and that blockade of interaction between PD-1 and PD-L may provide a promising strategy for specific tumor immunotherapy.

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EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

W Pao, V. Miller, M Zakowski … (2004)

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

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Author and article information

Contributors

N. A. Seebacher: nsee6009@uni.sydney.edu.au

A. E. Stacy: asta6801@uni.sydney.edu.au

G. M. Porter: g.porter@unsw.edu.au

A. M. Merlot:

ORCID: http://orcid.org/0000-0003-2599-3582

a.merlot@unsw.edu.au

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 11 April 2019

Publication date PMC-release: 11 April 2019

Publication date Collection: 2019

Volume: 38

Electronic Location Identifier: 156

Affiliations

[1 ]ISNI 0000 0004 1936 834X, GRID grid.1013.3, Faculty of Medicine, , The University of Sydney, ; Camperdown, New South Wales 2006 Australia

[2 ]ISNI 0000 0004 0402 6494, GRID grid.266886.4, Faculty of Medicine, , The University of Notre Dame, ; Darlinghurst, New South Wales 2010 Australia

[3 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, Children’s Cancer Institute, Lowy Cancer Research Centre, , University of New South Wales, ; Kensington, New South Wales 2031 Australia

[4 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, School of Women’s and Children’s Health, , Faculty of Medicine, University of New South Wales, ; Kensington, New South Wales 2031 Australia

[5 ]ISNI 0000 0004 4902 0432, GRID grid.1005.4, UNSW Centre for Childhood Cancer Research, , Faculty of Medicine, University of New South Wales, ; Kensington, New South Wales 2031 Australia

Author information

A. M. Merlot http://orcid.org/0000-0003-2599-3582

Article

Publisher ID: 1094

DOI: 10.1186/s13046-019-1094-2

PMC ID: 6460662

PubMed ID: 30975211

SO-VID: 61e18814-9acb-4527-b6f6-2146483cbc79

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 30 December 2018

Date accepted : 7 February 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: APP11105671

Funded by: FundRef http://dx.doi.org/10.13039/501100001171, Cancer Institute NSW;

Award ID: 15/ECF/1-08

Funded by: Cancer Australia and Cure Cancer Australia

Award ID: 1144868

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: targeted therapies,small molecule inhibitors,monoclonal antibodies,immunotherapies,clinical trials

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: targeted therapies, small molecule inhibitors, monoclonal antibodies, immunotherapies, clinical trials

Clinical development of targeted and immune based anti-cancer therapies

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Cancer Immunotherapy

Most cited references 221

The blockade of immune checkpoints in cancer immunotherapy.

Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.

EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

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