Citations

Chimeric antigen receptor (CAR) T cell therapy faces many challenges against solid tumors including T cell exhaustion and poor CAR durability. Here, we show that engaging the CAR T cell endogenous T cell receptor (TCR) using an oncolytic virus enhances CAR T cell functionality, durability, and therapy. Upon combination therapy of solid tumors with CAR T cells and vesicular stomatitis virus (VSV), a subpopulation of antiviral, TCR-primed CAR T cells was generated with enhanced effector functions, altered activation states, and differential gene and protein expression when compared to non–TCR-primed CAR T cells. Single-cell RNA sequencing showed clonal expansion of anti-VSV CAR T cells and enhancement of effector-associated genes with VSV-mediated CAR T cell expansion. CD4 T cells played a pivotal role in the development of these TCR-primed CAR T cells. These results provide a strong rationale both for a novel use of systemic oncolytic virotherapy and for directly exploiting the CAR T cell TCR to fine tune the CAR T cell phenotype and function.

ABSTRACT Background Superior vena cava isolation (SVCI) is performed as an adjunct to pulmonary vein isolation (PVI) for atrial fibrillation, yet whether an empiric or trigger‐guided strategy is preferable remains uncertain. Prior meta‐analyses have been largely restricted to index procedures in paroxysmal AF and have not explicitly stratified by ablation strategy. We sought to address these gaps through a systematic review of available randomized evidence. Methods Major databases were searched through November 2025 for RCTs comparing PVI+SVCI versus PVI alone. Trials were stratified by strategy: empiric SVCI (performed irrespective of SVC ectopy) or trigger‐guided SVCI (performed only upon demonstrated SVC triggers). The primary outcome was atrial tachyarrhythmia recurrence (≥30 s) beyond the blanking period. Random‐effects models, pre‐specified subgroup analyses, meta‐regression, and GRADE certainty assessment were performed. Results Eight RCTs ( n = 1231) were included; most enrolled paroxysmal AF, while two incorporated non‐paroxysmal AF subtypes and one evaluated repeat ablation procedures. Overall, SVCI+PVI significantly reduced recurrence versus PVI alone (97/604 vs. 135/627; RR 0.77, 95% CI 0.61–0.97; p = 0.03; I 2 = 0%). On stratified analysis, empiric SVCI demonstrated a significant recurrence reduction (RR 0.70, 95% CI 0.53–0.92; p = 0.01; I 2 = 0%), while trigger‐guided SVCI did not reach statistical significance (RR 0.80, 95% CI 0.37–1.74; p = 0.57; I 2 = 52%). In paroxysmal AF ( n = 1038), adjunctive SVCI significantly reduced recurrence compared with PVI alone (RR 0.68, 95% CI 0.52–0.90; p = 0.01; I 2 = 0%). Fluoroscopy time was longer with SVCI; total procedure duration was comparable. Major complications were infrequent but numerically higher with SVCI+PVI (15/604 vs. 7/627; RR 1.96, 95% CI 0.87–4.38; p = 0.10). Meta‐regression identified no significant effect modifiers. GRADE certainty was high for overall and empiric analyses, and moderate for trigger‐guided SVCI. Conclusions Empiric SVCI significantly reduced AT/AF recurrence as an adjunct to PVI, while trigger‐guided SVCI did not demonstrate a significant benefit. These findings suggest SVC isolation confers benefit independent of prior trigger documentation, supporting the role of empiric SVCI as an adjunct to AF ablation.

Introduction/Aim: Heart failure (HF) is a complex clinical syndrome, characterised by reduced exercise capacity (VO 2 peak) and quality of life leading to premature death. The reduction in VO 2 peak is a key prognostic indicator, and improving exercise capacity remains a critical therapeutic target. In athletes, the use of intermittent hypoxia training to improve VO 2 peak and performance is well established. Changes in VO 2 peak are typically accompanied by improved oxygen carrying capacity with increased haemoglobin (Hb) concentration mediated through increased erythropoietin (EPO) production in the kidney. The purpose of this pilot study was to examine the feasibility of using intermittent hypoxia training in individuals with HF, and examine changes in VO 2 peak, EPO and Hb. We hypothesised that intermittent hypoxia training would be feasible, well tolerated, and improve VO 2 peak, EPO production, Hb concentration in HF with reduced ejection fraction (HFrEF). Methods: Ten male participants with stable, optimally managed HFrEF (Age: 73 ± 5 yr; Ejection Fraction: 37 ± 11%) participated in the study. The training stimulus consisted of 12 x 60-minute sessions of intermittent hypoxia over a 2-week period. During each 60-minute session participants received 6 x 5 minutes of pulsed, reduced FIO 2 exposures interspersed with 5 min of normoxia (total of 30 min hypoxic exposure per session). All participants commenced at 18% FIO 2 , which was decreased to 12% by the 3-4th sesion, as tolerated. Throughout each exposure, oxygen saturation (SpO 2 ), heart rate, blood pressure and dyspnoea (modified Borg scale) were monitored every 5 min. Changes in VO 2 peak were measured using a cycle ergometry, cardiopulmonary exercise test. Changes in VO 2 peak, N-terminal pro B-type natriuretic peptide (NT-proBNP), EPO and Hb concentration were measured pre and immediately post intermittent hypoxic training. Results: All participants completed between 10-12 (median n=12) sessions over the 2-week period. Intermittent hypoxia was well-tolerated with no adverse events. The mean SpO 2 during the hypoxic exposure was 88 ± 4%, and median reported dyspnoea 0 (range 0-1). Following 2 weeks of intermittent hypoxic training, there were significant increases in VO 2 peak (mean difference[MD]: +1.18 mL·kg - ¹·min - ¹, 95% CI 0.47 to 1.89, p = 0.010); EPO (MD: +3.33 IU/L, 95% CI 1.35 to 5.32, p = 0.011); with a modest increase in Hb concentration that approached significance (MD: +4.00 g/L, 95% CI 0.51 to 7.49, p = 0.055). NT-proBNP remained unchanged (MD: –107 pg/mL, 95% CI –356 to 142, p = 0.424). Conclusion The results of this pilot study suggest that in clinically stable HFrEF, 2 weeks of intermittent hypoxic training results in a significant improvement in VO 2 peak, accompanied by increases in EPO and potentially levels of Hb. In our participants, this 60-minute pulsed intermittent hypoxic protocol was extremely well tolerated without any adverse effects, and may improve oxygen carrying capacity of the blood in HFrEF. Further research on the mechanisms of adaptation and the translation of the response into different HF phenotypes is warranted. Supported By: The Prince Charles Hospital Foundation Innovation Grant INN202-049 and Griffith University. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Most oncolytic viruses are delivered by intratumoural injection, and local administration can induce regression of both injected and distant tumours in mice and patients. However, the mechanisms by which local viral infection reprograms systemic immunity remain poorly understood. Here we show that intratumoural RP1, an oncolytic HSV-1 encoding GM-CSF and GALV-GP-R ⁻ , drives regression of injected and uninjected murine melanoma tumours and prolongs survival. RP1 elicits coordinated CD4 ⁺ and CD8 ⁺ T cell infiltration accompanied by local cytokine remodelling, reshaping the immune landscape at both tumour sites. Leveraging the Timer of Cell Kinetics and Activity (Tocky) system and Kaede photoconvertible protein technology, we resolve the temporal dynamics of CD8 ⁺ T cell responses following local virotherapy and identify two systemically induced, virus-driven CD8 ⁺ T cell populations distinguished by TCR engagement kinetics: antigen-engaged Timer-positive ‘viral-induced precursors’ (VIPs) and Timer-negative KLRG1 ⁺ ‘viral-induced terminal effectors’ (VITEs). Single-cell transcriptomic and pseudotime analyses reveal divergent differentiation trajectories; VIPs exhibit sustained antigen engagement within the tumour microenvironment (TME), a transcriptional programme associated with self-renewal, and preferential homing to draining lymph nodes. A VIP-associated gene signature correlates with clinical response to RP1 plus PD-1 blockade in the IGNYTE trial of RP1 and nivolumab in PD-1-refractory melanoma and is independently associated with response to immune checkpoint inhibitor (ICI) therapy in melanoma. These findings establish a mechanistic link between local oncolytic virotherapy, systemic CD8 ⁺ T cell reprogramming, and durable regression of distant lesions in patients.

Background Antitumor immune responses induced by oncolytic immunotherapy (OI) are often followed by upregulation of programmed death-ligand 1 (PD-L1). As such, the combination of OI with blockade of the programmed cell death protein-1 (PD-1)/PD-L1 axis has demonstrated therapeutic activity in preclinical and clinical trials. The purpose of this study is to understand further the immune-mediated mechanism of interaction between oncolytic viruses and anti-PD-1 therapy. Methods Tumor cells and immune cells (splenocytes) were cultured separately, or in co-culture with vusolimogene oderparepvec, an oncolytic herpes simplex virus expressing the fusogenic gibbon-ape leukemia virus-fusogenic membrane glycoprotein protein (GALV) and granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as RP1. Viral replication, interferon (IFN) responses and PD-L1 expression were analyzed using wild-type, IFNAR1, TNFAR1 and STING knockout splenocytes. In vivo studies evaluated immune cell infiltrates into the tumor following RP1 administration with anti-PD-1 therapy. Results RP1 replication was evident in tumor cells but not splenocytes. This was also accompanied by upregulated IFN expression in cultured splenocytes that was absent in cultured tumor cells. However, when these cell types were co-cultured, splenocytes mediated an interferon response to RP1 via STING that was transmitted to tumor cells in a non-touch-dependent manner. Tumor cells responded to these input signals via upregulation of cell surface major histocompatibility complex-I and PD-L1 through tumor intrinsic JAK-STAT signaling. In vivo, an IFN signature was observed following intratumoral injection of RP1, both in injected and non-injected tumors, which was further increased when combined with anti-PD-1 therapy. Marked upregulation of PD-L1 was observed in tumors injected with RP1 accompanied by the recruitment of CD11b+Ly6G+neutrophils into the tumor microenvironment, which stained positive for PD-L1. Conclusion Overall, the data demonstrate that RP1 remodels the tumor microenvironment through a combination of direct and indirect effects on both tumor and immune cells, resulting in an overall more inflamed phenotype.

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of liquid tumors but faces many challenges against solid tumors including T cell exhaustion and poor CAR durability. Here, we show that engaging the CAR T cell endogenous TCR using an oncolytic virus (OV) enhances CAR T cell functionality, durability, and therapy. Upon combination therapy of solid tumors with CAR T cells and vesicular stomatitis virus (VSV), a subpopulation of antiviral, TCR-primed CAR T cells was generated with enhanced effector functions, altered activation states, and differential gene and protein expression when compared to CAR T cells that do not undergo TCR priming. Single cell RNA-sequencing showed clonal expansion of anti-VSV CAR T cells, selective avoidance of exhaustion, and enhancement of effector-associated genes with VSV-mediated CAR T cell expansion. CD4 T cells played a pivotal role in both the generation and polarization of these TCR-primed CAR T cells. These results provide a strong rationale both for a novel use of intravenous administration of oncolytic viruses with separate applications from their direct oncolytic activity and for directly exploiting the TCR and its endogenous interactions as tools for fine tuning the phenotype and function of CAR T cells, with particular efficacy against solid tumors.

Abstract BACKGROUND Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors; germinoma accounts for two-thirds of cases. While neoadjuvant chemotherapy followed by response-based reduced radiotherapy dose and field is the established approach for managing localized CNS germinomas, controversy persists regarding the treatment of primary metastatic disease. Additionally, limited research exists on the utilization of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS A retrospective multi-institutional analysis was conducted to assess overall survival (OS) and event-free survival (EFS) among patients diagnosed with metastatic germinoma who were treated with various modalities. RESULTS We identified 88 patients, including 63 males and 25 females. The median age at presentation was 13.5 years. All patients, who had undergone both brain and spine MRIs, had their diagnoses confirmed through a biopsy, positive CSF cytology, and/or positive CSF tumor markers at presentation. Primary Tumor location was pineal (n=37), suprasellar (n=27), bifocal (n=14) and others (n=9). Eight patients underwent subtotal resection. Craniospinal irradiation (CSI; 21-24 Gy) was administered to 71 patients (81%), while eight patients (9%) received whole ventricular irradiation (WVI; 23.4-30 Gy). Whole brain radiation was given to four patients (5%; 24 Gy), and two patients (2%) had unknown fields. Boosts to primary and/or metastatic sites were administered in all but seven patients. Notably, thirty patients (34%) received CSI without neoadjuvant chemotherapy. At the end of therapy, 69 patients had complete response, 10 partial response and the response was unknown in six. Three patients did not receive irradiation, all died of disease progression. The median follow-up was 64 months (range 6-159 months), yielding an OS of 96.6%. Ongoing multi-institutional data collection and analysis will be presented at the meeting. CONCLUSION Our study is one of the largest studies to date in metastatic germinoma and may provide insight into the role of neoadjuvant chemotherapy with lower CSI doses.

AbstractPurposeTo study implant lead tip heating because of the RF power deposition by developing mathematical models and comparing them with measurements acquired at 1.5 T and 3 T, especially to predict resonant length.Theory and MethodsA simple exponential model and an adapted transmission line model for the electric field transfer function were developed. A set of wavenumbers, including that calculated from insulated antenna theory (King wavenumber) and that of the embedding medium were considered. Experiments on insulated, capped wires of varying lengths were performed to determine maximum temperature rise under RF exposure. The results are compared with model predictions from analytical expressions derived under the assumption of a constant electric field, and with those numerically calculated from spatially varying, simulated electric fields from body coil transmission. Simple expressions for the resonant length bounded between one‐quarter and one‐half wavelength are developed based on the roots of transcendental equations.ResultsThe King wavenumber for both models more closely matched the experimental data with a maximum root mean square error of 9.81°C at 1.5 T and 5.71°C at 3 T compared to other wavenumbers with a maximum root mean square error of 27.52°C at 1.5 T and 22.01°C for 3 T. Resonant length was more accurately predicted compared to values solely based on the embedding medium.ConclusionAnalytical expressions were developed for implanted lead heating and resonant lengths under specific assumptions. The value of the wavenumber has a strong effect on the model predictions. Our work could be used to better manage implanted device lead tip heating.

Background: Endothelial progenitor cells (EPCs) may originate from the bone marrow and are capable of contributing to cardiovascular regeneration. However, the identities of these bone marrow cells and the signaling pathways that regulate their differentiation into functional EPCs remain poorly understood. Hematopoiesis consists of a cascade by which hematopoietic stem cells (HSCs) give rise to either a common myeloid progenitor (CMPs) or common lymphoid progenitor (CLPs). The CMP cells can give rise to either granulocyte-monocyte progenitors (GMPs) or megakaryocyte-erythrocyte progenitors (MEPs). Methods and Results: Herein, we identify that CMPs and GMPs preferentially differentiate into CD34+KDR+ EPCs as measured by FACS, uptake of DiIacLDL and U.lex Lectin, matrigel studies, and endothelial markers. Co-culture studies in matrigel demonstrate increased network formation and incorporation when HUVECs were co-incubated with CMPs and GMPs only. Treatment of CMPs or GMPs with IFN-g blocked EPC differentiation, whereas treatment with TGF-b1 potently induced EPC differentiation. Conversely, EPC formation was markedly impaired using blocking antibodies or TGF-b1 deficient CMPs or GMPs, whereas IFN-g deficient mice have increased EPC differentiation. Functionally, EPCs derived from CMPs and GMPs more potently adhered to fibronectin-coated plates, migrated faster in transwell Boyden chambers, and released VEGF nearly ~2 to 2.5-fold higher than EPCs from MEPs and HSCs. Finally, we identified that a TGF-b1-responsive Kruppel-like transcription factor, KLF10, as robustly expressed ~60-fold in EPCs derived from CMPs and GMPs, compared to hematopoietic progenitors lacking EPC markers. Consistently, KLF10−/− mice have marked defects in EPC differentiation (−23.6% vs. WT, P<0.002), TGF-b1 responsiveness (completedly abolished), and impaired blood flow recovery in response to hindlimb ischemia (−23.8% vs. WT, P<0.008), an effect associated with reduced levels of circulating EPCs (−28.2% vs. WT, P<0.05). Conclusion: Among bone marrow progenitors, a hierarchy exists for EPC differentiation. Targeting KLF10 may alter EPC differentiation from bone marrow-derived CMPs and GMPs and influence cardiovascular repair.