Advances in cancer immunotherapy 2019 – latest trends

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Abstract

Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.

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Most cited references 57

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Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.

Naiyer A Rizvi, Matthew Hellmann, Alexandra Snyder … (2015)

Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy. Copyright © 2015, American Association for the Advancement of Science.

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Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

T A Chan, M. Yarchoan, E Jaffee … (2018)

Abstract Background Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required. Materials and methods In this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity. Results High TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established. Conclusions TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.

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Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts

Jessica A. Hartmann, Martina Schüßler‐Lenz, Attilio Bondanza … (2017)

Abstract Chimeric antigen receptor (CAR) T cell therapy, together with checkpoint inhibition, has been celebrated as a breakthrough technology due to the substantial benefit observed in clinical trials with patients suffering from relapsed or refractory B‐cell malignancies. In this review, we provide a comprehensive overview of the clinical trials performed so far worldwide and analyze parameters such as targeted antigen and indication, CAR molecular design, CAR T cell manufacturing, anti‐tumor activities, and related toxicities. More than 200 CAR T cell clinical trials have been initiated so far, most of which aim to treat lymphoma or leukemia patients using CD19‐specific CARs. An increasing number of studies address solid tumors as well. Notably, not all clinical trials conducted so far have shown promising results. Indeed, in a few patients CAR T cell therapy resulted in severe adverse events with fatal outcome. Of note, less than 10% of the ongoing CAR T cell clinical trials are performed in Europe. Taking lead from our analysis, we discuss the problems and general hurdles preventing efficient clinical development of CAR T cells as well as opportunities, with a special focus on the European stage.

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Contributors

Stephan Kruger: +49 (0) 89 4400 0 , stephan.kruger@med.uni-muenchen.de

Matthias Ilmer: matthias.ilmer@med.uni-muenchen.de

Sebastian Kobold: sebastian.kobold@med.uni-muenchen.de

Bruno L. Cadilha: bruno.cadilha@med.uni-muenchen.de

Stefan Endres: stefan.endres@med.uni-muenchen.de

Steffen Ormanns: steffen.ormanns@med.uni-muenchen.de

Gesa Schuebbe: gesa.schuebbe@med.uni-muenchen.de

Bernhard W. Renz: bernhard.renz@uni-muenchen.de

Jan G. D’Haese: jan.dhaese@med.uni-muenchen.de

Hans Schloesser: hans.schloesser@uk-koeln.de

Volker Heinemann: volker.heinemann@med.uni-muenchen.de

Marion Subklewe: marion.subklewe@med.uni-muenchen.de

Stefan Boeck: stefan.boeck@med.uni-muenchen.de

Jens Werner: jens.werner@med.uni-muenchen.de

Michael von Bergwelt-Baildon: michael.bergwelt@med.uni-muenchen.de

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): 19 June 2019

Publication date PMC-release: 19 June 2019

Publication date Collection: 2019

Volume: 38

Electronic Location Identifier: 268

Affiliations

[1 ]Department of Medicine III, University Hospital Munich, LMU Munich, Marchioninistr. 15, D-81377 Munich, Germany

[2 ]Department of General, Visceral, and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany

[3 ]Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, LMU Munich, Munich, Germany

[4 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Institute of Pathology, LMU Munich, ; Munich, Germany

[5 ]ISNI 0000 0000 8852 305X, GRID grid.411097.a, University Hospital of Cologne, ; Cologne, Germany

[6 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), ; Heidelberg, Germany

[7 ]Center for Molecular Medicine Cologne (CMMC), Cologne, Germany

[8 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Gene Center LMU, ; Munich, Germany

Article

Publisher ID: 1266

DOI: 10.1186/s13046-019-1266-0

PMC ID: 6585101

PubMed ID: 31217020

SO-VID: 6b00a2e9-f9c5-4669-9c4e-a44cdc56bac4

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 : 31 May 2019

Date accepted : 3 June 2019

Funding

Funded by: Else Kröner-Fresenius-Stiftung (DE)

Award ID: Else Kröner-Forschungskolleg: Cancer Immunotherapy

Award Recipient : Stephan Kruger

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: immunotherapy,programmed cell death protein 1 (pd-1),programmed cell death protein ligand 1 (pd-l1),chimeric antigen receptor t cells (car t cells),trends,regional distribution

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: immunotherapy, programmed cell death protein 1 (pd-1), programmed cell death protein ligand 1 (pd-l1), chimeric antigen receptor t cells (car t cells), trends, regional distribution

Advances in cancer immunotherapy 2019 – latest trends

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Abstract

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Cancer Immunotherapy

Most cited references 57

Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic

Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts

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