A guide to cancer immunotherapy: from T cell basic science to clinical practice

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Abstract

The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.

Abstract

T cells play a central role in immune responses to cancer. In this guide to cancer immunotherapy, the authors provide a comprehensive historical and biological perspective on cancer immunotherapy, with a focus on current and emerging therapeutic approaches that harness T cells to fight cancer.

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Most cited references 140

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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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CTLA-4 and PD-1 Pathways

Elizabeth I Buchbinder, Anupam Desai (2016)

Supplemental Digital Content is available in the text.

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CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

Terry Fry, Nirali Shah, Rimas Orentas … (2017)

Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)

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Author and article information

Contributors

Michael J. Lenardo:

ORCID: http://orcid.org/0000-0003-1584-468X

lenardo@nih.gov

Journal

Journal ID (nlm-ta): Nat Rev Immunol

Journal ID (iso-abbrev): Nat. Rev. Immunol

Title: Nature Reviews. Immunology

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1474-1733

ISSN (Electronic): 1474-1741

Publication date (Electronic): 20 May 2020

Pages: 1-18

Affiliations

[1 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

[2 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

Author information

Alex D. Waldman http://orcid.org/0000-0002-2016-6118

Michael J. Lenardo http://orcid.org/0000-0003-1584-468X

Article

Publisher ID: 306

DOI: 10.1038/s41577-020-0306-5

PMC ID: 7238960

PubMed ID: 32433532

SO-VID: 34ee88eb-3084-420e-88d4-e11b1c2d72f1

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This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

A guide to cancer immunotherapy: from T cell basic science to clinical practice

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Cancer Immunotherapy

Most cited references 140

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

CTLA-4 and PD-1 Pathways

CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

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