Review Articles

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  • Hotspot genetic alterations that confer the enzymes isocitrate dehydrogenase (IDH) 1 and 2 with neomorphic activity to produce the oncometabolite D-2-hydroxyglutarate are common in several cancer types, including acute myeloid leukaemia, cholangiocarcinoma, chondrosarcoma and glioma. Herein, Pirozzi and Yan describe the current understanding of the biological, pathogenetic and prognostic implications of IDH mutations in these cancers. They also review the available preclinical and clinical data on the various therapeutic strategies that are being pursued for IDH-mutant cancers and discuss whether treatment approaches will converge or be context dependent.

    • Christopher J. Pirozzi
    • Hai Yan
    Review Article
  • Despite being the most common primary bone cancer in children and young adults, osteosarcoma is a rare cancer, a fact that has complicated efforts to improve patient outcomes. Moreover, the molecular biology of disease is highly heterogeneous and most of the recurrent genetic alterations occur in tumour-suppressor genes that are challenging therapeutic targets. Herein, Gill and Gorlick discuss the new biological discoveries, technologies, and therapeutic agents and approaches that, through collaborative efforts, are poised to generate advances in the treatment of osteosarcoma after more than four decades of stagnation.

    • Jonathan Gill
    • Richard Gorlick
    Review Article
  • Limited penetration into tumour tissue can restrict the activity of systemically delivered cancer immunotherapies, whereas exposure of various non-malignant tissues to high levels of such agents can lead to problematic toxicities. Intratumoural administration and/or biotechnology strategies for selective targeting of tumour tissues have the potential to circumvent these issues and thereby increase the therapeutic index. Herein, the authors review the historical origins and current landscape of intratumoural and tumour tissue-targeted immunotherapies.

    • Ignacio Melero
    • Eduardo Castanon
    • Aurelien Marabelle
    Review Article
  • Advances in sequencing technology have rapidly improved our understanding of the biology of acute myeloid leukaemia and led to the development of several novel targeted therapies. In this Review, the authors summarize the landscape of novel targeted therapies for patients with acute myeloid leukaemia and provide guidance on future research directions.

    • Hartmut Döhner
    • Andrew H. Wei
    • Bob Löwenberg
    Review Article
  • The authors of this Review present the current considerations in the treatment of patients with early-stage lung cancer, discussing the critical determination of resectability by thoracic surgical oncologists and the management of both resectable and unresectable disease with a focus on systemic therapy selection. They also address innovations in drug development, trial design and efforts to identify early-stage cancers.

    • Jamie E. Chaft
    • Andreas Rimner
    • Tina Cascone
    Review Article
  • Various cancers can disseminate to the bone, including the most common malignancies in men and women, prostate and breast cancer, respectively. Herein, the authors review the roles of the bone microenvironment in skeletal metastasis, highlighting the biology and clinical relevance of circulating tumour cells and disseminated tumour cells. Notably, bone metastases are associated with considerable morbidity and a poor prognosis, and the authors also discuss established and future therapeutic approaches for targeting components of the bone microenvironment to prevent or treat skeletal metastases.

    • Lorenz C. Hofbauer
    • Aline Bozec
    • Klaus Pantel
    Review Article
  • Progress in precision medicine for colorectal cancer continues to lag behind the rapid improvements seen in patients with certain other solid tumour types. Nonetheless, owing largely to the availability of better translational models, novel and effective targeted therapy strategies based on tumour biology are beginning to be developed for subsets of patients. In this Review, the authors summarize these developments and discuss future directions in this rapidly evolving area of research.

    • Federica Di Nicolantonio
    • Pietro Paolo Vitiello
    • Alberto Bardelli
    Review Article
  • Despite considerable progress in the development of targeted therapies, only three biomarkers are currently used to guide the treatment of patients with gastric or gastro-oesophageal junction cancers using approved targeted therapies. Nonetheless, owing to advances in our understanding of tumour biology and sequencing technologies, several novel therapies are expected to soon become available. In this Review, the authors describe current and future biomarker-guided therapies for patients with G/GEJ cancers.

    • Yoshiaki Nakamura
    • Akihito Kawazoe
    • Kohei Shitara
    Review Article
  • Antibody–drug conjugates (ADCs) were originally developed for patients with haematological malignancies. In light of the recent increase in interest in this type of therapy, this Review describes the clinical experience with two ADCs — gemtuzumab ozogamicin and inotuzumab ozogamicin — in patients with haematological malignancies and provides guidance on the future directions for the development of novel ADCs for patients with leukaemias.

    • Elias Jabbour
    • Shilpa Paul
    • Hagop Kantarjian
    Review Article
  • The discovery that the anticancer activity of thalidomide and its analogues, such as lenalidomide, reflects drug-induced degradation of specific target proteins has heightened interest in novel ‘degrader’ drugs. Herein, the authors review the wide and expanding use of thalidomide analogues in the treatment of multiple cancers and outline how lessons learned from this experience, particularly with lenalidomide, can guide the clinical development of new targeted protein degradation platforms.

    • Max Jan
    • Adam S. Sperling
    • Benjamin L. Ebert
    Review Article
  • CD19-specific chimeric antigen (CAR)-modified T cells are approved for patients with advanced-stage forms of certain B cell malignancies. However, a subset of patients will have anti-CAR immune responses, leading to a lack of CAR T cell persistence and a rapid loss of any antitumour efficacy. In this Review, the authors describe the extent of anti-CAR immune responses in patients and suggest measures that could be used to better monitor for these events. Additionally, they describe novel approaches to CAR T cell therapy that might reduce the risk of such responses in the future.

    • Dimitrios L. Wagner
    • Enrico Fritsche
    • Mohamed Abou-el-Enein
    Review Article
  • PD-L1 expression is currently the best available biomarker for the prediction of responsiveness to immune-checkpoint inhibitors. However, several immunohistochemical assays are now approved for clinical use in various settings, despite imperfect inter-assay concordance, with important implications for pathology services and, potentially, for clinical outcomes. In this Review, the authors compare the performance of the various FDA-approved PD-L1 assays, discuss the varying implications of PD-L1 expression across different tumour types and provide guidance on possible novel approaches that might optimize the clinical utility of PD-L1 as a biomarker.

    • Deborah Blythe Doroshow
    • Sheena Bhalla
    • Fred R. Hirsch
    Review Article
  • Antibody–drug conjugates (ADCs) constitute a unique class of anticancer agents with demonstrated clinical efficacy against several different cancer types. Herein, the authors discuss the design and mechanisms of action of ADCs and how these properties are reflected in the clinical activity and toxicity profiles of such agents. Potential strategies to overcome the limitations of ADCs and thereby maximize their therapeutic benefit for patients with cancer are also proposed.

    • Joshua Z. Drago
    • Shanu Modi
    • Sarat Chandarlapaty
    Review Article
  • Ferroptosis is an iron-dependent form of regulated cell death driven by excessive lipid peroxidation. Pharmacological agents, ionizing radiation and cytokines can induce ferroptosis and thus suppress tumour growth, but ferroptosis can also trigger inflammation-associated immunosuppression. The authors describe the key molecular mechanisms of ferroptosis, including crosstalk with tumour-associated signalling pathways, and discuss potential therapeutic applications of ferroptosis.

    • Xin Chen
    • Rui Kang
    • Daolin Tang
    Review Article
  • A host of additional toxicities and/or potential late effects of chimeric antigen receptor (CAR) T cell therapy beyond cytokine release syndrome (CRS) warrant further investigation. Herein, experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation present six key focus research areas related to CAR T cell-related outcomes beyond CRS.

    • Haneen Shalabi
    • Juliane Gust
    • Nirali N. Shah
    Review Article
  • Personalized neoantigen-based therapeutic vaccines hold promise as cancer immunotherapies. This Review provides an overview of the complex personalized neoantigen vaccine production process, vaccine-induced T cell responses and strategies to enhance these responses. Completed and ongoing clinical studies testing such vaccines are discussed, and considerations for future clinical investigation of this novel, individualized form of immunotherapy are outlined.

    • Eryn Blass
    • Patrick A. Ott
    Review Article
  • Chronic inflammation can promote the development of various cancers. In this Review, the current clinical advances in ameliorating inflammation for the prevention or treatment of cancer are highlighted, and the experimental insights into the biological mechanisms supporting current and potential novel anti-inflammatory approaches to the management of cancer are discussed.

    • Jiajie Hou
    • Michael Karin
    • Beicheng Sun
    Review Article
  • Renal cell carcinomas (RCCs) are generally immunogenic, but only a subset of patients receiving currently approved immune-checkpoint inhibitors have long-term disease remission. In this Review, the authors provide a conceptual framework for developing novel immunotherapy approaches, including an overview of the most promising novel immune checkpoints and antigen-directed therapies, and highlighting the potential of these agents to further improve the outcomes in patients with RCC.

    • David A. Braun
    • Ziad Bakouny
    • Toni K. Choueiri
    Review Article
  • Nuclear import and export proteins, such as exportin 1(XPO1), regulate the transport of proteins and other molecules into and out of the nucleus, including several tumour suppressor proteins. The dysregulation of nuclear export can be observed in several types of haematological and solid tumours, providing a rationale for a novel form of targeted therapy. In this Review, the authors describe the development of XPO1 inhibitors, from basic research to clinical approval.

    • Asfar S. Azmi
    • Mohammed H. Uddin
    • Ramzi M. Mohammad
    Review Article
  • Despite the introduction of novel therapies, lung cancer remains the leading cause of cancer-related mortality worldwide. Randomized controlled trials of low-dose CT-based lung cancer screening in high-risk populations have shown a reduction in mortality. The authors of this Review discuss these studies and present the Screening Planning and Implementation RAtionale for Lung cancer (SPIRAL), a framework to define the scope of future implementation research on lung cancer screening.

    • Matthijs Oudkerk
    • ShiYuan Liu
    • John K. Field
    Review Article