15 research outputs found
Analysis of cardiac amyloidosis progression using model-based markers
Deposition of amyloid in the heart can lead to cardiac dilation and impair its pumping ability. This ultimately leads to heart failure with worsening symptoms of breathlessness and fatigue due to the progressive loss of elasticity of the myocardium. Biomarkers linked to clinical deterioration can be crucial in developing effective treatments. However, to date progression of cardiac amyloidosis is poorly characterized, and there is an urgent need to identify key features that can predict the disease progression and cardiac tissue function. In this proof of concept study, we estimate a group of new markers based on mathematical models of the left ventricle derived from routine clinical magnetic resonance imaging and follow-up scans from the National Amyloidosis Centre at the Royal Free in London. Using mechanical modelling and statistical classification, we show that it is possible to predict disease progression. Our predictions agree with clinical assessments in a double-blind test in six out of the seven sample cases studied. Importantly, we find that multiple factors need to be used in the classification, which includes mechanical, geometrical and shape features. No single marker can yield reliable prediction given the complexity of the growth and remodelling process of diseased hearts undergoing high-dimensional shape changes. Our approach is promising in terms of clinical translation but the results presented should be interpreted with caution due to the small sample size
Effects of HIF-1α and HIF2α on Growth and Metabolism of Clear-Cell Renal Cell Carcinoma 786-0 Xenografts
In cultured clear-cell renal carcinoma (CCRCC) 786-0 cells transfected with HIF1α (HIF-1+), HIF-2α (HIF-2+), or empty vector (EV), no significant differences were observed in the growth rates in vitro, but when grown in vivo as xenografts HIF-2α significantly increased, and HIF-1α significantly decreased growth rates, compared to EV tumors. Factors associated with proliferation were increased and factors associated with cell death were decreased in HIF-2+ tumors. Metabolite profiles showed higher glucose and lower lactate and alanine levels in the HIF-2+ tumors whilst immunostaining demonstrated higher pyruvate dehydrogenase and lower pyruvate dehydrogenase kinase 1, compared to control tumors. Taken together, these results suggest that overexpression of HIF-2α in CCRCC 786-0 tumors regulated growth both by maintaining a low level of glycolysis and by allowing more mitochondrial metabolism and tolerance to ROS induced DNA damage. The growth profiles observed may be mediated by adaptive changes to a more oxidative phenotype
Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.
BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients receivedââ€â6 monthly doses of dezamizumab in the Phase 2 trial (nâ=â7),ââ€â2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (nâ=â2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)
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Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.
BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients receivedââ€â6 monthly doses of dezamizumab in the Phase 2 trial (nâ=â7),ââ€â2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (nâ=â2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)
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In silico tumor immune microenvironment (TiME) analysis of non-small cell lung cancer (NSCLC) to inform clinical development of CDR404: A first-of-its-kind MAGE-A4 targeted T-cell engager
e20024 Background: CDR404 is an antibody-based bivalent MAGE-A4 targeted T-cell engager (TCE). One key mechanism-of-action of TCEs is CD8 T-cell redirection which involves T-cell intravasation into tumors [Damato et al, 2019]. CDR404 mediated TiME remodeling will likely be dependent on the inflammatory (INFLAM) and vascular (VASC) phenotype especially since tumor vasculature constitutes functional and physical barriers to T-cell infiltration [Sahu et al, 2022] [Desbois et al 2020] [Duru et al, 2020]. To identify biomarkers for CDR404 anti-tumor responses in NSCLC, we evaluated the associations between MAGE-A4 mRNA expression, immune cell populations and frequency of 9p21 deletions mediating T-cell infiltration [Han et al, 2021]. Methods: Expression of MAGE-A4 mRNA was evaluated by the Tempus xR RNA-Seq assay (Tempus AI, Inc. Chicago IL). Consensus TME bulk RNA-Sequencing deconvolution [JimĂ©nez-Sanchez et al, 2019] was used to analyze 16 TiME cell lineages in two NSCLC TCGA datasets â primary LUSC & LUAD [Giacomazzi et al, 2023]. Immune cell data was stratified by MAGE-A4 expression quartiles (Q): Null = not detected; MAGE-A4 LOW = Q1-Q3; MAGE-A4 HIGH = Q4. GISTIC2.0 was used to identify 9p21 gene deletions [Mermel et al, 2011]. Results: MAGE-A4 is enriched in LUSC. MAGE-A4 levels were similar across metastatic organ sites (e.g., liver vs. lymph nodes) in LUSC indicating that tumor location is not a confounding factor for TiME analysis. In LUSC, MAGE-A4 HIGH vs. MAGE-A4 NULL tumors had lower levels of 15/16 immune cell populations. Largest reductions were in endothelial cells (p=7.71-e05) and CD8 T-cells (p=0.00096). Deletions in 9p21 genes were more frequent in MAGE-A4 HIGH vs. MAGE-A4 NULL tumors, e.g., CDK2NA: 91% vs. 68% (p=0.0028), consistent with reduced CD8 T-cells in MAGE-A4 HIGH . In MAGE-A4 HIGH vs. MAGE-A4 LOW reductions in 4/16 immune cell populations were seen. In LUAD, immune cell levels were similar across MAGE-A4 subgroups except lower endothelial cells in MAGE-A4 HIGH vs. MAGE-A4 NULL (p=0.00055). Conclusions: LUSC MAGE-A4 HIGH tumors had a differentiated TiME profile. Our findings are consistent with an INFLAM LOW VASC LOW phenotype possibly indicative of an âimmune desertâ [Desbois et al 2020]. In contrast, LUAD MAGE-A4 HIGH tumors had an INFLAM HIGH VASC LOW phenotype indicating that MAGE-A4 associations with TiME may be histology dependent in NSCLC. Overall, in MAGE-A4 HIGH LUSC & LUAD, susceptibility to CDR404 mediated T-cell tumor intravasation may be better because of a lower angiogenic barrier. Translational baseline tumor biopsy sub-studies from the CDR404 Phase 1 trial are awaited to confirm if INFLAM/VASC phenotype is predictive of response in relapsed locally advanced/metastatic NSCLC patients. CDR-Life acknowledges Tempus AI, Inc. for the expression analysis using the Tempus xR RNA-Seq assay
Non-pineal supratentorial primitive neuro-ectodermal tumors (sPNET) in teenagers and young adults:Time to reconsider cisplatin based chemotherapy after cranio-spinal irradiation?
Background. Supratentorial PNET (sPNET) are rare CNS tumors of embryonal origin arising in children and adults. The treatment of sPNET for all age groups at our cancer center has been based on the management of medulloblastoma (MB), involving neurosurgical debulking followed by cranio-spinal irradiation (CSI) and systemic chemotherapy. Methods. Medical records were reviewed to gather demographic and clinical data about all embryonal CNS tumors in children and adults from 2001 to 2007. Tumor pathology, clinical management and survival data were also assessed, particularly as regards those patients who received the Packer chemotherapy regimen for either sPNET or MB. Results. Eleven patients (five children and six adults) were identified with non-pineal sPNET, three children with pineal sPNET, and 19 patients (18 children and 1 adult) with MB. There was no difference in overall survival (OS) rates between pediatric and adult sPNET. When all sPNET were compared to all MB, 5-year OS was 14% versus 73%, respectively, but was only 9% for non-pineal sPNET. When only considering those patients treated with the Packer chemotherapy regimen, the 5-year OS was 12% for sPNET versus 79% for MB. Conclusion. This retrospective study demonstrates that non-pineal sPNET are clinically distinct from MB and are resistant to the Packer chemotherapy regimen. We suggest that it is time to reconsider the use of this regimen in teenage and young adult non-pineal sPNET and to investigate the utility of alternative approaches.</p