Biological sciences articles within Nature Reviews Clinical Oncology

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  • Review Article |

    Following the introduction of blinatumomab in 2014, the past 4 years have seen the approval of a further ten bispecific antibodies, reflecting substantial research effort and clinical interest in these agents. In this Review, the authors describe the developments leading to the approval of these novel agents and highlight important future research directions, including clinical optimization as well as innovative antibody engineering approaches.

    • Maria-Elisabeth Goebeler
    • , Gernot Stuhler
    •  & Ralf Bargou

  • News & Views |

    The majority of patients with cancers of unknown primary have unfavourable outcomes when they receive empirical chemotherapy. The shift towards using precision medicine-based treatment strategies involves two options: tissue-agnostic or site-specific approaches. Here, we reflect on how cytology-based deep learning tools can be leveraged in these approaches.

    • Elie Rassy
    •  & Nicholas Pavlidis

  • Review Article |

    Following their successful implementation in the COVID-19 pandemic, the technology behind mRNA vaccines is now being applied to cancer. In this Review, the authors described the several decades of development of mRNA vaccines for patients with cancer, including initial developments in this area involving cell-based vaccines as well as more recent developments with nanoparticle-encapsulated vaccines, which are beginning to show promising clinical activity.

    • Elias J. Sayour
    • , David Boczkowski
    •  & Smita K. Nair

  • Comment |

    Certain subsets of patients with multiple myeloma or its precursor conditions are overtreated with current approaches to therapy. Herein, we highlight several key areas where we believe de-escalation of treatment is needed. Dedicated trials to assess these de-escalation approaches and urgent changes to current clinical practices are needed.

    • Ghulam Rehman Mohyuddin
    •  & Aaron M. Goodman

  • Perspective |

    The benefit of combining antiangiogenic agents with immune-checkpoint inhibitors has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, other phase III trials have had negative results. The authors of this Perspective discuss the variable outcomes of these trials, considering factors that account for these differences and suggesting future initiatives for improving the outcomes in patients receiving these combinations.

    • Hung-Yang Kuo
    • , Kabir A. Khan
    •  & Robert S. Kerbel

  • Review Article |

    Nucleic acid-based therapies offer an alternative to traditional cancer treatment modalities, with promising data beginning to emerge. In this Review, the authors describe the design and development of nucleic acid-based therapies administered virally and non-virally, including discussions of the advantages and disadvantage of each approach, as well as the role of patient-specific factors such as the tumour microenvironment, and consider the most promising future research directions.

    • Sebastian G. Huayamares
    • , David Loughrey
    •  & Eric J. Sorscher

  • News & Views |

    The composition of the gut microbiota has emerged as a tumour-extrinsic factor that modulates response to immune-checkpoint inhibitors (ICIs), although the lack of consistency in microbiota signatures across studies has limited their value as reliable biomarkers. Herein, we discuss a recent study in which longitudinal microbiome profiling identified several taxa that are persistently enriched in patients with melanoma and a favourable response to ICIs.

    • Saman Maleki Vareki
    •  & Diwakar Davar

  • News & Views |

    The benefits and potential harms of mammography-based screening for breast cancer are often a matter of debate. Here, I discuss the promises and limitations of a recent study that tested an artificial intelligence-based tool for the detection of breast cancer in digital mammograms in a large, prospective screening setting.

    • Despina Kontos

  • Review Article |

    FGFR inhibitors are now approved for use in patients with advanced-stage urothelial carcinoma, cholangiocarcinoma and myeloid or lymphoid neoplasms that harbour certain FGFR alterations. Nonetheless, challenges such as tolerability and acquired resistance limit the clinical potential of these agents. In this Review, the authors summarize the available clinical data on FGFR inhibitors, describe promising novel agents and highlight future research directions that might optimize the efficacy of FGFR-targeted therapies.

    • Masuko Katoh
    • , Yohann Loriot
    •  & Masaru Katoh

  • Review Article |

    Various BRAF alterations are found and function as oncogenic drivers across diverse cancer types. BRAF inhibitor-based therapy has improved outcomes for patients with cancers harbouring BRAFV600 mutations, although resistance develops in most, and the current inhibitors are not effective against other types of BRAF alterations. In this Review, the authors describe the mechanisms underlying oncogenic BRAF signalling, as well as pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. They also discuss novel RAF inhibitors and drug combinations designed to overcome these resistance mechanisms and/or expand the applicability of molecularly targeted therapy to a broader range of BRAF-mutant cancers.

    • Aphrothiti J. Hanrahan
    • , Ziyu Chen
    •  & David B. Solit

  • Review Article |

    Lung cancer is a disease typically associated with tobacco smoking; however, lung cancer in individuals who have never smoked (LCINS) is estimated to be the fifth most common cause of cancer-related deaths globally. Moreover, smoking rates are declining around the world and therefore LCINS is likely to increase as a proportion of all lung cancers over time. Thus, understanding the aetiology and features of LCINS is increasingly important. Herein, the authors review the emerging data on the epidemiology, clinical characteristics and molecular features of LCINS as well as the genetic and environmental risk factors for this disease. They also summarize the unique diagnostic and management paradigms of LCINS.

    • Jaclyn LoPiccolo
    • , Alexander Gusev
    •  & Pasi A. Jänne

  • Review Article |

    Antibody–drug conjugates (ADCs) are effective cancer drugs that have been approved for more than 20 specific indications. Nonetheless, acquired resistance and adverse events both limit the effectiveness of these agents. In this Review, the authors describe the development of novel ADC designs, including bispecific ADCs, probody–drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs. all of which have the potential to address these challenges and provide more effective ADCs.

    • Kyoji Tsuchikama
    • , Yasuaki Anami
    •  & Chisato M. Yamazaki

  • Review Article |

    Despite dramatic progress over the past decade, only around 50% of patients with advanced-stage melanoma derive durable benefit from immune-checkpoint inhibitors (ICIs) and/or BRAF and MEK (BRAF/MEK) inhibitors. Over the past few years, adoptive cell therapy with tumour-infiltrating lymphocytes (TILs) has demonstrated encouraging efficacy including in patients with disease progression on ICIs or BRAF/MEK inhibitors. In this Review, the authors summarize the role of TIL therapies in the management of these patients and describe future research strategies that might improve safety or efficacy.

    • Sebastian Klobuch
    • , Tom T. P. Seijkens
    •  & John B. A. G. Haanen

  • Comment |

    The FDA approval of perioperative pembrolizumab, an approach that combines neoadjuvant and adjuvant therapy with this agent, for patients with early stage non-small-cell lung cancer (NSCLC) contradicts its own stated standard for combination therapies. Given the large population of patients with early stage NSCLC and the high costs of pembrolizumab, whether the adjuvant component provides incremental benefit is an important question.

    • Garth W. Strohbehn
    •  & Bishal Gyawali

  • Comment |

    Through Project Optimus, the FDA calls for radical changes in the design of early phase trials to identify the optimal doses of oncology drugs to achieve maximal efficacy with better tolerability and patient acceptability. Herein, we discuss approaches that will enable the implementation of this initiative as well as some concerns that the draft guidance has raised in the oncology community.

    • Simon Rodney
    •  & Udai Banerji

  • Review Article |

    Cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with endocrine therapy have become the standard-of-care therapy for patients with advanced-stage hormone receptor-positive breast cancer. However, this success has created several challenges, such as the need to better understand resistance to these agents and develop novel therapies accordingly. Here, the authors provide an update on the clinical activity of the established CDK4/6 inhibitors along with a summary of ongoing research efforts attempting to address the new challenges created by the success of these agents.

    • Laura Morrison
    • , Sibylle Loibl
    •  & Nicholas C. Turner

  • News & Views |

    Recent results from the FLAURA2 and MARIPOSA-2 trials underline the continued role of chemotherapy in the treatment of patients with EGFR-mutated non-small-cell lung cancer in the era of targeted therapies. Herein, we argue that the most appropriate and rational sequence and/or combination of therapies remains a matter of discussion.

    • Rafael Rosell
    •  & María González-Cao

  • Perspective |

    The current standard-of-care adjuvant treatment for patients with colorectal cancer is chemotherapy selected on the basis of conventional histopathological staging criteria; however, the clinical benefit from these regimens is limited. The authors of this Perspective discuss strategies to minimize toxicity and monitor efficacy of these regimens, and propose new tools for disease staging that could enable more personalized treatment decisions.

    • Li Yang
    • , Jinlin Yang
    •  & David J. Kerr

  • Review Article |

    Identifying patients who are likely to benefit from immune-checkpoint inhibitors remains one of the major challenges in immunotherapy. Cancer immunogenomics is an emerging field that bridges genomics and immunology. The authors of this Review provide an overview of the computational approaches currently available to analyse bulk tissue and single-cell sequencing data from cancer, stromal and immune cells.

    • Venkateswar Addala
    • , Felicity Newell
    •  & Nicola Waddell

  • Perspective |

    Despite some success in patients with certain B cell malignancies and relapsed and/or refractory multiple myeloma, studies testing chimeric antigen receptor (CAR) T cells in patients with advanced-stage solid tumours have been largely unsuccessful, with a few notable exceptions. In this Perspective, the author provides some possible reasons for the failures of most CAR T cell-based approaches and suggests strategies that might address some of these challenges.

    • Steven M. Albelda

  • Perspective |

    The use of composite end points in clinical trials can expedite drug development and approval, and thus improve patient access to novel treatments, but are often vaguely and heterogeneously defined, with considerable inter-study variation in the component events that are included. The different component events can vary in clinical significance and be differentially affected by treatment but, nevertheless, are rarely reported separately. In this Perspective, Walia et al. define composite outcomes that are commonly used in oncology, discuss the advantages and challenges of using composite end points, and advocate for transparent reporting including a full breakdown of the component events to facilitate accurate interpretation of trial results and the true benefit of an intervention.

    • Anushka Walia
    • , Jordan Tuia
    •  & Vinay Prasad

  • News & Views |

    Epstein–Barr virus (EBV)-based biomarkers are used for nasopharyngeal carcinoma (NPC) screening in endemic regions. A recent prospective study describes the use of a new serological biomarker, antibodies targeting the EBV protein BNLF2b, for NPC screening in >20,000 participants. This biomarker yielded both higher sensitivity and specificity for NPC detection in the screening cohort compared with the conventionally used antibodies. Herein, we highlight the key findings of this study and discuss the implications of these results.

    • W. K. Jacky Lam
    •  & Anthony T. C. Chan

  • Review Article |

    Ovarian carcinoma is a highly heterogeneous tumour type, both spatially and temporally. As a consequence, these carcinomas are often associated with poor outcomes. Ovarian carcinoma comprises various subtypes with distinct complex molecular features. The authors of this Review discuss the molecular, cellular and anatomical heterogeneity of ovarian carcinoma, and outline the current and future treatment strategies for this malignancy.

    • Ana C. Veneziani
    • , Eduardo Gonzalez-Ochoa
    •  & Amit M. Oza

  • Perspective |

    Despite improved effectiveness, most systemic cancer therapies are not curative and most patients will develop acquired resistance that often cannot be explained by the emergence of specific genomic alterations. In this Perspective, the authors describe the potential role of a small population of tumour cells, termed drug-tolerant persister cells, that are able to survive therapy and, on continued treatment exposure, develop stable mechanisms of resistance to systemic therapies.

    • Yi Pu
    • , Lu Li
    •  & Shensi Shen

  • Comment |

    In 2023, a decade after granting Accelerated Approval to the first-in-class BTK inhibitor ibrutinib for the treatment of mantle cell lymphoma, the FDA requested this indication be withdrawn. Herein, we discuss the seemingly inconsistent results from the SHINE and TRIANGLE trials, which relate to the distinct patient populations of these trials, and posit that regulatory approaches should take these nuances into account.

    • Edward R. Scheffer Cliff
    • , Talal Hilal
    •  & Aaron S. Kesselheim

  • Review Article |

    The availability of regimens containing one or more immune-checkpoint inhibitors (ICIs) has improved the outcomes in patients with advanced-stage hepatocellular carcinoma. However, clinical benefit from these regimens is difficult to predict, indicating the need for novel biomarkers. In this Review, the authors describe the available evidence on biomarkers to guide the use of ICIs in these patients and discuss promising future research directions.

    • Tim F. Greten
    • , Augusto Villanueva
    •  & Xin W. Wang

  • Review Article |

    In oncology, mRNA–lipid nanoparticles (LNPs) have been used either to achieve intratumoural expression of immune-stimulating cytokine combinations or as cancer vaccines, and new strategies are in development to enable the selective delivery of payloads into cancer cells previously considered unreachable. The authors of this Review present various approaches for delivering mRNA–LNPs to tumours and discuss improvements that will improve the selective targeting of cancer cells with mRNA–LNPs.

    • Edo Kon
    • , Nitay Ad-El
    •  & Dan Peer

  • Review Article |

    Advances over the past decade have established a prominent role of the gut microbiota in the modulation of immune homeostasis and function, including in patients with cancer receiving immune-checkpoint inhibitors. In this Review, the authors summarize current knowledge of the role of the microbiota in this context, describe several methods of modulating the microbiota clinically to improve patient outcomes, and highlight important future directions in this expanding area of research.

    • Rebecca C. Simpson
    • , Erin R. Shanahan
    •  & Georgina V. Long

  • Review Article |

    Several trials are testing immune-checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, in patients with resectable non-small-cell lung cancer as an adjuvant, neoadjuvant or perioperative approach. However, the optimal use of ICIs with curative intent in patients with early stage non-small-cell lung cancer remains unclear. The authors of this Review discuss the current trial landscape and discuss challenges and opportunities.

    • Giannis Mountzios
    • , Jordi Remon
    •  & Solange Peters

  • News & Views |

    A recent report from the ATLAS trial comparing different maintenance strategies following haematopoeitic stem cell transplantation for multiple myeloma provides an opportunity to explore various themes of critical appraisal, including end points, the equipoise of trial design, and the part censoring can play in the validity of results.

    • Ghulam Rehman Mohyuddin
    •  & Tomer Meirson

  • Review Article |

    Many studies attempting to identify biomarkers for predicting of immune-checkpoint inhibitor (ICI) efficacy have led to the description of Gut OncoMicrobiome Signatures (GOMS). Several GOMS support an association between oncogenesis and intestinal dysbiosis, and other GOMS are shared between patients with several cancer subtypes and individuals with seemingly unrelated chronic inflammatory disorders. The authors of this Review discuss these patterns as well as the findings from a meta-analysis of GOMS associated with clinical benefit from ICIs, and propose practical guidelines to incorporate GOMS in decision-making in immuno-oncology.

    • Andrew Maltez Thomas
    • , Marine Fidelle
    •  & Laurence Zitvogel

  • Review Article |

    Immune-checkpoint inhibitors (ICIs) and other immunotherapies have revolutionized the treatment of patients with cancer. Nonetheless, most patients do not derive durable benefit, indicating a need for biomarkers to guide treatment selection. In this Review, the authors describe the role of antigen presentation in response to ICIs and other immunotherapies, with a focus on the role of molecular and/or genomic alterations affecting antigen presentation.

    • Kailin Yang
    • , Ahmed Halima
    •  & Timothy A. Chan

  • Review Article |

    Radiotherapy has several key attributes that make it an attractive combination partner for immunotherapy; however, numerous clinical trials investigating the combination of these two treatment modalities have failed to demonstrate clear improvements in patient outcomes. In this Review, Galluzzi and colleagues discuss the evidence indicating that radiotherapy administered according to standard schedules and target volumes might impair immune fitness and, therefore, propose that adaptation of the radiotherapy regimens to immunotherapy (and not vice versa) might synergistically enhance the antitumour immune response to achieve meaningful clinical benefits.

    • Lorenzo Galluzzi
    • , Molykutty J. Aryankalayil
    •  & Silvia C. Formenti

  • Perspective |

    The authors of this Perspective propose that, with further improvement in detection efficiency, circulating tumour cells (CTCs), which are released early during cancer development, have the potential to be used for the early detection of clinically relevant, aggressive cancers. Thus, use of CTCs as diagnostic biomarkers might improve outcomes by enabling the identification of cancers at a stage at which they are more amenable to treatment while avoiding overtreatment of patients with indolent tumours.

    • Rachel Lawrence
    • , Melissa Watters
    •  & Yong-Jie Lu

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