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Terbium-161 (161Tb) emits beta-radiation similar to lutetium-177 (177Lu), with additional radiation over ultra-short path lengths from Auger electrons. 161Tb has shown superior in-vitro and in-vivo efficacy compared with 177Lu. We aimed to evaluate the safety of [161Tb]Tb-PSMA-I&T in patients with metastatic castration-resistant prostate cancer (mCRPC). VIOLET was an investigator-initiated, single-centre, phase 1/2 trial, conducted at the Peter MacCallum Cancer Centre (Melbourne, VIC, Australia). Eligible patients were men aged 18 years or older with progressive mCRPC (histologically or cytologically confirmed adenocarcinoma of the prostate or unequivocal diagnosis of metastatic prostate cancer with an elevated serum prostate specific antigen) previously treated with an androgen receptor pathway inhibitor and taxane chemotherapy (unless medically unsuitable), Eastern Cooperative Oncology Group performance status of 0–2, and prostate-specific membrane antigen (PSMA) positivity (maximum standardised uptake value ≥20 on PSMA PET-CT) without discordance on 2-[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT. Dose escalation (3 + 3 design) had three prespecified radioactivities (4·4 GBq, 5·5 GBq, and 7·4 GBq). Up to six cycles of [161Tb]Tb-PSMA-I&T were administered intravenously every 6 weeks, reduced by 0·4 GBq for each cycle. Primary endpoints of phase 1 were dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose, and the primary objective of phase 2 was evaluation of adverse events as defined by Common Terminology Criteria for Adverse Events version 5.0. We present here an interim analysis, with follow-up ongoing and recruitment reopened for an additional dose level (9·5 GBq). The trial is registered at ClinicalTrials.gov (NCT05521412). Between Oct 14, 2022 and Feb 15, 2024, 30 eligible patients were enrolled. Median age was 69·0 years (IQR 66·0–74·8), screening PSA 26·9 ng/mL (10·1–70·0), PSMA mean standardised uptake value 8·2 (7·4–10·8), and 20 (67%) of 30 patients had received previous docetaxel. There were no dose-limiting toxicities. The maximum administered dose and recommended phase 2 dose was 7·4 GBq. Grade 3 treatment-related adverse events (TRAEs) were limited to pain (one [3%] of 30; the only serious TRAE) and lymphopenia (one [3%] of 30). No grade 4 TRAEs or treatment-related deaths occurred. No dose reductions or treatment discontinuation occurred for toxicity. [161Tb]Tb-PSMA-I&T is safe at the maximum administered dose of 7·4 GBq. Further investigation of this promising radionuclide is warranted in larger, randomised clinical trials. Prostate Cancer Foundation, Peter MacCallum Cancer Foundation, National Health and Medical Research Council Investigator Grant, Isotopia Molecular Imaging.

Lutetium-177 [177Lu]Lu-PSMA-I&T (177Lu-PSMA-I&T) and the bone-seeking α-emitter radium-223 (223Ra) are established life-extending therapies for patients with metastatic castration-resistant prostate cancer; however, resistance and progression are inevitable. We aimed to evaluate the safety and preliminary antitumour activity of 177Lu-PSMA-I&T combined with 223Ra in this patient group. We conducted an investigator-initiated, single-centre, single-arm, phase 1/2 trial (AlphaBet) at the Peter MacCallum Cancer Centre in Melbourne, Australia. Adults (aged ≥18 years) with a diagnosis of progressive, metastatic castration-resistant prostate cancer, an Eastern Cooperative Oncology Group performance status score of 0–2, at least two visible bone metastases not treated with radiotherapy, previous exposure to an androgen receptor pathway inhibitor, prostate-specific membrane antigen (PSMA)-positive disease (defined by maximum standardised uptake value ≥20 at a site of disease), and no discordant sites (ie, avid on 2-[18F]fluoro-2-deoxy-D-glucose-PET–CT with minimal PSMA expression and no uptake on bone scintigraphy) were eligible for inclusion. Phase 1 dose-escalation assessed two dose levels of 223Ra (27·5 kBq/kg and 55·0 kBq/kg) combined with 7·4 GBq 177Lu-PSMA-I&T, administered intravenously every 6 weeks for up to six cycles. Phase 2 dose expansion continued with the recommended phase 2 dose. Co-primary endpoints were the maximum tolerated or administered dose and the recommended phase 2 dose (phase 1), and the PSA response rate (phase 2), analysed in all patients treated at the maximum tolerated or administered dose in either phase. Safety was assessed in all patients who received at least one dose of either protocol treatment in phase 1 or 2. Herein, we report the results of an interim analysis, which was added to the protocol following an amendment on May 30, 2024. This trial is registered at ClinicalTrials.gov (NCT05383079) and follow-up is ongoing. Between Nov 3, 2022, and Nov 5, 2024, 37 patients were enrolled, of whom 36 (97%; median age 72·5 years [IQR 67·0–78·0]) were included in the safety analysis and 33 (89%) were included in the preliminary activity analysis. No dose-limiting toxicities were observed. The recommended phase 2 dose of 223Ra was 55·0 KBq/kg combined with 7·4 GBq 177Lu-PSMA-I&T, administered every 6 weeks. With a median follow-up of 13·3 months (IQR 8·7–17·1), 11 (31%) patients completed all six cycles of both treatments. 18 (50%) patients discontinued treatment early, primarily due to unequivocal disease progression (11 [61%]) or adverse events (three [17%]). A reduction in PSA of at least 50% was observed in 18 (55%; 95% CI 36–72) patients. Grade 3 or higher treatment-related adverse events occurred in five (14%) of 36 patients, including anaemia (four [11%]) and neutropenia (three [8%]), with no treatment-related deaths. Non-clinically significant grade 3 lymphopenia occurred in ten (28%) patients. The combination of 177Lu-PSMA-I&T and 223Ra is safe and feasible in patients with metastatic castration-resistant prostate cancer and bone metastases. These findings warrant further evaluation of combined α-emitting and β-emitting approaches. Prostate Cancer Foundation, Bayer, and National Health and Medical Research Council.

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS) . Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive . Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma . We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes 1 , 2 . The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution 1 , 3 , 4 . Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9 ,  MCL1 , ARNT (also known as HIF1B ), TERT and MYC ) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT ), 5p15.33 ( TERT ), 11q13.3 ( CCND1 ), 19q12 ( CCNE1 ) and 8q24.1 ( MYC ) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC ) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1 ) in HER2 + breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution. Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.

Key Points Neurofeedback is a type of biofeedback in which neural activity is measured and presented through one or more sensory channels to the participant in real time to facilitate self-regulation of the putative neural substrates that underlie a particular behaviour or pathology Animal and human brain self-regulation has been demonstrated using various invasive and non-invasive recording methods and with different features of the brain signals, such as frequency spectra, functional connectivity or spatiotemporal patterns of brain activity Neurofeedback provides the possibility of endogenously manipulating brain activity as an independent variable, making it a powerful neuroscientific tool Neurofeedback training results in specific neural changes relevant to the trained brain circuit and the associated behavioural changes. These changes have been shown to last anywhere from hours to months after training and to correlate with changes in grey and white matter structure The underlying neural circuitry relating to the process of brain self-regulation is becoming clearer. Accumulating evidence suggests the involvement of the thalamus and the dorsolateral prefrontal, posterior parietal and occipital cortices in neurofeedback control, and the dorsal and ventral striatum, anterior cingulate cortex and anterior insula in neurofeedback reward processing Psychological factors, such as the differential influence of feedback, reward and experimental instructions, and other factors, such as sense of agency and locus of control, are now being investigated for their effects on neurofeedback The demonstration of robust clinical effects remains a major hurdle in neurofeedback research. The results of randomized controlled trials in attention deficit and hyperactivity disorder and stroke rehabilitation have been mixed, and have been affected by differences in study design, difficulty of identifying responders and the scarcity of homogenous patient populations Future neurofeedback research will probably clarify the psychological and neural mechanisms that may help to address issues in clinical translation In neurofeedback, an individual receives online feedback of their neural activity to facilitate self-regulation of a brain region and, as a result, a particular behaviour or pathology. In this Review, the authors examine how this technique has been used and its underlying mechanisms. Neurofeedback is a psychophysiological procedure in which online feedback of neural activation is provided to the participant for the purpose of self-regulation. Learning control over specific neural substrates has been shown to change specific behaviours. As a progenitor of brain–machine interfaces, neurofeedback has provided a novel way to investigate brain function and neuroplasticity. In this Review, we examine the mechanisms underlying neurofeedback, which have started to be uncovered. We also discuss how neurofeedback is being used in novel experimental and clinical paradigms from a multidisciplinary perspective, encompassing neuroscientific, neuroengineering and learning-science viewpoints.

Tumor-resident (TR) T cells, known as tissue-resident memory (TRM) T cells in mice, play a central role in melanoma immunosurveillance, yet their contribution to immune checkpoint inhibitor (ICI) therapy has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant and ICI-responsive patients. Here we show that tumor areas in ICI-responders were enriched for both CD8 and CD4 TR. CD8 TR cells were clonally expanded, and both CD8 and CD4 TR cells upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ response pathways, linked to T cell exhaustion. We further identified a spatially organized immune triad composed of CD8⁺ TR, CD4⁺ TR, and type-3 dendritic cells (DC3) that is exclusive to responding tumors. These findings define coordinated cellular interactions within the tumor microenvironment that underpin successful immunotherapy and provide a framework for spatial biomarkers of response.

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)—the Pfizer-BioNTech mRNA COVID-19 vaccine—in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit–risk profile remains strongly in favor of COVID-19 vaccination in this population. A rare case of cytokine release syndrome in a patient on anti-PD-1 blockade that was likely related to BNT162b2 vaccination supports prospective monitoring of patients with cancer after COVID-19 vaccine administration.

Purpose The immune checkpoint inhibitors (ICIs) have resulted in subgroups of patients with metastatic melanoma achieving high-quality durable responses. Metastatic melanoma survivors are a new population in the era of cancer survivorship. The aim of this study was to evaluate metastatic melanoma survivors in terms of health-related quality of life (HRQoL), immune-related adverse events (irAEs) and exposure to immunosuppressive agents in a large single centre in the UK. Methods We defined the survivor population as patients with a diagnosis of metastatic melanoma who achieved a durable response to an ICI and had been followed-up for a minimum of 12 months from initiation of ICI without disease progression. HRQoL was assessed using SF-36. Electronic health records were accessed to collect data on demographics, treatments, irAEs and survival. HRQoL data was compared with two norm-based datasets. Results Eighty-four metastatic melanoma survivors were eligible and 87% ( N  = 73) completed the SF-36. ICI-related toxicity of any grade occurred in 92% of patients and 43% had experienced a grade 3 or 4 toxicity. Almost half (49%) of the patients required steroids for the treatment of ICI-related toxicity, whilst 14% required treatment with an immunosuppressive agent beyond steroids. Melanoma survivors had statistically significant lower HRQoL scores with regard to physical, social and physical role functioning and general health compared with the normative population. There was a trend towards inferior scores in patients with previous exposure to ipilimumab compared with those never exposed to ipilimumab. Conclusions Our results show that metastatic melanoma survivors have potentially experienced significant ICI-related toxicity and experience significant impairments in specific HRQoL domains. Future service planning is required to meet this population’s unique survivorship needs.

Biomarkers that predict response to combined radiation and anti-PD-1 therapy in clear cell renal cell carcinoma (ccRCC) are poorly defined. RAPPORT trial (NCT02855203) is a prospective phase I/II study of stereotactic ablative body radiotherapy (SABR) and pembrolizumab in 30 patients with oligometastatic ccRCC. The primary endpoint was safety; secondary endpoints included overall survival, time to local progression, distant progression-free survival, objective and disease control rates, duration of response and patient-reported pain. Here, we report the pre-specified exploratory translational analyses. In pre-treatment tumours, responders had greater intra-tumoural cytotoxic T cell infiltration in close proximity to tumour cells, whereas non-responders showed enrichment of immunosuppressive, TGF-β and angiogenic signatures. In peripheral blood post-treatment, responders developed a proliferative burst of activated CD8 T cells and sustained sharing of pre-existing tumour-enriched TCR clones. These findings identify trafficking and maintenance of pre-existing tumour-enriched T cell clones as determinants of response to SABR plus anti-PD-1 in ccRCC.