Metastatic solid tumors remain the principal cause of cancer mortality worldwide. High tumor burden impairs responses to chimeric antigen receptor (CAR) T cell therapy, yet off-tumor toxicity limits the doses that can be safely delivered. Strategies to selectively enhance CAR T cell activity at tumor sites could widen the therapeutic window. Using syngeneic models of extensive...
Type 1 conventional dendritic cells (cDC1s) are key antigen-presenting cells (APCs) for cross-priming of CD8+ T cells against cancer. They can capture and cross-present dead cell antigens via DNGR-1 (CLEC9A), a receptor for F-actin exposed on cell corpses. However, cDC1s are scarce in human and murine tumors, and this restricts anticancer immunity. We show that abundant tumor...
The prognosis of newly diagnosed metastatic prostate cancer is highly variable. The primary objective of the PARADIGM prospective cohort study was to evaluate predictors of survival in blood collected at the start of each of the first six treatment cycles from 114 patients with high-volume metastatic prostate cancer (biologically male) who were starting androgen deprivation...
Over 50% of persons with unresectable stage III non-small cell lung cancer (NSCLC) treated with standard-of-care concurrent chemoradiotherapy (CCRT) and durvalumab consolidation progress or die within 18 months. Here adults with untreated, unresectable stage III NSCLC were randomized to nivolumab plus CCRT followed by consolidation with nivolumab plus ipilimumab (arm A) or...
Glioblastoma is a fatal disease with a median prognosis of 12–18 months. Recent studies have shown encouraging results using neoantigen-based vaccines to stimulate glioblastoma-directed immune responses, but overall immunogenicity has been low. Here, we report the results of an open-label, single-arm, phase 1 clinical trial (GT-20) to evaluate the safety and feasibility (primary...
This phase 1, open-label, nonrandomized, dose-escalation study evaluated MP0317 (FAP x CD40 DARPin) in adults with advanced solid tumors. Forty-six patients across nine cohorts received MP0317 at doses ranging from 0.03 to 10 mg kg−1 intravenously weekly or every 3 weeks. The primary outcome measure was safety; secondary and exploratory outcome measures included antitumor...
CD40 activation on dendritic cells (DCs) enhances tumor antigen cross-priming of tumor-specific cytotoxic T lymphocytes, strengthening anticancer immune responses. RO7300490 is a fibroblast activation protein (FAP)-targeted CD40 agonist antibody. In this phase I study, 80 patients with advanced and/or metastatic solid tumors received RO7300490 biweekly (dose range 16–1,100 mg...
Most membrane-bound organelles have been linked to the initiation and execution of ferroptosis. However, the role of the Golgi apparatus and its resident proteins in ferroptosis remain elusive. Here we show that ferroptosis inducer triggers rapid oxidation of Golgi membrane lipids in the early phase of ferroptosis, resulting in disruption of Golgi pH. The Golgi-localized...
Lymph node (LN) function requires the organization of cells into higher-order spatial units. However, the principles governing LN architecture in health and disease remain poorly understood. Here, we used single-cell and spatial mapping to investigate the mechanisms directing immune cell organization in human LNs and its disruption in architecturally distinct lymphoma entities...
Artificial intelligence (AI) tools can improve breast screening performance but different screening sites have varying needs. Here the GEMINI prospective evaluation of 10,889 women, within one UK region, used both live AI integration and simulations to model 17 different ways AI could be used in breast screening. All women received routine care. One AI tool was assessed. When the...
The impact of incorporating artificial intelligence (AI) into a double-read breast-screening workflow, including arbitration, is unclear. This retrospective study included 50,000 representative women from two NHS breast-screening centers. All the women had long-term follow-up, allowing us to determine whether use of AI leads to earlier cancer detection. Cases requiring...
Artificial intelligence (AI) promises to enhance breast cancer screening. Here we evaluated Google’s mammography AI system (version 1.2) across two phases: a retrospective study using 115,973 mammograms from five National Health Service screening services with 39-month follow-up and prospective noninterventional feasibility deployment at 12 sites (9,266 cases). The primary...
The clinical success of cancer drug candidates depends on efficacy across many different individuals. Because xenografts are challenging to scale, we currently rely on a limited set of in vivo preclinical models. Here, to address this limitation, we introduce GENEVA, a scalable single-cell-resolution platform for measuring responses to drug perturbations. GENEVA models cancer...
Cell-free DNA analysis via methylation and fragmentation profiling has advanced minimally invasive cancer detection; however, broader application has been limited by small cohorts and inconsistent data processing. Here we collated 1,074 cfMeDIP-seq profiles across 9 studies, comprising cancer samples from 11 cancer types, carriers of Li-Fraumeni syndrome and healthy controls. We...
Cerebrospinal fluid (CSF) liquid biopsies serve as a rich source of tumor-derived cell-free DNA (cfDNA) for evaluating persons with central nervous system (CNS) tumors. However, challenges stemming from trace cfDNA yields and low mutational burden have hindered sensitivity, whereas first-generation clinical assays have relied on genetic alterations as biomarkers. Leveraging the...
The phase 2 SWOG S1512 trial (NCT02775851) was designed to evaluate the response to pembrolizumab (anti-PD-1) in individuals with desmoplastic melanoma. Here we report the results of cohort A of the trial, evaluating the pathological complete response (pCR) rate of neoadjuvant PD-1 blockade in surgically resectable desmoplastic melanoma. Secondary endpoints included clinical...
In the SCORES study (NCT04908787), women with ovarian cancer that progressed within 6 months after completing platinum-based therapy were randomized (2:1) to receive suvemcitug (1.5 mg kg−1), an antibody to vascular endothelial growth factor or placebo every 2 weeks, with chemotherapy (paclitaxel, topotecan or PEGylated liposomal doxorubicin). The primary endpoint was progression...
Multiple myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We developed an Immune Atlas of MM by generating profiles of 1,397,272 single cells from the bone marrow (BM) of 337...
Individuals with non-small-cell lung cancer (NSCLC) with metastases to the ipsilateral mediastinum or subcarinal lymph nodes (N2 disease) have poor long-term survival. This exploratory analysis from the randomized phase 3 CheckMate 77T study assessed clinical outcomes by nodal status in individuals with stage III NSCLC who received neoadjuvant nivolumab plus chemotherapy followed...
As part of canonical Wnt signaling, T cell factor (TCF)–β-catenin complexes promote MYC-dependent proliferation. Lesions of the β-catenin protein degradation machinery are common oncogenic drivers. Here, we show that B cell acute lymphoblastic leukemia (B-ALL) lacks these mutations and critically depends on unencumbered β-catenin protein degradation. Compared to solid tumors, we...
Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination...
The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that ligand-bound progesterone receptor interacts directly with the estrogen receptor (ER) and reprograms ER transcriptional activity. Progestogen cotreatment enhances the antitumor activity of antiestrogen therapy in mouse xenografts. We report PIONEER, a 198-participant, three...
Diffuse midline glioma (DMG) is a highly aggressive and untreatable pediatric cancer primarily arising in the pontine brainstem region, necessitating the development of representative models for treatment advance. Here we developed an FGF4-driven human brainstem organoid model, which we used to genetically engineer H3.3K27M-altered DMG. We demonstrated that brainstem pontine...