Deroose CM, Leupe H, Hicks RJ
… +33 more, Virgolini I, Braat AJAT, Mittra ES, Albert NL, Bailey DL, Bodei L, Chan DL, Dekervel J, Denecke T, Dromain C, Falconi M, Fournier L, Grozinsky-Glasberg S, Hofland J, Hope TA, Karfis I, Kos-Kudła B, Koumarianou A, Lamarca A, Litière S, Pavel M, Stroobants S, Strosberg J, Sundin A, Taïeb D, Trikalinos N, Unterrainer M, Verslype C, Vijayvergia N, Wild D, Kjaer A, Ambrosini V, Prasad V
Somatostatin receptor PET imaging is integral to the management of patients with neuroendocrine tumours (NETs), yet standardised criteria for therapy response assessment with the use of this modality are not available. T...Somatostatin receptor PET imaging is integral to the management of patients with neuroendocrine tumours (NETs), yet standardised criteria for therapy response assessment with the use of this modality are not available. This Policy Review reports the development of the European Neuroendocrine Tumor Society somatostatin receptor PET response assessment framework, established through a structured modified Delphi process coordinated by the European Neuroendocrine Tumor Society. 34 international experts from nuclear medicine, radiology, oncology, endocrinology, surgery, and related disciplines participated in four iterative rounds evaluating 76 statements, with consensus defined as at least 75% agreement. The framework proposes response categorisation based primarily on volumetric changes in somatostatin receptor-expressing target lesions, complemented by assessment of new lesions, rather than reliance on standardised uptake value-based metrics. Partial response is defined by at least 40% reduction in target lesion volume without new lesions, whereas progressive disease is defined by at least 40% volume increase of target lesions or the emergence of new lesions. Complete response requires absence of pathological tracer uptake, and a category of unconfirmed progressive disease is introduced for equivocal cases warranting short-interval reassessment. Although not yet validated against survival outcomes, this expert-derived framework (SSTR-PeRForm) provides a pragmatic foundation for harmonising somatostatin receptor PET-based response assessment in clinical trials and routine practice and represents a key step towards outcome-based validation.
BACKGROUND: Baseline exposure to antibiotics and proton pump inhibitors has been associated with reduced efficacy of immune checkpoint inhibitors in patients with advanced tumours, possibly through gut microbiome disrupt...BACKGROUND: Baseline exposure to antibiotics and proton pump inhibitors has been associated with reduced efficacy of immune checkpoint inhibitors in patients with advanced tumours, possibly through gut microbiome disruption. Whether this outcome extends to those with earlier-stage disease remains unclear. We aimed to assess the association of baseline antibiotics and proton pump inhibitors with progression-free survival and overall survival in patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS: PACIFIC was a randomised, double-blind, placebo-controlled phase 3 trial done in patients aged 18 years or older with unresectable stage III squamous or non-squamous NSCLC, WHO performance status 0-1, and no progression after two or more cycles of concurrent chemoradiotherapy. Patients were randomly assigned (2:1) to durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months or placebo, starting 1-42 days after chemoradiotherapy; patients were stratified by age, sex, and smoking history. This post-hoc analysis was based on the final 5-year data cutoff date of the completed trial and included the treated population with consent for exploratory analyses. Co-primary endpoints were progression-free survival and overall survival, assessed according to baseline exposure to proton pump inhibitors and systemic antibiotics. This trial is registered on ClinicalTrials.gov (NCT02125461). FINDINGS: Between May 9, 2014, and April 22, 2016, 713 patients were randomly assigned; 660 were included in this post-hoc analysis, of whom 449 received durvalumab and 211 received placebo; 203 (30·8%) were female and 453 (68·6%) were male. Race was reported as Asian in 153 (23·1%) patients, Black or African American in five (0·7%), White in 424 (64·2%), and unknown in 78 (11·8%). Baseline proton pump inhibitor exposure was recorded in 263 (40%) of 660 patients and antibiotic exposure was recorded in 69 (10%). Median follow-up in the pooled population was 62·4 (IQR 61·9-63·2) months. In the durvalumab group baseline exposure to proton pump inhibitors was associated with shorter progression-free survival (9·4 months [95% CI 7·6-13·7] vs 17·2 months [15·4-23·2]; hazard ratio [HR] 1·57 [95% CI 1·28-1·93]; p<0·0001) and overall survival (33·0 months [95% CI 21·9-46·7] vs 57·9 months [48·7-not computable (NC)]; HR 1·66 [95% CI 1·30-2·13]; p<0·0001) compared to no exposure to proton pump inhibitors, while baseline exposure to antibiotics was associated with shorter progression-free survival (9·2 months [95% CI 4·9-18·1] vs 15·6 months [13·6-17·6]; HR 1·50 [95% CI 1·08-2·10]; p=0·016) compared to no exposure to antibiotics, but there was no significant change in overall survival (37·7 months [95% CI 18·8-NC; 28 events] vs 49·2 months [39·7-57·3]; HR 1·33 [95% CI 0·90-1·97]; p=0·16). In the placebo group, neither proton pump inhibitor exposure nor antibiotic exposure was associated with changes in progression-free survival and overall survival. Interactions between treatment and proton pump inhibitors for progression-free survival (p=0·023) and overall survival (p<0·0001) were significant, but not for antibiotics. INTERPRETATION: Baseline exposure to proton pump inhibitors and antibiotics was associated with inferior outcomes with durvalumab, but not with placebo, consistent with potential attenuation of the benefit of durvalumab with proton pump inhibitors and antibiotics in patients with unresectable stage III NSCLC. FUNDING: None.
BACKGROUND: Acute promyelocytic leukemia (APL) is among the most curable acute leukemias, but real-world early mortality continues to undermine population-level cure. This study evaluated long term outcomes and prognosti...BACKGROUND: Acute promyelocytic leukemia (APL) is among the most curable acute leukemias, but real-world early mortality continues to undermine population-level cure. This study evaluated long term outcomes and prognostic factors among adults with APL treated in a single tertiary center in Qatar. METHODS: We conducted a retrospective cohort study of consecutive adults diagnosed with APL between 2012 and 2024. Demographic, clinical, and laboratory data at baseline, treatment protocols, and response were extracted from electronic records. Overall survival (OS) was estimated using the Kaplan-Meier method, and prognostic variables were assessed with log-rank tests and Cox regression. This retrospective cohort included 87 adults. Patients were stratified by Sanz risk criteria: low risk (WBC ≤10×10⁹/L and platelets >40×10⁹/L), intermediate risk (WBC ≤10×10⁹/L and platelets ≤40×10⁹/L), and high risk (WBC >10×10⁹/L). RESULTS: Of 87 patients (median age 36 years; 47.1% Sanz high-risk), 26.4% (n=23) died within 30 days of diagnosis, principally from intracranial hemorrhage (47.8% of early deaths). Among 71 treated patients, the complete remission (CR) rate was 84.1%; the highest CR rate was observed with ATRA-ATO (Lo-Coco, 90.9%). Treatment-related complications occurred in 73.2%; infection (66.2%) and differentiation syndrome (21.1%) were most frequent. Three-year overall survival (OS) was 93% (low-risk), 88% (intermediate-risk), and 56% (high-risk; log-rank p=0.001). ICU admission and non-receipt of treatment were independent predictors of death (multivariable HR 5.42 and 8.06, respectively). Excluding patients presenting with ICH, early mortality was 14.7%, and 5-year OS reached 87.6%. CONCLUSION: The study highlights the effectiveness of contemporary APL treatments but also underscores persistent early mortality due to hemorrhagic complications. Timely diagnosis and rapid initiation of therapy are crucial for improving patients' outcomes. Embedding APL-recognition bundles in emergency pathways, ensuring immediate empiric ATRA availability, and prompt coagulopathy correction are the most actionable priorities for reducing mortality.
Hu H, Shen X, Li Y
… +35 more, Zhou J, Liu P, Zhang J, Hou Y, Wang X, Deng J, Zheng Z, Li J, Lan P, Wu X, Kang L, Huang M, He Z, He X, Yang Z, Huang L, Wang H, Wang H, Luo S, Chen D, Xie X, Zhang Y, Zhai X, Li S, Li W, Hu J, Yang T, Wang C, Deng W, Huang Y, Cao W, Li F, Shi L, Ling L, Deng Y
BACKGROUND: Neoadjuvant immune checkpoint blockade has shown remarkable activity in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H), locally advanced colorectal cancer. Preclinical studies sug...BACKGROUND: Neoadjuvant immune checkpoint blockade has shown remarkable activity in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H), locally advanced colorectal cancer. Preclinical studies suggest that COX-2 inhibition might modulate the inflammatory tumour microenvironment and augment the effect of PD-1 blockade. We aimed to investigate whether the addition of the COX-2 inhibitor celecoxib to neoadjuvant toripalimab would increase the pathological complete response in this population. METHODS: PICC-2 was a multicentre, open-label, randomised, controlled, phase 2 trial conducted at three academic hospitals in China. Eligible patients were aged 18-75 years; had histologically confirmed dMMR or MSI-H colorectal cancer, of clinical stage T3-T4 or any clinical T stage with lymph node positivity (N+); had an Eastern Cooperative Oncology Group performance status score of 0 or 1; and had adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1) via an interactive web response system, stratified by tumour location and clinical T stage, to receive neoadjuvant toripalimab plus celecoxib or toripalimab monotherapy every 14 days for 12 cycles, followed by surgery. Toripalimab 3 mg/kg was administered intravenously on day 1 in both groups; patients in the toripalimab plus celecoxib group also received celecoxib 200 mg orally twice daily on days 1-14. The primary endpoint was the proportion of patients with pathological complete response, defined as no presence of residual viable tumour in the primary tumour and all sampled lymph nodes at surgery, assessed by central blinded independent pathological review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03926338, and is ongoing. FINDINGS: Between May 5, 2022, and Jan 20, 2025, 110 patients were randomly assigned to toripalimab plus celecoxib (n=55) or toripalimab monotherapy (n=55). Overall, 65 (59%) patients were male, all patients were Chinese, 76 (69%) had cT4 tumours, and 105 (95%) had clinically node-positive disease. At the data cutoff date (Oct 10, 2025), median follow-up was 18·1 months (IQR 11·5-25·3). 49 (89%) of 55 patients in each group completed all 12 planned cycles of neoadjuvant therapy. Surgery was done in 53 (96%) of 55 patients in the toripalimab plus celecoxib group and 51 (93%) of 55 in the monotherapy group. Pathological complete response was observed in 49 of 55 patients (89% [95% CI 78-96]) in the toripalimab plus celecoxib group versus 38 of 55 (69% [55-81]) in the monotherapy group (between-group difference 19 percentage points [95% CI 4-34]; p=0·014). Grade 3 treatment-related adverse events occurred in three (5%) patients and four (7%) patients, respectively; grade 3 treatment-related adverse events were tumour perforation (two [4%]) and bowel obstruction (one [2%]) in the toripalimab plus celecoxib group, and rash (one [2%]), tumour perforation (one [2%]), increased aminotransferase (one [2%]), and hypothyroidism (one [2%]) in the monotherapy group. No grade 4 or 5 treatment-related adverse events occurred. INTERPRETATION: In patients with dMMR or MSI-H locally advanced colorectal cancer, neoadjuvant toripalimab plus celecoxib significantly increased the proportion of patients attaining pathological complete response compared with toripalimab monotherapy, with a similar safety profile. These findings support further investigation of this combination strategy in larger phase 3 trials. FUNDING: The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research, the National Key Clinical Discipline of China, the Program of Guangdong Provincial Clinical Research Center for Digestive Diseases, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Yao H, Zhang Q, Li H
… +38 more, Yin Y, Wang S, Ouyang Q, Sun T, Li W, Wang X, Yan M, Wang B, Cheng J, Tong Z, Wei W, Wang X, Xie W, Sun Z, Yuan P, Geng C, Gan L, Han X, Li W, Zhou S, Yan X, Gao J, Yi T, Wu J, Niu Z, Fu F, Nie J, Wang Y, Zhao B, Wu Z, Zhu Z, Yang Y, Zhao J, Sheng Z, Zhang Y, Cheng L, Zhu X, Song E
BACKGROUND: Trastuzumab rezetecan has shown antitumour activity in a phase 1 trial. Pyrotinib plus capecitabine is the current standard treatment for patients with HER2-positive advanced or metastatic breast cancer after...BACKGROUND: Trastuzumab rezetecan has shown antitumour activity in a phase 1 trial. Pyrotinib plus capecitabine is the current standard treatment for patients with HER2-positive advanced or metastatic breast cancer after trastuzumab and chemotherapy (taxane or anthracycline). We aimed to evaluate the efficacy and safety of trastuzumab rezetecan versus pyrotinib plus capecitabine in this patient population. METHODS: This interim analysis of a multicentre, open-label, randomised, controlled, phase 3 trial was conducted at 50 hospitals in China. Eligible patients were aged 18-75 years with histologically confirmed HER2-positive unresectable or metastatic breast cancer; previously received a taxane and trastuzumab at the advanced stage or had disease progression within 12 months after (neo)adjuvant treatment with an anti-HER2 monoclonal antibody and taxane-based regimen; had measurable lesions; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1; stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease), using permuted blocks to intravenous trastuzumab rezetecan (4·8 mg/kg) on day 1 of each 21-day cycle or oral pyrotinib 400 mg once per day continuously plus oral capecitabine 1000 mg/m twice per day on days 1-14 of each 21-day cycle. Protocol amendments led to a temporary modification (between Nov 29, 2022, and July 12, 2023) of trastuzumab rezetecan dose to 6·4 mg/kg; primary evaluation focuses on the 4·8 mg/kg group. The primary endpoint was progression-free survival per blinded independent central review in the modified intention-to-treat population 1 (defined as all patients randomly assigned to the trastuzumab rezetecan 4·8 mg/kg or control groups). Results presented here are from a prespecified interim analysis. This study was registered with ClinicalTrials.gov, NCT05424835 (active, not recruiting). FINDINGS: From Aug 4, 2022, to Aug 9, 2024, 414 patients with HER2-positive metastatic breast cancer were assessed for eligibility, 127 were ineligible and 287 were randomly assigned to trastuzumab rezetecan (n=142) or pyrotinib plus capecitabine (control group; n=145) in the modified intention-to-treat population 1. All 287 patients were female and the median age was 55·0 years (IQR 49·0-60·0). 268 (93%) patients self-reported as Han Chinese and 19 (7%) as other Chinese ethnicity. At data cutoff of the interim analysis on June 30, 2025, after a median follow-up of 15·0 months (IQR 12·9-18·5) for the trastuzumab rezetecan group versus 13·9 months (11·4-17·8) for the control group, 124 progression-free survival events had occurred (37 [26%] vs 87 [60%]). The median progression-free survival was 30·6 months (95% CI 16·8-not reached [NR]) with trastuzumab rezetecan and 8·3 months (6·9-11·0) with pyrotinib plus capecitabine (HR 0·22 [0·15-0·34]; p<0·0001). The 12-month progression-free survival rate was 84·7% (77·0-90·0) in the trastuzumab rezetecan group versus 35·5% (26·8-44·2) in the control group. The most common (grade ≥3) treatment-related adverse events were decreased neutrophil count (77 [54%] with trastuzumab rezetecan vs 13 [9%] with the control), decreased white blood cell count (29 [20%] vs four [3%]), and decreased platelet count (15 [11%] vs two [1%]); whereas treatment-related serious adverse events occurred in 19 (13%) versus 17 (12%). Two adverse events led to death (one [1%] septic shock unrelated to trastuzumab rezetecan treatment and one [1%] unknown reason related to pyrotinib plus capecitabine treatment). Interstitial lung disease occurred in four (3%) patients in the trastuzumab rezetecan group. INTERPRETATION: Trastuzumab rezetecan improved progression-free survival versus pyrotinib plus capecitabine and showed a distinct safety profile in patients with HER2-positive breast cancer, presenting as a potential new treatment option. FUNDING: Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
St-Denis-Bissonnette F, Mediratta K, Ho N
… +10 more, Kirkby M, Stalker A, Muradia G, Shrestha A, Ardolino M, Lee SH, Burger D, Mer A, Wang L, Lavoie JR
Mol Ther Oncol
· 2026 Sep · PMID 42383255
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Natural killer (NK) cells are part of the body's first line of defense that rapidly destroy stressed, infected, or cancerous cells. These immune cells release nanosized biological packages called extracellular vesicles (...Natural killer (NK) cells are part of the body's first line of defense that rapidly destroy stressed, infected, or cancerous cells. These immune cells release nanosized biological packages called extracellular vesicles (EVs), which transfer molecular signals between cells and influence immune function. Although NK cell-derived EVs (NK92-EVs) have shown the ability to directly kill cancer cells, how they shape the broader human immune response has remained unclear. Here, NK92-EVs were shown to reprogram cellular human immunity to enhance tumor cytotoxicity using single-cell transcriptomics and functional cytotoxicity assays. When human peripheral blood mononuclear cells (PBMCs) from healthy and cancer patients (who exhibit systemic dysregulation) were exposed to NK92-EVs, widespread shifts in gene activity occurred across key immune populations, notably CD8 T cells and NK cells. These changes enhanced the cells' ability to recognize and eliminate tumor targets and were consistent across all donors. Functional depletion and enrichment experiments, together with transcriptomic profiling, provide direct evidence that NK92-EV-mediated immune reprogramming enhances NK cell-driven, MHC-I-independent tumor cytotoxicity, but not for CD4 and CD8 T cells. This work advances understanding of immune communication and highlights NK92-EVs as promising, cell-free candidates for the next generation of cancer immunotherapies that unite potency with clinical scalability.
Bragato N, Dias AB, Ohradanova-Repic A
… +15 more, Dupanovic A, Horvat F, Fischer P, Appel LM, Walch L, Kleinwächter A, Röhrer A, Kerschbaum-Gruber S, Barna S, Fossati P, Georg D, Widder J, Podar K, Cohen M, Slade D
Mol Ther Oncol
· 2026 Sep · PMID 42383254
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Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer with a poor prognosis and resistance to conventional radio- and chemotherapy. Radiation can induce pro-inflammatory signaling by acti...Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of pancreatic cancer with a poor prognosis and resistance to conventional radio- and chemotherapy. Radiation can induce pro-inflammatory signaling by activating the type 1 interferon (IFN-I) response, which can be enhanced by targeting negative regulators of the IFN-I pathway, such as ADP-ribosyltransferase PARP7. Here, we show that PARP7 inhibitors (PARP7i) enhance radiation-induced cell death and promote STING- and NF-κB-dependent immunogenic signaling in PDAC cells, leading to inflammatory gene expression and cytokine release. These effects were most pronounced in BxPC-3 cells, which exhibit higher baseline expression of , , and interferon response genes. PARP7i potentiated the immunogenic effects of hypofractionated radiation by inducing a STING-dependent IFN-I response, leading to immunogenic cell death and activation of monocytes and NK cells. Carbon ion irradiation elicited stronger immunogenicity than X-rays when combined with PARP7i. KRAS-mutated PANC-1 cells showed a higher expression of enzymes that convert ATP to immunosuppressive adenosine, which was enhanced by radiation. This may explain why PARP7i were more effective as monotherapy in PANC-1 cells, promoting NK cell activation. These findings support further evaluation of PARP7i in PDAC in combination with radiotherapy or as monotherapy, depending on the immunosuppressive effects of radiation.
With improved cancer survival, cancer therapy-related cardiovascular toxicity has emerged as a major non-cancer cause of morbidity and mortality in cancer survivors. The marked heterogeneity of CTR-CVT cannot be fully ex...With improved cancer survival, cancer therapy-related cardiovascular toxicity has emerged as a major non-cancer cause of morbidity and mortality in cancer survivors. The marked heterogeneity of CTR-CVT cannot be fully explained by single-pathway models, underscoring the need for a systems-level framework centered on regulated cell death networks. This review integrates recent advances to propose an RCD-cellular process interaction network in CTR-CVT, focusing on apoptosis, ferroptosis, pyroptosis, necroptosis, and selected emerging RCD modalities. We emphasize the mitochondrial dynamics-autophagic flux-metabolic reprogramming axis as a central regulatory module that shapes RCD activation, pathway crosstalk, and cell fate under anticancer drug stress. We also incorporate the reverse cardio-oncology concept to discuss potential bidirectional interactions between myocardial injury and tumor progression, and to identify therapeutic targets that enable cardioprotection while preserving antitumor efficacy. Building on this framework, we outline a translational strategy that integrates mechanism-based risk stratification, biomarker-guided early warning, and targeted cardioprotection, with reference to the 2022 ESC Cardio-Oncology Guidelines and representative clinical scenarios including breast cancer, hematological malignancies, and lung cancer. This mechanism-oriented approach may support biomarker discovery, mechanism-matched intervention, and the development of precision cardio-oncology. Future studies should prioritize mitochondrial quality control and metabolic plasticity as therapeutic entry points to reduce cardiovascular risk without compromising cancer treatment outcomes.
Antignani G, Feodoroff M, Chiaro J
… +26 more, Feola S, Russo S, Hamdan Hissaoui F, Fusciello M, D'Alessio F, Bottega P, Giannoula Y, Sakalauskaite M, Sandberg J, Kosonen M, Stigzelius V, Luck TJ, Ferrari V, Ciampi D, Haapala M, Branca RM, Partanen J, Koskela S, Rescigno M, Sikanen T, Lehtiö J, Ndika J, Kari OK, Pietiäinen VM, Grönholm M, Cerullo V
Mol Ther Oncol
· 2026 Sep · PMID 42375394
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Immunotherapy has revolutionized cancer treatment, yet clinical success remains limited, with only a fraction of patients responding. Tumor heterogeneity and patient-specificity hinder response prediction, emphasizing th...Immunotherapy has revolutionized cancer treatment, yet clinical success remains limited, with only a fraction of patients responding. Tumor heterogeneity and patient-specificity hinder response prediction, emphasizing the need for human-based models that accurately reproduce tumor-immune interactions. Conventional preclinical platforms, such as murine models, lack the human-specific HLA-TCR complexity, limiting their ability to accurately evaluate immunotherapy responses. To address this, we established a patient-specific pipeline for precision immunotherapy in renal cell carcinoma (RCC) and bladder cancer (BC). Tumor and adjacent tissues were used to generate patient-derived tumor organoids (PDTOs) and patient-derived cells (PDCs) for immunopeptidome profiling. Using our in-house microfluidic platform, PeptiCHIP, we identified tumor-associated HLA-I peptides as potential T cell targets. Their immunogenicity was evaluated using peptide-expanded, HLA-matched peripheral blood mononuclear cells (PBMCs), revealing peptides capable of inducing antigen-specific CD8 T cell activation and cytotoxicity against the patient's tumor. This study integrates PDCs, immunopeptidomics, and functional immune assays to design and test personalized cancer immunotherapies. By recreating patient-specific tumor-immune interactions , our platform enables the discovery of therapeutic targets, the evaluation of immune responses, and validation in a patient-specific context. This approach demonstrates the feasibility of bridging a major gap in translational immunotherapy research and supports the development of personalized cancer immunotherapy strategies.
Cutmore LC, Lam N, Amatya C
… +4 more, Weissler KA, Hewitt SM, Natrakul DA, Kochenderfer JN
Mol Ther Oncol
· 2026 Sep · PMID 42375393
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T cell malignancies expressing γδ T cell receptors (TCRs) have poor prognoses. No approved treatments specifically target γδ T cell malignancies. To address this deficiency, we aimed to develop chimeric antigen receptors...T cell malignancies expressing γδ T cell receptors (TCRs) have poor prognoses. No approved treatments specifically target γδ T cell malignancies. To address this deficiency, we aimed to develop chimeric antigen receptors (CARs) targeting the γδ TCR. We generated a panel of CARs with variations in antigen-recognition domains, hinge and transmembrane (HTM) domains, and costimulatory domains. We expressed CARs in human T cells by γ-retroviral transduction. By assessing CAR T cell cytokine release in response to γδ TCR-expressing target cells, we identified two single-chain variable fragments (scFvs) with superior antigen specificity for the γδ TCR. CARs containing one of the two scFvs, which was designated maximal gamma-delta-long (MGDL), exhibited higher transduction efficiency. We compared three MGDL-containing CARs: MGDL-28Z (CD28 HTM and costimulatory domains), MGDL-CD828Z (CD8α HTM domains and CD28 costimulatory domain), and MGDL-CD8BBZ (CD8α HTM domains and 4-1BB costimulatory domain). Levels of antigen-specific cytokine release were higher for T cells expressing MGDL-28Z compared with the other MGDL CARs. We tested T cells expressing the three MGDL-containing CARs in two murine γδ T cell leukemia treatment models. MGDL-28Z-expressing T cells caused the most anti-leukemia activity and longest mouse survival. These findings support testing MGDL-28Z-expressing T cells in a clinical trial.
Biau J, Beddok A, Sharma M
… +19 more, Malik N, Ghosh Laskar S, Cacicedo J, Embring A, Nuyts S, Mayo C, Paradis KC, Ward MC, Bonomo P, Gan GN, Bahl A, Balermpas P, Chua MLK, Popovtzer A, Simone CB, Vasquez Osorio E, Yom SS, Blanchard P, Reirradiation Collaborative Group (ReCOG) and ESTRO Reirradiation Focus Group Collaborators
Reirradiation can be considered for some patients with recurrent or second primary head and neck squamous cell carcinoma arising within previously irradiated regions, a clinical scenario associated with few therapeutic o...Reirradiation can be considered for some patients with recurrent or second primary head and neck squamous cell carcinoma arising within previously irradiated regions, a clinical scenario associated with few therapeutic options. The increasing use of modern conformal radiotherapy techniques, including intensity-modulated radiotherapy, proton therapy, and stereotactic body radiotherapy, has expanded the feasibility of reirradiation in clinical practice. However, evidence remains heterogeneous, and clinical choices are challenged by substantial variability in patient presentation, previous treatments, and toxicity risk. This international expert consensus statement aims to provide pragmatic guidance across key domains, including patient selection, imaging, target delineation, treatment planning, dose accumulation, and toxicity management. Developed through a structured expert consensus process with formal agreement assessment, this document reflects current expert practice. By offering a shared clinical framework, this consensus seeks to promote more consistent practice, facilitate communication across centres, and support future research efforts in this complex and evolving field.
Adriaansen LME, Merks JHM, van Dalen EC
… +33 more, Andersen KF, Asaftei SD, Bernabeu D, Boye K, Campello A, Capra M, Costa Dias S, Dávila Fajardo R, Dziuk M, van Ewijk R, Gaspar N, Gerrand C, Herrmann K, Isnardi V, Jehanno N, von Kalle T, Lancharro Zapata AM, van Langevelde K, Morland D, Mulder RL, Palmerini E, Rajesparan K, Rogasch JMM, Safwat A, Sirvent Cerdá S, Spinnato P, Strauss SJ, Vieth V, Vöö S, Woering MP, Ter Horst SAJ, Braat AJAT, van Rijn RR
Imaging is central to diagnosing, staging, evaluating treatment response, and guiding post-therapy surveillance in osteosarcoma and Ewing sarcoma, yet no international consensus defines optimal modalities or schedules. T...Imaging is central to diagnosing, staging, evaluating treatment response, and guiding post-therapy surveillance in osteosarcoma and Ewing sarcoma, yet no international consensus defines optimal modalities or schedules. This European guideline, developed by 36 multidisciplinary experts, seeks to standardise imaging for research and enhance patient care. A systematic review identified 2026 studies, of which 13 met criteria, revealing marked heterogeneity in diagnoses, chemotherapy regimens, and imaging protocols. Evidence remains inconclusive regarding the optimal modality for detecting bone metastases, and no metabolic imaging indices or MRI parameters consistently predict response or survival. Data are similarly insufficient to define the ideal frequency of post-treatment surveillance. Recommendations for clinical practice were formulated according to International Guideline Harmonization Group standards, based on evidence and expert opinion. In total, 32 consensus-based recommendations were issued. Substantial evidence gaps persist, underscoring the need for international prospective imaging studies to establish robust, harmonised standards for future patient care.
Triple-negative breast cancer-the most aggressive breast cancer subtype-has a high propensity for brain metastases, with limited treatments and poor prognosis. The blood-brain barrier, long viewed as an impermeable thera...Triple-negative breast cancer-the most aggressive breast cancer subtype-has a high propensity for brain metastases, with limited treatments and poor prognosis. The blood-brain barrier, long viewed as an impermeable therapeutic sanctuary, is the core barrier to effective care. This Review advocates a key paradigm shift for clinical and translational research: from merely circumventing the blood-brain barrier to actively targeting and exploiting its biology. We delineate triple-negative breast cancer-specific mechanisms of blood-brain barrier breach and evaluate emerging therapies via a clinically actionable three-pillar framework: physical and focal blood-brain barrier disruption, biological blood-brain barrier exploitation, and microenvironmental modulation. We also summarise advances in preclinical models for blood-brain barrier-targeted drug development. Synthesising the latest preclinical and clinical evidence, this Review provides a translational roadmap for unmet clinical needs, emphasising that integrated, blood-brain barrier-centric strategies are crucial to improving patient outcomes.