Reviews & Analysis

Genomics-based precision medicine has improved the outcomes of patients with certain types of cancers, although most do not derive benefit. Here, the authors describe the development of functional patient-specific assays, including those based on organoids, spheroids and explants, and how clinical implementation of these models might extend the benefits of precision medicine to a much broader range of patients.

Neoadjuvant chemotherapy offers a pragmatic alternative to the difficulties associated with delivering timely adjuvant chemotherapy in rectal cancer. Enthusiasm for administering neoadjuvant therapy to all patients with locally advanced rectal cancer is based on data from several phase III trials. Data from the RAPIDO trial are a critical component of this evidence.

Cachexia is a multi-organ syndrome characterized by substantial weight loss that affects a majority of patients with cancer and contributes to cancer-related mortality. The authors of this Review discuss the contribution of both the tumour macroenvironment and microenvironment to the inflammatory and metabolic processes involved in cancer-associated cachexia and provide an overview of the therapeutic strategies developed to manage this syndrome.

Lung cancers harbouring ‘rare’ alterations (defined as those with a prevalence of <5% of oncogene-driven lung cancers) can be detected in around a third of all oncogene-driven lung cancers and are diagnosed in thousands of patients each year. Advances in our understanding of tumour biology, diagnosis and the development of novel therapies are enabling increasing use of specific therapies targeting these alterations. In this Review, the authors provide an overview of the epidemiology, diagnosis, prognosis and treatment of patients with lung cancers harbouring these rare alterations. The importance of expedited drug approval pathways and cooperation between multiple stakeholders is also emphasized.

Plasma cell-free DNA analysis has emerged as a powerful liquid biopsy assay to assess circulating tumour DNA in response to cancer treatments. A new study shows that cell-free DNA can also inform on expansion kinetics and tumour-infiltration patterns in patients receiving chimeric antigen receptor T cells and, together with circulating tumour DNA, provides vivid prognostic insights into intratumoural dynamics.

Protein degraders constitute a new class of agents that eliminate, rather than just inhibit, their target proteins. These novel agents have recently entered testing in oncology trials, with initial data providing clinical proof of concept for the mechanism of action as well as the antitumour activity of heterobifunctional protein degraders. In this Review, the authors outline the progress in the development of such protein degraders for the treatment of cancer and consider prospects and potential challenges for these agents.

Data obtained using omics technologies can offer important insights into various aspects of chimeric antigen receptor (CAR) T cell therapy. In this Review, the authors provide an overview of the multidimensional profiling technologies that have been applied in investigations of CAR T cell therapy. They then discuss the ways in which multi-omics data obtained through such analyses can be used to elucidate CAR targets, factors associated with response or resistance to therapy, and mechanisms underlying the associated toxicities, which could potentially be exploited to improve the efficacy and safety of CAR T cell therapies.

Caring for individuals with thyroid nodules requires accurate estimation of their risk of thyroid cancer; however, available diagnostic tools offer only imprecise estimates. Novel biomarkers might help to clarify thyroid cancer risk and facilitate more-accurate diagnostic decision-making, although limitations in this area continue to exist.

Immune-checkpoint inhibitors (ICI) constitute a paradigm shift in the treatment of non-small-cell lung cancer (NSCLC); however, identifying the minority of patients who derive long-term benefit remains problematic, particularly among those with targetable oncogenic drivers who have typically been under-represented in or excluded from clinical trials of ICIs. This Review summarizes the associations of common oncogenic drivers of NSCLC with sensitivity or resistance to ICIs as well as the underlying effects on the immune tumour microenvironment. Potential vulnerabilities that could potentially be exploited to overcome primary resistance to ICIs conferred by certain oncogenic drivers are also highlighted.

Preclinical models that faithfully recapitulate interactions between the human immune system and tumours are necessary to evaluate human-specific immunotherapies in vivo; however, their number is currently limited. The authors of this Review discuss the currently available humanized mouse models, which are immunodeficient mice co-engrafted with human tumours and immune components, with a focus on their applicability in translational research.

Oncolytic viruses (OVs) provide a novel cancer treatment strategy, with a mechanism of action and toxicity profiles that are distinctly different to those of more traditional therapies. Thus far, four OVs have entered clinical use globally, yet only talimogene laherparepvec (T-VEC) has entered widespread clinical use. In this Review, the authors describe the clinical and regulatory experience with T-VEC thus far, and how this can guide the development of novel OVs. Discussions of a range of novel OVs with the potential for clinical implementation in the near future are also provided.

New genetic analyses demonstrate that the presence of low-frequency subclonal populations, including high-risk subclones, at diagnosis in multiple myeloma can contribute to disease relapse and poor clinical outcomes. Thus, sensitive detection approaches are required to detect these subclones at diagnosis together with innovative treatment strategies to eradicate low-frequency, high-risk subclones and prevent them from becoming dominant.

γδ T cells are lymphocytes with properties of both typical αβ T cell and natural killer cells, notable tissue tropisms, and MHC-independent antitumour functions that make them attractive agents for cancer immunotherapy. In this Review, the authors provide an overview of human γδ T cell subsets, discuss the antitumour and pro-tumour activities of these cells and their prognostic value in patients with cancer, and describe the current landscape of γδ T cell-based immunotherapies.

Immunotherapies have dramatically improved the outcomes of a subset of patients with advanced-stage cancers. Nonetheless, most patients will not respond to these agents and adverse events can be severe. In this Review, the authors describe the potential to address these challenges by combining immunotherapies with currently available thermal therapies as well as by using thermal immuno-nanomedicines.

Although almost all patients with uveal melanoma have localized disease at diagnosis, and despite effective treatment of the primary tumour, metastatic recurrence is common and holds a dismal prognosis. Unlike its cutaneous counterpart, therapeutic advances for uveal melanoma have not been forthcoming, although the recent approval of the first systemic therapy for this disease has ushered in a new era of hope. This Review summarizes the biology of uveal melanoma and the management of primary disease, including molecular risk classification, adjuvant therapy and follow-up strategies. The discussion is then focused on the established and emerging regional and systemic treatments for metastatic uveal melanoma.

Although radiotherapy affects multiple cellular pathways, treatments are generally planned with the assumption that all tumours respond similarly to radiation. The authors of this Review summarize the effect of various pathways activated by radiotherapy on tumour responses to radiotherapy and present the current knowledge on genomic classifiers designed to inform treatment decisions.

Despite a considerable increase in research output over the past decades, the translation of radiomic research into clinically useful tests has been limited. In this Review, the authors provide 16 key criteria to guide the clinical translation of radiomics with the hope of accelerating the use of this technology to improve patient outcomes.

PADA-1 is the first trial to demonstrate benefit from a treatment-switching strategy guided by active monitoring of ESR1 mutations in plasma circulating tumour DNA (ctDNA) from patients with breast cancer. The results of this trial raise important questions about the specific treatment approach tested, and the feasibility of trials incorporating longitudinal ctDNA analyses to anticipate resistance and guide treatment.

The first phase III trial to test perioperative immune-checkpoint inhibitor therapy for high-risk renal cell carcinoma yielded highly promising results, leading to regulatory approvals of adjuvant pembrolizumab. However, subsequent phase III trials, including the IMmotion010 trial of adjuvant atezolizumab, did not demonstrate similar benefits. Although molecular biomarkers are urgently needed to better delineate responder subgroups, the unique design of each trial might partially explain some of the patterns identified.

Chimeric antigen receptor (CAR) T cells are effective therapies for patients with relapsed and/or refractory B cell malignancies, partly owing to the ability to target B cell-specific antigens. However, CAR T cells targeting solid tumour antigens are likely to carry a higher risk of on-target, off-tumour toxicity (OTOT). Here, the authors summarize the available data on OTOT in the context of CAR T cells targeting solid tumour antigens and describe novel CAR T cell designs that might overcome such toxicities.