Focus on cancer therapy

Childhood cancers are developmentally distinct from adult cancers and arise from cellular reprogramming as a result of epigenetic mutations or gene fusions, providing unique therapeutic opportunities.

The microbiome influences response to cancer therapy, including cancer immunotherapy, and also plays a role in therapeutic toxicity.

Responders and non-responders to cancer immunotherapy can be identified through a range of genomic markers.

Targeting epigenetic modifications is an effective cancer therapeutic approach and can be combined with other therapeutics for maximal effect.

A neoadjuvant approach using combined anti-CTLA4/anti-PD1 treatment prior to lymph node surgery is evaluated in two phase I trials of later stage melanoma finding this a therapeutic angle worth pursuing.

The tumor immune microenvironment influences tumor progression and response to immunotherapy; its further characterization will improve therapeutic outcome.

Cancer registries that track tumors as they spread could reveal how these growths metastasize

Georgina V. Long is co-medical director of Melanoma Institute Australia and Chair of Melanoma Medical Oncology and Translational Research. She is the first woman president of the Society for Melanoma Research.

Samra Turajlic is a consultant medical oncologist at the Royal Marsden National Health Service Foundation Trust and a clinician–scientist at the Francis Crick Institute.

Neoadjuvant PD-1 blockade in patients with resectable melanoma followed by adjuvant maintenance results in early immunological effects driving clinical benefit and reveals transcriptional and genomic mechanisms of response.

Neoadjuvant pembrolizumab promotes a survival benefit with intratumoral and systemic immune responses in patients with recurrent glioblastoma.

Fry et al. report the first results from a human trial of a CD22-directed chimeric antigen receptor (CAR) T cell therapy providing evidence of efficacy in the treatment of pre–B cell acute lymphoblastic leukemia that is immunotherapy-naive or resistant to CD19-directed CAR T cells.

Neoadjuvant nivolumab treatment in patients with glioblastoma induces intratumoral immune activation and underscores the need for rationale-based combination approaches for improving clinical responses.

Initial results from a first-in-human study show that PET imaging with PD-L1 antibodies outperforms immunohistochemistry- or RNA-sequencing-based biomarkers for prediction of clinical response to immunotherapy.

Radiotherapy-induced abscopal responses enhance the efficacy of anti-CTLA-4 in patients with non-small-cell lung cancer.

Neoadjuvant combination immunotherapy in patients with advanced melanoma shows favorable activity over adjuvant treatment and warrants future evaluation with modified dosing schedules to reduce treatment-related adverse events.

Neoadjuvant combination treatment with nivolumab and ipilimumab in patients with high-risk melanoma results in higher response rates than nivolumab monotherapy and warrants future optimization of dosing regimens to preserve efficacy while limiting toxicity.

Microsatellite instability and Epstein–Barr virus positivity represent novel biomarkers of clinical response to PD-1 blockade in patients with metastatic gastric cancer.

Reactive astrocytes expressing STAT3 support the metastatic growth of tumor cells colonizing the brain and can be pharmacologically targeted to improve the clinical management of patients with secondary brain tumors.

Targeting of mitochondrial metabolism in combination with BCL-2 inhibition eradicates leukemia stem cells and induces long-lasting responses in patients with acute myeloid leukemia.

The phase 3 TNT Trial in subjects with triple-negative breast cancer supports the superiority of carboplatin over docetaxel in BRCA1/2-mutated tumors and a greater response to taxanes in the nonbasal subtype.

In a phase I trial, highly individualized peptide vaccines against unmutated tumour antigens and neoepitopes elicited sustained responses in CD8⁺ and CD4⁺ T cells, respectively, in patients with newly diagnosed glioblastoma.

Neoantigen-targeting vaccines are a feasible therapy for tumours with a low mutation burden and immunologically ‘cold’ tumour microenvironment, as neoantigen-specific T cells from the peripheral blood migrate into intracranial glioblastoma, thereby altering the immune milieu of the glioblastoma.

The results of a phase I trial assessing a personal neoantigen multi-peptide vaccine in patients with melanoma, showing feasibility, safety, and immunogenicity.

The authors report the first-in-human application of personalized neo-antigen RNA vaccines in patients with melanoma.

Circulating tumour DNA profiling in early-stage non-small-cell lung cancer can be used to track single-nucleotide variants in plasma to predict lung cancer relapse and identify tumour subclones involved in the metastatic process.

Genomic, transcriptomic, and microenvironmental analyses of samples from patients with glioblastoma treated with nivolumab or pembrolizumab identifies features associated with treatment response that may help in refining patient stratification.

A blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer.

Comprehensive integration of mutational and structural alterations in clinically-annotated DLBCL patient samples provides a novel molecular classification of the disease.

An exploratory randomized controlled clinical trial of renal cell carcinoma identifies molecular patterns distinguishing responders to immune checkpoint blockade alone or combined with angiogenesis inhibitor versus angiogenesis inhibitor alone.

MSK-IMPACT is a clinical sequencing platform able to detect genomic mutations, copy number alterations and structural variants in a panel of cancer-related genes. This assay is implemented prospectively to inform patient enrollment in genomically matched clinical trials at Memorial Sloan Kettering Cancer Center (MSKCC). Sequencing results of tumor and matched normal tissue from a cohort of >10,000 patients with detailed clinical annotation provide an overview of the genomic landscape of advanced solid cancers and bring new insights into molecularly guided cancer therapy.

HRDetect represents a model integrating whole-genome sequencing mutation signatures associated with BRCA1 and BRCA2 deficiency. The implementation of this predictor across different tumor types identifies a larger proportion of patients displaying ‘BRCAness’ than previously recognized; they might derive benefit from platinum and PARP-inhibitor therapies.

Copy-number alterations detected in circulating tumor cells at time of diagnosis predict chemosensitive versus chemorefractory responses; however, CTCs obtained after subsequent relapse bear a chemosensitive copy-number alteration profile, which suggests that different mechanisms drive initial and acquired chemoresistance.

Somatic mutations detected years before diagnosis increase the odds of development of acute myeloid leukemia in women.

Adoptive T cell therapy induced complete and durable remission in a patient with refractory metastatic breast cancer, providing proof of principle for this approach in breast cancer therapy.

A multi-omics survey of progressive compared to regressive carcinoma in situ lesions provides a molecular map of early lung cancer development.

Rearrangements in MAP3K8 respond to MEK inhibition and represent the most common genetic driver in pediatric spitzoid melanoma, and in some adult melanomas lacking other MAPK alterations and for which clinical testing is warranted.