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      Emerging therapies for small cell lung cancer

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          Abstract

          Currently, chemotherapy remains the standard treatment for first- and second-line management of small cell lung cancer (SCLC). Immunotherapy has made progress in the treatment of SCLC, and nivolumab, pembrolizumab, atezolizumab, and durvalumab have led to significant improvements in clinical outcomes of SCLC. Regarding options in other classes of therapy, the cytotoxic drug lurbinectedin was granted orphan drug status based on a remarkable objective response rate of 39.3%. In addition, an increase in progression-free survival (PFS) was achieved in a phase II study of anlotinib (ALTER 1202). Future prospects for even better outcomes in SCLC lie in novel ways to integrate immunotherapy and small-molecule TKI drugs. Innovative clinical trial designs are needed to efficiently explore the increasing number of options with new drugs and new combinations thereof for SCLC.

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          PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.

          Michael Curran, Welby Montalvo, Hideo Yagita … (2010)
          Vaccination with irradiated B16 melanoma cells expressing either GM-CSF (Gvax) or Flt3-ligand (Fvax) combined with antibody blockade of the negative T-cell costimulatory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) promotes rejection of preimplanted tumors. Despite CTLA-4 blockade, T-cell proliferation and cytokine production can be inhibited by the interaction of programmed death-1 (PD-1) with its ligands PD-L1 and PD-L2 or by the interaction of PD-L1 with B7-1. Here, we show that the combination of CTLA-4 and PD-1 blockade is more than twice as effective as either alone in promoting the rejection of B16 melanomas in conjunction with Fvax. Adding alphaPD-L1 to this regimen results in rejection of 65% of preimplanted tumors vs. 10% with CTLA-4 blockade alone. Combination PD-1 and CTLA-4 blockade increases effector T-cell (Teff) infiltration, resulting in highly advantageous Teff-to-regulatory T-cell ratios with the tumor. The fraction of tumor-infiltrating Teffs expressing CTLA-4 and PD-1 increases, reflecting the proliferation and accumulation of cells that would otherwise be anergized. Combination blockade also synergistically increases Teff-to-myeloid-derived suppressor cell ratios within B16 melanomas. IFN-gamma production increases in both the tumor and vaccine draining lymph nodes, as does the frequency of IFN-gamma/TNF-alpha double-producing CD8(+) T cells within the tumor. These results suggest that combination blockade of the PD-1/PD-L1- and CTLA-4-negative costimulatory pathways allows tumor-specific T cells that would otherwise be inactivated to continue to expand and carry out effector functions, thereby shifting the tumor microenvironment from suppressive to inflammatory.
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            A small cell lung cancer genome reports complex tobacco exposure signatures

            Erin Pleasance, Philip J. Stephens, Sarah O’Meara … (2009)
            SUMMARY Cancer is driven by mutation. Worldwide, tobacco smoking is the major lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. 22,910 somatic substitutions were identified, including 132 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in-frame, and another two lines carrying PVT1-CHD7 fusion genes, suggesting that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.
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              Effect of Anlotinib as a Third-Line or Further Treatment on Overall Survival of Patients With Advanced Non–Small Cell Lung Cancer

              Baohui Han, Kai Li, Qiming Wang … (2018)
              Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. A phase 2 trial showed anlotinib to improve progression-free survival with a potential benefit of overall survival, leading to the phase 3 trial to confirm the drug's efficacy in advanced non-small cell lung cancer (NSCLC).
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                Author and article information

                Contributors
                Qiming Wang:
                ORCID: http://orcid.org/0000-0003-3217-1077
                qimingwang1006@126.com
                Journal
                Journal ID (nlm-ta): J Hematol Oncol
                Journal ID (iso-abbrev): J Hematol Oncol
                Title: Journal of Hematology & Oncology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1756-8722
                Publication date (Electronic): 2 May 2019
                Publication date PMC-release: 2 May 2019
                Publication date Collection: 2019
                Volume: 12
                Electronic Location Identifier: 47
                Affiliations
                ISNI 0000 0004 1799 4638, GRID grid.414008.9, Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, , Henan Cancer Hospital, ; Zhengzhou, 450008 China
                Author information
                http://orcid.org/0000-0003-3217-1077
                Article
                Publisher ID: 736
                DOI: 10.1186/s13045-019-0736-3
                PMC ID: 6498593
                PubMed ID: 31046803
                SO-VID: 16b0ef4e-8eb6-4a4d-a494-7945ed68539b
                Copyright © © The Author(s). 2019
                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 : 7 March 2019
                Date accepted : 18 April 2019
                Funding
                Funded by: Medical Science and Technology Foundation of Henan Province
                Award ID: 201601026
                Award Recipient :
                Funded by: National Natural Science Foundation of China
                Award ID: 81272600
                Award Recipient :
                Funded by: Henan Provincial Training Abroad Foundation for Leaders of Medical Science
                Award ID: 201082
                Award Recipient :
                Funded by: Henan Provincial Special Funds for Health and Technological Innovative Talents
                Award ID: 2011020155
                Award Recipient :
                Funded by: Henan Provincial Research Program of Application Foundation and Advanced Technology
                Award ID: 112300410033
                Award Recipient :
                Funded by: Henan Province and Ministry of Health of Medical Science and Technology Program
                Award ID: 201601026
                Award Recipient :
                Funded by: the 51282 project Leading Talent of Henan Provincial Health Science and Technology Innovation Talents
                Award ID: [2016]32
                Award Recipient :
                Funded by: Wu Jieping Medical Foundation for Clinical Research
                Award ID: 320.6799.15018
                Award Recipient :
                Funded by: Program for Science and Technology Innovation Talents in Universities of Henan Province
                Award ID: 18HASTIT044
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: small cell lung cancer,chemotherapy,immunotherapy,targeted therapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: small cell lung cancer, chemotherapy, immunotherapy, targeted therapy

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