Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma.

In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell-engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.).

Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial.

CD19-directed chimerical antigen receptor T-cell (CAR-T) products have gained US Food and Drug Administration approval for systemic large B-cell lymphoma. Because of concerns about potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary central nervous system (CNS) lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. We conducted a phase 1/2 clinical trial of tisagenlecleucel in a highly refractory patients with PCNSL and significant unmet medical need. Here, we present results of 12 relapsed patients with PCNSL who were treated with tisagenlecleucel and followed for a median time of 12.2 months (range, 3.64-23.5). Grade 1 cytokine release syndrome was observed in 7/12 patients (58.3%), low-grade ICANS in 5/12 (41.6%) patients, and only 1 patient experienced grade 3 ICANS. Seven of 12 patients (58.3%) demonstrated response, including a complete response in 6/12 patients (50%). There were no treatment-related deaths. Three patients had ongoing complete remission at data cutoff. Tisagenlecleucel expanded in the peripheral blood and trafficked to the CNS. Exploratory analysis identified T-cell, CAR T, and macrophage gene signatures in cerebrospinal fluid following infusion when compared with baseline. Overall, tisagenlecleucel was well tolerated and resulted in a sustained remission in 3/7 (42.9%) of initial responders. These data suggest that tisagenlecleucel is safe and effective in this highly refractory patient population. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

Immunotherapy for Brain Tumors: Where We Have Been, and Where Do We Go From Here?

OPINION STATEMENT: Immunotherapy for glioblastoma (GBM) remains an intensive area of investigation. Given the seismic impact of cancer immunotherapy across a range of malignancies, there is optimism that harnessing the power of immunity will influence GBM as well. However, despite several phase 3 studies, there are still no FDA-approved immunotherapies for GBM. Importantly, the field has learned a great deal from the randomized studies to date. Today, we are continuing to better understand the disease-specific features of the microenvironment in GBM-as well as the exploitable antigenic characteristic of the tumor cells themselves-that are informing the next generation of immune-based therapeutic strategies. The coming phase of next-generation immunotherapies is thus poised to bring us closer to treatments that will improve the lives of patients with GBM.

Suppression of antitumor immune signatures and upregulation of VEGFA as IDH-mutant gliomas progress to higher grade.

OBJECTIVE: Several studies have compared the immune microenvironment of isocitrate dehydrogenase (IDH)-wildtype glioma versus IDH-mutant glioma. The authors sought to determine whether histological tumor progression in a subset of IDH-mutant glioma was associated with concomitant alterations in the intratumoral immune microenvironment. METHODS: The authors performed bulk RNA sequencing on paired and unpaired samples from patients with IDH-mutant glioma who underwent surgery for tumor progression across multiple timepoints. They compared patterns of differential gene expression, overall inflammatory signatures, and transcriptomic measures of relative immune cell proportions. RESULTS: A total of 55 unique IDH-mutant glioma samples were included in the analysis. The authors identified multiple genes associated with progression and higher grade across IDH-mutant oligodendrogliomas and astrocytomas. Compared with lower-grade paired samples, grade 4 IDH-mutant astrocytomas uniquely demonstrated upregulation of VEGFA in addition to counterproductive alterations in inflammatory score reflective of a more hostile immune microenvironment. CONCLUSIONS: Here, the authors have provided a transcriptomic analysis of a progression cohort for IDH-mutant glioma. Compared with lower-grade tumors, grade 4 astrocytomas displayed alterations that may inform the timing of antiangiogenic and immune-based therapy as these tumors progress.

Mental Health Treatment Use, Perceived Treatment Need, and Reasons for Non-Use Among U.S. Adults with Serious Suicidal Thoughts During the COVID-19 Pandemic.

Analyzing the 2021 National Survey on Drug Use and Health data with generalized linear models, we examined: (1) COVID pandemic-related and other correlates of mental health treatment use and unmet perceived treatment need among U.S. adults who experienced serious suicidal thoughts (N = 3,177); and (2) correlates of self-reported reasons for not receiving treatment. We found that 61% used any mental health treatment, and 48% of users and 37% of nonusers reported perceived treatment need. Significant correlates of treatment use were demographic factors, insurance, major depressive disorder, and illicit drug use disorder. Significant correlates of perceived treatment need were age 18-34, some college education, and major depressive episode. Perceived negative effect of the COVID pandemic on mental health was a significant factor for both treatment use and perceived need. The most frequent reasons for not getting treatment were the cost of treatment or lack of insurance and stigma-related concerns.

Suicide from intimate partner and other relationship conflicts: demographic and clinical correlates'.

BACKGROUND: A significant portion of suicides are precipitated by interpersonal relationship problems. AIMS: To examine demographic and clinical correlates of any intimate partner conflicts (IPC) and other interpersonal conflicts (OPC) as suicide precipitants. METHODS: We analyzed data on 92,805 (72,628 male; 20,177 female) adult suicide decedents from the 2017 to 2019 U.S. National Violent Death Reporting System, using multinomial and binary logistic regression models. We included case examples from coroners/medical examiner (CME) and law enforcement (LE) agency reports. RESULTS: Of all decedents, 23.6% had IPC and 8.0% had OPC as a suicide precipitant. Compared to those without any relationship conflict, those who had IPC or OPC were younger and more likely to have had previous suicide attempt(s), alcohol/other substance use problems, and job/finance/housing and legal problems. Compared to those with OPC, those with IPC were more likely to be male and Hispanic and had higher odds of previous suicide attempt, depression diagnosis, alcohol problems, and more acute crises. CME/LE reports showed distress of divorce/break-up, other life stressors, prior suicide attempt(s), alcohol/other substance involvement, and/or loss of family support. CONCLUSIONS: Access to behavioral health treatment for those at risk of suicide in the face of IPC or OPC is essential for suicide prevention.

Associations of Depression/Anxiety with Technology Use, Discontinued Use, and Nonuse in Older Adults.

OBJECTIVES: To examine correlates of the changes in technology use among older adults and the associations of depression/anxiety symptoms with technology use changes. METHODS: We used the 2019-2021 U.S. National Health and Aging Trends Study (N = 3,063; age 70+). We fitted multinomial logistic regression models to examine: (1) correlates of never use and discontinued use versus use of email/texting and the internet during the 3-year study period; and (2) associations of past-month depression/anxiety symptoms in 2021 with use and discontinued use versus never use of email/texting and social network site (SNS). RESULTS: The findings show age, socioeconomic, and health barriers to technology use. Email/texting and SNS use in 2021, compared to never use in all 3 years, was associated with a lower likelihood of moderate/severe depression/anxiety symptoms in 2021 (RRR = 0.54, 95% CI = 0.37-0.81 for email/texting use; RRR = 0.56, 95% CI = 0.33-0.97 for SNS use). Video calls with family/friends were not associated with depression/anxiety symptoms. CONCLUSIONS: The findings expand the existing knowledge base regarding potential impact of technology use on mental health beyond the early months of the COVID-19 pandemic. CLINICAL IMPLICATIONS: More concerted efforts are warranted to help older adults' technology uptake and continued use and to promote mental health benefits of technology use.

Healthcare Cost Burden and Self-Reported Frequency of Depressive/Anxious Feelings in Older Adults.

Using the 2018-2021 National Health Interview Survey data, we examined the associations between healthcare cost burden and depressive/anxious feelings in older adults. Nearly12% reported healthcare cost burden and 18% daily/weekly depressive/anxious feelings. Healthcare cost burden was higher among women, racial/ethnic minorities, those with chronic illnesses, mobility impairment, and those with Medicare Part D, but lower among individuals with Medicare-Medicaid dual eligibility, Medicare Advantage, VA/military insurance, and private insurance. Daily/weekly depressive/anxious feelings was higher among healthcare cost burden reporters. The COVID-19 pandemic-related medical care access problems were also associated with a higher risk of reporting healthcare cost burden and depression/anxiety.

Comparison of guidelines for biological ancillary materials used for the manufacture of gene and cellular therapy products in Asia.

BACKGROUND AIMS: Although biologiocal ancillay materials (AMs) have specific risk associated with their derivations, it plays key role to manufature cell and gene therapy (CGT) products. It is important to understand the regulation relevant to AMs for developers. METHODS: The authors investigated the guidelines and pharmacopeia (hereinafter referred to as "guidelines") for biological AMs used for the manufacture of CGT products in Asia (China, India, Japan, Korea and Taiwan). In addition, the authors benchmarked the relevant guidelines in the United States (US) and European Union (EU). RESULTS AND DISCUSSIONS: The guidelines could be classified into two types based on whether specific AMs are scoped: (i) general guidelines for risk assessment of AMs and (ii) guidelines for specific AMs. The authors compared the risk categories for each type of AM provided in the general guidelines between the US and China and the specific requirements for bovine serum and trypsin in the guidelines of China, Japan, Taiwan, US and EU. The authors further compiled in-depth descriptions of the respective regulations in China, India, Japan, Korea and Taiwan. There is limited availability of some guidelines for specific AMs. Moreover, there are no common requirements established across the surveyed countries and regions. Therefore, the authors suggest a risk assessment approach for AMs with consideration of their biological origin and traceability, production steps applied and ability to control or remove AMs from the final medicinal product over the CGT manufacturing process.

County-level disparities in care for patients with glioblastoma.

OBJECTIVE: Racial and socioeconomic disparities in neuro-oncological care for patients with brain tumors remain underexplored. This study aimed to analyze county-level disparities in glioblastoma (GBM) care in the United States, focusing on access to surgery and the use of adjuvant temozolomide chemotherapy and radiation therapy. METHODS: Using repeated cross-sectional data from the Surveillance, Epidemiology, and End Results 17 database; the Area Health Resources File; and the American Community Survey, from 2010 to 2019, the authors performed multivariate regression analyses to understand the associations between county-level racial and socioeconomic characteristics, as well as the rates of surgery performed, delays in surgery, and use of adjuvant chemotherapy and radiation therapy for newly diagnosed GBM. RESULTS: In total, 29,609 GBM patients from 602 different US counties over a decade were included in this study. Counties with lower rates of surgery for GBM were associated with a higher percentage of Black residents (coefficient [CE] -0.001, 95% CI -0.002 to 0; p < 0.05) and being located in the Midwest (CE -0.132, 95% CI -0.195 to -0.069; p < 0.001) or West (CE -0.127, 95% CI -0.189 to -0.065; p < 0.001) relative to the Northeast. Counties with delayed surgical treatment were more likely to lack neurosurgeons (adjusted OR [aOR] 2.52, 95% CI 1.77-3.60; p < 0.001), have a higher percentage of Black residents (aOR 1.011, 95% CI 1.00-1.02; p < 0.05), and be located in the Midwest (aOR 3.042, 95% CI 1.12-8.24; p < 0.05) or West (aOR 3.175, 95% CI 1.12-8.97 p < 0.05). Counties with high rates of adjuvant radiation therapy were less likely to have higher percentages of Black residents (aOR 0.987, 95% CI 0.980-0.995; p < 0.01) and uninsured individuals (aOR 0.962, 95% CI 0.937-0.987; p < 0.01). CONCLUSIONS: Counties without neurosurgeons and those with a higher percentage of Black patients have delays in surgical care and demonstrate lower overall rates of surgery and adjuvant therapy for GBM. This study underscores the need for targeted interventions and policies that address structural barriers in healthcare access, improve equitable distribution of the neurosurgery workforce, and ensure timely and comprehensive GBM care to all populations.

Suicidal intent disclosure among adult suicide decedents: Four age group comparisons.

Research on who does/does not disclose suicidal intent (SI) and related factors has important implications for suicide risk management. In this paper based on the 2017-2019 National Violent Death Reporting System, we compared four age groups (18-24, 25-44, 45-64, and 65+ years) of suicide decedents with respect to associations between SI disclosure and (1) suicide contributing/precipitating factors, and (2) suicide means. The results shows that those age 18-44 were more likely to disclose SI than those age> =45, especially among those with relationship problems. Physical health problems and death/suicide of family/friend increased the likelihood of SI disclosure in the 65+ age group.

Changes in Older Adults' Frequency of Going Outside between 2020 and 2021: Associations with Health Status and Environmental Factors.

OBJECTIVES: To examine the changes in the frequency of going outside among U.S. older adults between 2020 and 2021 (post-COVID vaccine) and correlates of those changes. METHODS: We used the 2019-2021 National Health and Aging Trend Study (NHATS) (N = 3,063, age 70+) and multinomial logistic regression to analyze associations of increased and decreased frequencies in going outside with physical, psychosocial, and cognitive health, environmental (COVID concerns and transportation) factors, and social media use as the independent variables. RESULTS: In 2021 compared to 2020, 13% and 16% of those age 70+ reported increased and decreased frequencies, respectively. Increased frequency was associated with social media use. Decreased frequency was associated with poor physical health, depression/anxiety, and perceived memory decline. COVID concerns and transportation problems, as well as female gender, age 90+, and being non-Hispanic Black, were also significant correlates of decreased frequency. CONCLUSIONS: Most U.S. adults age 70+ appear to have resumed their 2019 level of frequency of going outside in 2021 after the COVID vaccines became available; however, 16% reported decreased frequency of going outside in 2021 compared to 2020. CLINICAL IMPLICATIONS: Older adults with physical, mental, and cognitive health challenges need help to increase their frequency of going outside.

A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties.

Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.

Implications of IDH mutations on immunotherapeutic strategies for malignant glioma.

Immunotherapy has emerged as a promising approach for treating aggressive solid tumors, even within the CNS. Mutation in the metabolic gene isocitrate dehydrogenase 1 (IDH1) represents not only a major glioma defining biomarker but also an attractive therapeutic neoantigen. As patients with IDH-mutant glioma enter early-phase vaccine and immune checkpoint inhibitor clinical trials, there is emerging evidence that implicates the oncometabolite, 2-hydroxyglutarate (2HG), generated by the neomorphic activity of mutant IDH, as a potential barrier to current immunotherapeutic approaches. Here, the authors review the immunomodulatory and immunosuppressive roles of 2HG within the unique IDH-mutant glioma tumor immune microenvironment and discuss promising immunotherapeutic approaches currently being investigated in preclinical models.

Opioid poisoning cases aged 50+ in the 2015-2020 National Poisoning Data System: suspected suicides versus unintentional poisoning and other intentional misuse/abuse.

High rates of opioid overdose and suicide among the 50+ age group call for an examination of suicidal intent in overdose incidents. Using 2015-2020 National Poison Data System opioid poisoning cases aged 50+ (n = 83 153), we examined the types of opioids and other substances associated with suspected suicides compared to intentional misuse/abuse without suicidal intent. During the six years, prescription opioid cases decreased, while illicit opioid cases increased. Among both types of opioid poisoning cases, the proportions of suspected suicides decreased and those of intentional misuse/abuse without suicidal intent increased. However, due to the large increase in illicit opioid cases, the number of suspected suicide cases involving illicit opioids increased. Multivariable analyses showed that among prescription opioids, acetaminophen with opioid (IRR = 1.17, 95% CI = 1.11-1.24) and tramadol (IRR = 1.12, 95% CI = 1.06-1.47) were associated with higher risk of suspected suicides than intentional misuse/abuse without suicidal intent. Among illicit opioid cases, fentanyl poisoning cases were associated with lower risk of suspected suicides (IRR = 0.40, 95% CI = 0.17-0.94). Of other medications, use of benzodiazepines and antipsychotics was consistently associated with higher risk of suspected suicides in both prescription and illicit opioid cases. Alcohol and cocaine were also associated with higher risk of suspected suicide. Along with continued reductions in opioid prescribing, more effective monitoring of individual patient misuse/abuse behaviors and suicide risk assessment are needed. Healthcare professionals should also review other prescription medications frequently co-prescribed with opioids that may have additive effects on suicidal behaviors among older adults.

Cannabis and binge alcohol use among older individuals with major depressive episode.

Background: Research shows significant associations of major depression with cannabis and binge alcohol use. However, despite increasing cannabis and binge alcohol use rates among the 50+ age group, research on this age group is scant. Methods: We used the 2015-2019 National Survey on Drug Use and Health data (n = 44,007 age 50+) and multinomial logistic regression models to examine associations of a major depressive episode (MDE) with cannabis and binge alcohol use and co-use and associations of binge alcohol use with nonmedical and medical cannabis use. Results: Of individuals age 50+, 89.6% had no history of MDE, 5.7% had prior-to-past-year MDE, and 4.7% had past-year MDE. The rates of past-month cannabis use were 4.3%, 7.7%, and 11.6% and binge alcohol use were 17.3%, 18.7%, and 19.9% among those with no MDE history, prior-to-past-year MDE, and past-year MDE, respectively. Compared to no MDE history, prior-to-past-year MDE (RRR = 1.70, 95% CI = 1.30-2.23) and past-year MDE (RRR = 1.80, 95% CI = 1.27-2.55) were significantly associated with past-month cannabis use (with or without binge alcohol use). However, MDE status was not associated with past-month binge alcohol use. Among cannabis users, binge alcohol use was significantly associated with nonmedical cannabis use only (RRR = 2.50, 95% CI = 1.95-3.21). Users of cannabis and/or binge alcohol also had a higher likelihood of using tobacco products and illicit drugs. Conclusions: Healthcare professionals treating individuals age 50+ with depression should screen for substance use, provide education on the potential adverse effects of polysubstance use, and help them access treatment for co-occurring depression and substance use problems.

Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma.

Chimeric antigen receptor (CAR) T cells targeting CD19 have emerged as a leading engineered T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. The phase 1/2 clinical trials that led to US Food and Drug Administration approval excluded patients with central nervous system (CNS) involvement, due to strict eligibility criteria. Here, we report on our institutional experience with 8 secondary CNS lymphoma patients treated with commercial tisagenlecleucel. No patient experienced greater than grade 1 neurotoxicity, and no patient required tocilizumab or steroids for CAR T-cell-mediated toxicities. Biomarker analysis suggested CAR T-cell expansion, despite the absence of systemic disease, and early response assessments demonstrated activity of IV infused CAR T cells within the CNS space.

A Distinct Transcriptional Program in Human CAR T Cells Bearing the 4-1BB Signaling Domain Revealed by scRNA-Seq.

T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have produced impressive outcomes for the treatment of B cell malignancies, but different products vary in kinetics, persistence, and toxicity profiles based on the co-stimulatory domains included in the CAR. In this study, we performed transcriptional profiling of bulk CAR T cell populations and single cells to characterize the transcriptional states of human T cells transduced with CD3ζ, 4-1BB-CD3ζ (BBζ), or CD28-CD3ζ (28ζ) co-stimulatory domains at rest and after activation by triggering their CAR or their endogenous T cell receptor (TCR). We identified a transcriptional signature common across CARs with the CD3ζ signaling domain, as well as a distinct program associated with the 4-1BB co-stimulatory domain at rest and after activation. CAR T cells bearing BBζ had increased expression of human leukocyte antigen (HLA) class II genes, ENPP2, and interleukin (IL)-21 axis genes, and decreased PD1 compared to 28ζ CAR T cells. Similar to previous studies, we also found BBζ CAR CD8 T cells to be enriched in a central memory cell phenotype and fatty acid metabolism genes. Our data uncovered transcriptional signatures related to costimulatory domains and demonstrated that signaling domains included in CARs uniquely shape the transcriptional programs of T cells.

Prescription Pain Reliever Use and Misuse among Cannabis Users Aged 50+ Years.

Objectives: To examine rates and correlates of dual cannabis and prescription pain reliever (PPNR) use and misuse among U.S. individuals aged 50+ who reported past-year cannabis use. Methods: Using the 2015-2018 National Survey of Drug Use and Health, we examined cannabis nonuse/use and PPNR nonuse/use/misuse among all 35,229 respondents, and then focused on 2,632 past-year cannabis users to examine the risk of PPNR use but no misuse and the risk of PPNR misuse, compared to PPNR nonuse. Results: More than one-half of older cannabis users used PPNR in the past year. Multinomial logistic regression results show that the risks of PPNR use/no misuse and PPNR misuse were higher among those who had more chronic medical conditions and a major depressive episode. The risk of PPNR use/no misuse was also associated with high frequency and medical cannabis use. The risk of PPNR misuse was also associated with younger cannabis initiation age and cannabis and other illicit drug use disorders. Conclusions: Correlates of dual cannabis and PPNR use/misuse among older adults are poor physical and mental health problems and problematic cannabis use. Clinical Implications: Older adults with cannabis and PPNR misuse need access to evidence-based treatment, including medication-assisted treatment when needed.