Citations

Abstract Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation‐induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation‐induced senescence in non‐neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence‐associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor‐promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas.

Abstract Microglia, the major resident immune cells in the central nervous system, serve as the frontline soldiers against cerebral ischemic injuries, possibly along with metabolic alterations. However, signaling pathways involved in the regulation of microglial immunometabolism in ischemic stroke remain to be further elucidated. In this study, using single‐nuclei RNA sequencing, a microglial subcluster up‐regulated in ischemic brain tissues is identified, with high expression of Igf1 and Trem2, neuroprotective transcriptional signature and enhanced oxidative phosphorylation. Microglial depletion by PLX3397 exacerbates ischemic brain damage, which is reversed by repopulating the microglia with high Igf1 and Trem2 phenotype. Mechanistically, Igf1 serves as one of the major down‐stream molecules of Trem2, and Trem2‐Igf1 signaling axis regulates microglial functional and metabolic profiles, exerting neuroprotective effects on ischemic stroke. Overexpression of Igf1 and supplementation of cyclocreatine restore microglial glucometabolic levels and cellular functions even in the absence of Trem2. These findings suggest that Trem2‐Igf1 signaling axis reprograms microglial immunometabolic profiles and shifts microglia toward a neuroprotective phenotype, which has promising therapeutic potential in treating ischemic stroke.

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET patterns and its relation to RHI exposure in former professional and college American football players.MethodIn this study, 218 DIAGNOSE CTE participants, ages 45‐74, with flortaucipir PET were included; 104 were former National Football League players (PRO), 58 were former college football players (COL), and 56 had no history of contact sports, other exposure to RHI, or traumatic brain injury (UE). Regional flortaucipir uptake was quantified using established procedures for three previously defined statistical regions (superior frontal, left parietal, and medial temporal) and compared across the three groups. Association analyses were also performed to examine the relationship between flortaucipir uptake and exposure to RHI using the cumulative head impact index for linear acceleration g‐force (CHII‐G). The potential clinical utility of flortaucipir PET for CTE was also investigated by examining its ability to differentiate participants meeting criteria for traumatic encephalopathy syndrome (TES) and probable or possible level of certainty for CTE pathology from those who do not meet those criteria.ResultSignificantly higher flortaucipir uptake was observed in former football players than in participants without RHI exposure, controlling for age and race for the superior frontal region (Fig. 1A), left parietal, and medial temporal regions. Association between regional flortaucipir uptake and CHII‐G was only observed in the superior frontal region in former players (PRO+COL) 60 years and older (Fig. 1B) and no association was observed in the full PRO+COL group. Flortaucipir PET was not able to differentiate TES groups in former football players (Fig. 1C).ConclusionElevated flortaucipir uptake was observed in former American football players to a group of unexposed men. The association between flortaucipir uptake and exposure to RHI may require a long latent period to manifest. Further investigation of more sensitive tau PET tracers and quantification techniques is warranted to better characterize CTE related tau pathology.

AbstractINTRODUCTIONTau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project.METHODWe compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same‐age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES).RESULTSSignificantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups.DISCUSSIONAdditional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code–based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code–based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.

Background: DNA mismatch repair (MMR) deficiency (dMMR), which leads to genomic and microsatellite instability, is a biomarker that predicts response to immunotherapies and has variable prognostic effects for chemotherapies in solid tumors. The dMMR can be detected using gene sequencing or immunohistochemistry for four essential MMR proteins: MSH6, MSH2, MLH1, and PMS2. Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Previous studies have suggested the role of MMR gene variants in DLBCL lymphomagenesis, yet the prognostic role of dMMR in DLBCL has not been well studied. Methods: We performed targeted next-generation sequencing and immunohistochemistry for MSH6, MSH2, MLH1, and PMS2 in a large cohort of DLBCL patients treated with standard chemoimmunotherapy. Gene expression profiling (GEP) was performed using the Affymetrix GeneChip Human Genome HG-U133 Plus 2.0 microarray (data in GSE31312). Fluorescent multiplex immunohistochemistry (mIHC) was performed using MultiOmyx multiplexing immunofluorescence staining protocols and antibodies against 13 immune markers. We investigated the frequencies of dMRR and MMR protein expression and correlated the mutation status and expression levels with patient survival and DLBCL biology, including the number of mutated genes, GEP data, previously analyzed DLBCL biomarkers, and immune cell immunophenotypes. Results: MMR gene mutations and loss of MMR protein expression were infrequent in DLBCL (Figure A) and did not show a significant prognostic impact. MMR proteins were commonly expressed in DLBCL samples and the germinal centers of reactive tonsil controls (Figure B), with higher mean and median percentages of tumor cells expressing MSH6 and MLH1 proteins than in the solid tumor samples used for comparison. High expression of MMR proteins was associated with Ki-67, MYC, and p53 overexpression as determined by immunohistochemistry. GEP analysis identified significantly upregulated genes involved in the mitotic cell cycle and DNA metabolism and prominent downregulated immune gene signatures in DLBCL with high MMR protein expression. Fluorescent mIHC confirmed the associations with decreased T cell abundance in MSH6/MSH2/MLH1/PMS2 highly expressing DLBCL (Figure C) independent of p53 and MYC expression status, whereas MSH6/ MLH1 mutations were associated with increased T cell frequencies. High versus low expression of MSH6, MLH1, and PMS2 showed significant unfavorable prognostic effects in DLBCL when the optimal cutoffs were used for high expression. However, when the median percentages were used as cutoffs, the prognostic effects were not significant; nonetheless, MSH6 and PMS2 high expression showed significant adverse prognostic effects in the MYC¯ DLBCL subset. Interestingly, when we used Ki-67, MYC + or BCL2 + percentages in DLBCL assessed by immunohistochemistry to subtract MMR protein percentages and then correlated the differences to survival, we found significant favorable prognostic impact by higher percentage expression differences between MMR proteins and BCL2, or by intermediately higher differences between MMR proteins and MYC. For MSH2/MLH1/PMS2, the higher percentages compared with MYC/BCL2 showed no significant correlations with T cell infiltration levels, whereas the higher differences between MSH6 and MYC/BCL2 were associated with significantly lower T cell frequencies (Figure D). Conclusions: This study revealed that high expression of MMR proteins is a common feature of DLBCL associated with lower tumor-infiltrating T cells, MYC and p53 overexpression, and context-dependent prognostic effects. In contrast, dMMR and loss of MMR proteins are infrequent and have no significant prognostic effects in DLBCL treated with standard chemoimmunotherapy. These results may have implications for understanding DLBCL biology and the low efficacy of PD-1 blockade immunotherapy in DLBCL.

Introduction: Axi-cel utilization expanded after demonstration of superior event-free survival in patients (pts) with early relapsed or primary refractory LBCL (Locke, et al. NEJM. 2022) and was reinforced by improved overall survival (OS) among these pts (Westin, et al. NEJM. 2023). Despite increased demand, limited data exist on the impact of bridging therapies (BT) on pt outcomes. Thus, BT use between leukapheresis and lymphodepletion (LD) is largely at the discretion of treating physicians. Here, we assessed the impact of BT on effectiveness and safety outcomes after axi-cel. Methods: Pts receiving axi-cel for 3L+ LBCL in the US between 2017-2020 were prospectively collected through the CIBMTR registry in a post-authorization safety study; data up to May 2023 were included. Effectiveness outcomes were overall response rate (ORR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), and OS. Safety outcomes were cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT grading, non-relapse mortality (NRM), and other key adverse events. Propensity score-based inverse probability of treatment weighting (IPTW) was used in logistic and Cox regressions to account for potential confounding in BT use. For pts who had BT, effects of BT types and responses on outcomes were evaluated using conventional logistic and Cox regressions. Results: Of 1497 pts registered, 1307 had BT data available and were included (median follow-up, 36 mo). Overall, 430 pts (33%) received BT (median time from leukapheresis to LD, 23 days [IQR, 21-28]). Systemic therapy was used in 403 pts (31%), including 305 (23%) with chemotherapy (CT)-based BT (19% treated with CT + anti-CD20 monoclonal antibody [mAb; mainly rituximab] and 4% with CT only), and 98 (7%) with non-CT systemic therapy (Table). Radiotherapy (± systemic therapy) was used in 44 pts (3%). Pts with ≥3 lines of prior therapy (odds ratio [OR], 10.67 [95% CI, 7.17−15.87]) or mild hepatic impairment prior to infusion (OR, 1.64 [1.06−2.55]) were more likely to receive BT, while those with histologic transformation (OR, 0.69 [0.51−0.92]) or longer time from diagnosis to leukapheresis were less likely to receive BT. ORRs to axi-cel were 70% and 79% (CR rates 51% and 64%) for pts with or without BT, respectively. Unadjusted DOR, PFS, and OS at 3 years were 40%, 28%, and 37%, respectively, in pts with BT vs 49%, 39%, and 49%, respectively, in those without BT. After multivariate adjustment, no statistical significance was found between BT and any effectiveness outcome. Adjusted hazard ratios (HRs) for BT were 1.13 (95% CI, 0.94-1.36) for PFS and 1.11 (95% CI, 0.92-1.34) for OS, respectively (Figure). Most safety endpoints were consistent regardless of BT. Grade ≥3 CRS and ICANS occurred in 12% and 30% of pts, respectively, who received BT vs 10% and 24% of pts who did not. Use of BT was associated with more frequent prolonged neutropenia (OR, 2.24 [1.44-3.50]) and thrombocytopenia (OR, 2.33 [1.67-3.24]), but not associated with a higher rate of infections or NRM (Table). Among pts receiving BT, 74 (17%) had a CR or partial response to BT. Of them, median PFS and median OS post infusion were 12.7 mo (3.8-not estimable [NE]) and 48.7 mo (18.6-NE), respectively. Response to BT was associated with increased CR rate (OR, 2.00 [1.07-3.75]), PFS (HR, 0.69 [0.49-0.99]), and OS (HR, 0.59 [0.40-0.88]) and decreased any-grade ICANS (OR, 0.51 [0.29-0.92]). When different BT strategies were considered, effectiveness and most safety outcomes for CT + anti-CD20 mAb vs non-CT treatment were comparable without significant difference. CT + anti-CD20 mAb was associated with improved ORR (OR, 1.90 [1.00-3.60]), PFS (HR, 0.69 [0.49-0.98]), and OS (HR, 0.66 [0.46-0.95]) but increased any-grade CRS (OR, 2.16 [1.02-4.57]) vs CT only. CT use was associated with an increased risk of prolonged thrombocytopenia (41% vs 24% for pts receiving non-CT treatment; OR, 2.37 [1.39-4.02]). No significant association was found between use of radiotherapy as BT and any outcome. Conclusion: These US real-world findings suggest that the addition of BT prior to axi-cel is associated with more frequent prolonged cytopenias but does not impact effectiveness or other critical safety outcomes. Response to BT may prognosticate more favorable outcomes after axi-cel infusion. Further study is warranted to identify the optimal bridging regimen.

While acknowledging that newer therapies have improved survival rates in chronic lymphocytic leukemia (CLL), patients with high-risk disease features are at an increased risk of treatment failure. Allogeneic hematopoietic cell transplantation (allo-HCT) was traditionally offered as front-line consolidation in high-risk CLL; however, with the emergence of targeted therapies like Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitors, the role of allo-HCT has been relegated to later stages of the disease. Patients with relapsed/refractory (R/R) CLL who have failed both BTK and BCL-2 inhibitors represent a therapeutic challenge owing to a poor prognosis. Chimeric antigen receptor T-cell (CAR T) therapies targeting CD19 have improved response rates and overall survival in various types of R/R B-cell non-Hodgkin lymphomas. For CLL, no approved CAR T-cell therapies are yet available. Emerging data appear to show a therapeutic benefit of CAR T-cell therapy in patients with R/R CLL, even after failing an allo-HCT.

Abstract Few methods exist via which to assess treatment response with high fidelity in gliomas. While CSF has previously been used as a source of cfDNA, it remains unknown how cfDNA abundance and sequencing changes throughout treatment and inevitable recurrence in gliomas. We utilized our biobank of longitudinal intracranial CSF specimens to determine the potential utility of CSF cfDNA as a monitoring tool for treatment response in patients with gliomas. Longitudinal CSF specimens were acquired via Ommaya reservoirs (NCT04692337) or ventriculoperitoneal shunts (NCT04692324) in patients with gliomas. cfDNA was extracted from 1-5 mL of CSF, and next-Generation sequencing or low-pass whole genome sequencing (LPWGS) was performed by Predicine, Inc. CSF acquired prior to versus after resection demonstrated an increase in quantified cfDNA (2.97x, range: 1.58-5.26x), consistent with the impact of increased parenchymal disruption and closer contact with CSF. Thereafter, CSF cfDNA continued to decrease throughout chemoradiation and adjuvant treatment and increased at recurrence, including in patients co-enrolled in immunotherapy trials for IL-7 agonists and pembrolizumab. Copy number burden (CNB) increased by the time of recurrence in three patients with known disease progression, and continued to decrease throughout immunotherapy treatment in one patient despite concerns of pseudoprogression. In one patient with a hypermutated glioblastoma, CSF cfDNA revealed over 59 genomic alterations, including MAP2K1, KIT, and PDGFRA, excluding even more variants of unknown significance, each of which had been detected in sequencing of the tissue acquired at resection and subsequently decreased with chemoradiation. In another patient with a known progressing EGFR-amplified GBM, over 200 new variants were identified by the patient’s final sample and EGFR copy number increased from 2 to over 30. In conclusion, cfDNA analysis over a patient’s disease course, including resection and treatment with standard-of-care and experimental therapies, may be of use for disease monitoring and treatment response.

Background Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing. Methods ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies. Results Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells. Conclusions These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.