Reviews & Analysis

Chimeric antigen receptor (CAR) T cell therapy, the first approved therapeutic approach with a genetic engineering component, holds substantial promise in the treatment of a range of cancers but is nevertheless limited by various challenges, including toxicities, intrinsic and acquired resistance mechanisms, and manufacturing issues. In this Review, the authors describe the innovative approaches to the engineering of CAR T cell products that are providing solutions to these challenges and therefore have the potential to considerably improve the safety and effectiveness of treatment.

Numerous neoepitope-based vaccination strategies are in testing for clinical use in the treatment of cancer. Rapid identification of immunostimulatory neoantigen targets hastens neoantigen vaccine development. Papers recently published in Nature Biotechnology describe two independent machine-learning-based algorithms that demonstrate improved identification of MHC class II-binding peptides. Herein, we outline the benefits of these algorithms and their implications for future immunotherapies.

HER2-targeted therapy has greatly improved the outcomes of patients with HER2-positive breast cancer, with a range of agents now approved or in late-stage clinical development. In the era of precision medicine, efforts are being made to further improve patient outcomes by personalizing HER2-targeted treatment regimens, primarily though escalation or de-escalation of therapy according to the disease biology. In this Review, the authors provide an overview of the current landscape of HER2-targeted therapy and discuss the evidence supporting such tailored therapeutic strategies.

Cancer stem cells (CSCs) are implicated in cancer development, progression and resistance to treatment; therefore, the signalling pathways that mediate the CSC phenotype are attractive therapeutic targets. In this Review, the authors provide an update on the progress in targeting the Notch, WNT, Hedgehog and Hippo signalling pathways. Additionally, they discuss the interactions of CSCs with the immune system, the roles of CSC-related signalling pathways in immune cells and novel approaches to CSC-directed immunotherapy.

The identification of biomarkers and the development of genomics-based assays predictive of outcomes following radiotherapy, in an effort to help guide the treatment of patients with cancer, is an area of increasing research interest. Here, we discuss the validity of one such classifier, ARTIC, in the context of complementary genomic approaches designed to predict both tumour response and the susceptibility of nonmalignant tissues to toxicities resulting from radiotherapy.

Systemic hormone therapies and chemotherapy are the cornerstones of treatment for patients with de novo metastatic prostate cancer, with a currently limited role for local treatments. Herein, the authors outline the pathobiological and immunological rationale for local cytoreductive treatment of the primary tumour and/or metastases in patients with this disease. They also review the preclinical and clinical evidence for the use of radical prostatectomy, prostate radiotherapy, minimally invasive ablative therapies, and metastasis-directed therapy (predominantly with stereotactic ablative radiotherapy) in this population.

Virtually all patients with resectable pancreatic ductal adenocarcinoma (PDAC) will have disease progression, which is generally associated with dismal outcomes. However, novel targeted therapies and immunotherapies, selected based on the genomic and/or clinical features of patients’ tumours are beginning to improve the outcomes in subsets of patients. In this Review, the authors describe progress in novel therapies for patients with PDAC.

In the past few years, several studies have addressed the possibility of using immunotherapies to treat patients with mesothelioma. Herein, we discuss two recent trials, one testing the immune-checkpoint inhibitor nivolumab and the other testing a mesothelin-directed therapeutic vaccine, and reflect on the advances and challenges remaining in this research area.

A systems biology-based approach incorporating multiscale, longitudinal measurements (from single-cell analyses to whole-body monitoring) would help to decipher the complexity of cancer and would facilitate the development of personalized therapies. The authors of this Perspective discuss how systems biology-based approaches can provide data for early detection of disease transitions, prediction of therapeutic responses and clinical outcomes, and for the design of personalized treatments.

Oncolytic viruses are beginning to enter clinical use in patients with cancer despite regulatory and practical considerations precluding the widespread use of such therapies. Here, the authors describe the potential of non-viral methods in achieving oncolytic effects and how these effects might prime the development of antitumour immune responses in patients with cancer.

BRCA1/2 mutations and poly (ADP-ribose) polymerase (PARP) inhibitors are paradigmatic of synthetic lethal therapy. However, the activity of PARP inhibitors seems to vary considerably across BRCA1/2-mutant cancers and new insights into the tumour-lineage dependency of this synthetic lethal relationship might explain why BRCA1/2 mutations are not tumour-agnostic biomarkers of a response to PARP inhibitors.

The use of epigenetic drugs (epi-drugs) as single agents according to a ‘one size fits all’ approach has generally resulted in disappointing therapeutic activity. In this Review, the mechanisms by which epi-drugs can modulate the sensitivity of cancer cells to other diverse forms of anticancer therapy are described, and completed and ongoing clinical trials relating to combination therapies incorporating epi-drugs are discussed. In addition, clinical trial designs and drug development strategies aimed at optimizing the development of such combinations are outlined.

HER2-targeted therapies have dramatically improved the outcomes in women with HER2-positive breast cancer. Furthermore, genetic sequencing studies have revealed HER2 alterations in a range of other cancers, including gastric cancer, colorectal cancer and non-small-cell lung cancer. In this Review the authors describe the available data on HER2-targeted therapies beyond breast cancer.

Despite promising responses in a minority of patients with cancer, considerable scope remains to improve the efficacy of both immune-checkpoint inhibitors and epigenetic drugs, with one potential strategy involving the combination of these two types of treatment. Here, the authors describe the mechanisms underlying the synergy between immune-checkpoint inhibitors and epigenetic drugs and discuss the ongoing clinical development of such combinations.

In the past few years, efforts have been made to combine two approaches — immune-checkpoint inhibition and locally ablative radiation therapy — to treat patients with metastatic non-small-cell lung cancer. Herein we discuss the implications of two studies that support the existence of a systemic therapy augmented by radiotherapy (STAR) effect in this setting.

The presence and prognostic relevance of the intratumoural microbiota in pancreatic cancer, and the roles of intratumoural bacteria in oncogenesis and therapeutic response are beginning to be elucidated. The feasibility of characterizing intratumoural microbial communities from paraffin-embedded tissues has now been validated, providing greater opportunities for retrospective research. Prospective studies are also needed to test the efficacy of rational approaches combining microbial modulation with chemotherapy and/or immunotherapy.

Oncology phase I trials have been traditionally referred to as ‘toxicity trials’. The distinction of clinical trials into three phases has been challenged in the past few years, leading to the current situation in which response rates are increasingly reported from phase I trials. The authors dissect the ethical dilemmas surrounding the therapeutic intent of phase I trials and provide evidence of contemporary phase I trials as a therapeutic option for patients with cancer.

The authors of this Perspective critically evaluate various artificial intelligence (AI)-based computational approaches used for digital pathology and provide a broad framework to incorporate these tools into clinical oncology, discussing challenges such as the need for well-curated validation datasets, regulatory approval and fair reimbursement strategies.

Attempts to incorporate additional criteria into the traditional tumour-node-metastasis staging classification have often resulted in inaccuracy and confusion in the use of terminology. In this Position paper, the authors provide guidance on the consistent use of the terminology relating to cancer staging.

The majority of patients with cancer have at least one chronic health condition at the time of diagnosis. Nonetheless, how such conditions influence the timeliness of diagnosis remains largely unknown. In this Review the authors describe the available evidence on the complex relationships between cancer and other chronic diseases, and the implications for diagnosis and screening programmes.