Pre-Clinical Models for CAR T-Cell Therapy for Glioma.

Immunotherapy represents a transformative shift in cancer treatment. Among myriad immune-based approaches, chimeric antigen receptor (CAR) T-cell therapy has shown promising results in treating hematological malignancies. Despite aggressive treatment options, the prognosis for patients with malignant brain tumors remains poor. Research leveraging CAR T-cell therapy for brain tumors has surged in recent years. Pre-clinical models are crucial in evaluating the safety and efficacy of these therapies before they advance to clinical trials. However, current models recapitulate the human tumor environment to varying degrees. Novel in vitro and in vivo techniques offer the opportunity to validate CAR T-cell therapies but also have limitations. By evaluating the strengths and weaknesses of various pre-clinical glioma models, this review aims to provide a roadmap for the development and pre-clinical testing of CAR T-cell therapies for brain tumors.

Cannabis use disorder and substance use treatment among U.S. adults.

INTRODUCTION: Recent expansion of cannabis legalization in multiple states calls for reexamination of the prevalence of cannabis use, cannabis use disorder (CUD), and the associations between CUD severity and substance use treatment. We used Andersen's behavioral model of healthcare use as the conceptual/analytic framework for examining treatment use. METHODS: We used data from the 2022 National Survey on Drug Use and Health (NSDUH; N = 47,100, age 18+) to describe the prevalence of past-year cannabis use, CUD and CUD severity, other substance use disorders, and substance use treatment. We compared sociodemographic, mental health, healthcare use, and cannabis and other substance use characteristics by CUD severity. Finally, we used logistic regression models to examine the associations between CUD severity and substance use treatment. RESULTS: Of the U.S. adult population, 23.0 % used cannabis in the past year; 7.0 % had a CUD (3.9 % mild, 1.9 % moderate, and 1.2 % severe CUD); and 4.7 % received substance use treatment. Of past-year cannabis users, 30.3 % had CUD (16.9 % mild, 8.4 % moderate, and 5.0 % severe CUD), and 9.6 % received substance use treatment. Cannabis users had 3-4 times higher rates of other substance use disorders than nonusers. Of those with CUD, 38.4 % had moderate/severe mental illness, 52.4 % had other substance use disorders, and 16.5 % received substance use treatment. Among all cannabis users, moderate (aOR [adjusted odds ratios] = 1.48, 95 % CI = 1.03-2.13) and severe (aOR = 2.57, 95 % CI = 1.60-4.11) CUDs were associated with greater odds of substance use treatment. Among cannabis users without nicotine dependence and alcohol, opioid, tranquilizer/sedative, and stimulant use disorders, only severe CUD (aOR = 6.03, 95 % CI = 3.37-10.78) was associated with greater odds of substance use treatment. CONCLUSIONS: This study shows increased prevalence of cannabis use and CUD among U.S. adults, and with or without other substance use disorders, CUD was associated with greater odds of substance use treatment. However, the overall low rate of treatment use among those with CUD is concerning. Healthcare providers need to provide education for both medical and recreational users on the development of tolerance and dependence. Harm reduction strategies to minimize the negative consequences of CUD are also needed.

Associations between Cannabis Consumption Methods and Cannabis Risk Perception.

Given diversified cannabis products, we examined associations between cannabis consumption methods and cannabis risk perception of smoking cannabis 1-2 times a week. Using the 2022 U.S. National Survey on Drug Use and Health data (N = 12,796 past-year adult cannabis users; M = 6127 and F = 6669), we used multinomial and binary logistic regression models. Smoking was the most prevalent method, followed by eating/drinking, vaping, and dabbing. One-half of cannabis users reported no perceived risk of smoking cannabis 1-2 times a week, 37.5% perceived slight risk, 9.2% moderate risk, and 2.9% great risk. Those with moderate or great risk perception had a lower likelihood of using 4+ methods of consumption (e.g., RRR = 0.40, 95% CI = 0.20, 0.77 for great risk perception). Any perceived risk was associated with higher odds of edibles/drinks only (e.g., aOR = 2.81, 95% CI = 1.43, 5.54 for great risk perception). Along with medical use and CUD, sociodemographic factors, mental illness, and other substance use were also significant correlates of cannabis consumption methods. Understanding the varying risk perceptions associated with different consumption methods is needed for harm reduction initiatives. More research is needed on cannabis products, particularly edibles/drinks and dabs/concentrates, to better understand the potential risks associated with them.

Perceived Risk of Binge Drinking among Older Alcohol Users: Associations with Alcohol Use Frequency, Binge Drinking, Alcohol Use Disorder, and Alcohol Treatment Use.

Despite the high prevalence of alcohol use and binge drinking among older adults, little research has been conducted on the association between their alcohol risk perception and alcohol use patterns. Using data on past-year alcohol users aged 50 and older (N = 6693) in the 2022 National Survey on Drug Use and Health, we examined the (1) associations between risk perception of binge alcohol use 1-2 times a week and alcohol use frequency, binge use frequency, and alcohol use disorder (AUD), and (2) the association between alcohol treatment use and risk perception. About 40% of past-year alcohol users perceived great risk of binge alcohol use 1-2 times a week, and 27% of past-year users had binge drinking in the past month. Multivariable analyses showed the negative association between great risk perception and alcohol use frequency (IRR = 0.60, 95%CI = 0.48-0.74 for daily use) and past-month binge alcohol use (IRR = 0.33, 95%CI = 0.19-0.57 for 6-19 days of binge use). The odds of great risk perception were also lower among those with mild AUD. Risk perception was not significantly associated with alcohol treatment. The lower likelihood of risk perception among problematic alcohol users and low treatment use is concerning. Education and interventions to reduce harm from alcohol are needed.

Mutant IDH Modulates Suppressive Myeloid Populations in Malignant Glioma.

PURPOSE: Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 have critical diagnostic and prognostic significance in diffuse gliomas. Neomorphic mutant IDH activity has been previously implicated in T-cell suppression; however, the effects of IDH mutations on intratumoral myeloid populations remain underexplored. In this study, we investigate the influence of IDH status on the myeloid compartment using human glioma specimens and preclinical models. EXPERIMENTAL DESIGN: We performed RNA sequencing and quantitative immunofluorescence on newly diagnosed, treatment-naive IDH-mutant grade 4 astrocytoma and IDH-wild-type (IDH-WT) glioblastoma (GBM) specimens. We also generated a syngeneic murine model, comparing transcriptomic and cell-level changes in paired isogenic glioma lines that differ only in IDH mutational status. RESULTS: Among patient samples, IDH-mutant tumors displayed an underrepresentation of suppressive myeloid transcriptional signatures, which was confirmed at the cellular level with decreased numbers of intratumoral M2-like macrophages and myeloid-derived suppressor cells. Introduction of the mutant IDH enzyme into murine glioma was sufficient to recapitulate the transcriptomic and cellular shifts observed in patient samples. CONCLUSIONS: We provide transcriptomic and cellular evidence that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model. These data advance our understanding of high-grade gliomas by identifying key myeloid cell populations that are reprogrammed by mutant IDH and may be targetable through therapeutic approaches.

Navigated Intraoperative Ultrasound Offers Effective and Efficient Real-Time Analysis of Intracranial Tumor Resection and Brain Shift.

BACKGROUND AND OBJECTIVES: Neuronavigation is a fundamental tool in the resection of intracranial tumors. However, it is limited by its calibration to preoperative neuroimaging, which loses accuracy intraoperatively after brain shift. Therefore, surgeons rely on anatomic landmarks or tools like intraoperative MRI to assess the extent of tumor resection (EOR) and update neuronavigation. Recent studies demonstrate that intraoperative ultrasound (iUS) provides point-of-care imaging without the cost or resource utilization of an intraoperative MRI, and advances in neuronavigation-guided iUS provide an opportunity for real-time imaging overlaid with neuronavigation to account for brain shift. We assessed the feasibility, efficacy, and benefits of navigated iUS to assess the EOR and restore stereotactic accuracy in neuronavigation after brain shift. METHODS: This prospective single-center study included patients presenting with intracranial tumors (gliomas, metastasis) to an academic medical center. Navigated iUS images were acquired preresection, midresection, and postresection. The EOR was determined by the surgeon intraoperatively and compared with the postoperative MRI report by an independent neuroradiologist. Outcome measures included time to perform the iUS sweep, time to process ultrasound images, and EOR predicted by the surgeon intraoperatively compared with the postoperative MRI. RESULTS: This study included 40 patients consisting of gliomas (n = 18 high-grade gliomas, n = 4 low-grade gliomas, n = 4 recurrent) and metastasis (n = 18). Navigated ultrasound sweeps were performed in all patients (n = 83) with a median time to perform of 5.5 seconds and a median image processing time of 29.9 seconds. There was 95% concordance between the surgeon's and neuroradiologist's determination of EOR using navigated iUS and postoperative MRI, respectively. The sensitivity was 100%, and the specificity was 94%. CONCLUSION: Navigated iUS was successfully used for EOR determination in glioma and metastasis resection. Incorporating navigated iUS into the surgical workflow is safe and efficient and provides a real-time assessment of EOR while accounting for brain shift in intracranial tumor surgeries.

Regulatory systems and requirements for clinical trials of AAV-based gene therapies - Perspectives from six Asian countries or regions: Report from the 6th Asia Partnership Conference of Regenerative Medicine - April 20, 2023.

Gene therapies, which include viral-vector gene delivery, genome editing, and genetically modified cell therapy, are innovative treatments with the potential to address the underlying genetic causes of disorders and to provide life-changing value in terms of curing disease. Although adeno-associated virus (AAV)-based gene therapy is one of the most advanced types of gene therapy, far fewer AAV-based gene therapy studies have been conducted in Asia than in North America and Europe. The 6th Asia Partnership Conference of Regenerative Medicine (APACRM) was held on April 20, 2023 in Tokyo, Japan. APACRM Working Group 3 comprehensively analyzed the regulatory processes that occur prior to the initiation of clinical trials as well as the regulatory requirements for AAV-based gene therapies for six Asian countries or regions (China, India, Japan, Singapore, South Korea, and Taiwan). In this article, we report the outcomes of this conference, summarizing the regulatory requirements for initiating clinical trials for AAV-based gene therapies in terms of the laws, regulations, and guidelines for gene therapy; consultations or reviews required by the health authorities; points to consider for scientific reviews by the health authorities; and specific challenges to address when developing gene therapy products in these locations. Finally, we present several policy recommendations, including simplifying the regulatory review system for multiple scientific review areas; simplifying the regulatory consultation system; and providing training programs and regulatory guidance to support the advancement of gene therapy development in Asia.

Altered cancer metabolism and implications for next-generation CAR T-cell therapies.

This review critically examines the evolving landscape of chimeric antigen receptor (CAR) T-cell therapy in treating solid tumors, with a particular focus on the metabolic challenges within the tumor microenvironment. CAR T-cell therapy has demonstrated remarkable success in hematologic malignancies, yet its efficacy in solid tumors remains limited. A significant barrier is the hostile milieu of the tumor microenvironment, which impairs CAR T-cell survival and function. This review delves into the metabolic adaptations of cancer cells and their impact on immune cells, highlighting the competition for nutrients and the accumulation of immunosuppressive metabolites. It also explores emerging strategies to enhance CAR T-cell metabolic fitness and persistence, including genetic engineering and metabolic reprogramming. An integrated approach, combining metabolic interventions with CAR T-cell therapy, has the potential to overcome these constraints and improve therapeutic outcomes in solid tumors.

Intentional benzodiazepine poisoning in older adults reported to United States Poison Centers.

INTRODUCTION: Despite known contraindications, benzodiazepines are frequently prescribed for older adults. This study utilizes poison control center data on benzodiazepine-involved cases aged 50 and above to compare the characteristics of suspected suicide attempt with other intentional misuse cases. We also examined associations of major medical outcomes (major effect/death) with demographic characteristics and other co-used substances in each group. METHODS: The study employed data from the America's Poison Center National Poison Data System from 2015-2022. Descriptive statistics and binary logistic regression models were used. RESULTS: Of the benzodiazepine-poisoning cases of intentional misuse (n = 93,245), 85 percent were suicide attempts and 15 percent were other intentional misuses. Reports to poisons centers showed a decline from 2019-2022 when compared to 2015-2016. However, the likelihood of a reported suicide attempt, compared to other intentional misuse, was greater in 2019-2022 compared to 2015-2016 and among those who co-used antidepressants, anxiolytics, atypical antipsychotics, other benzodiazepines, other analgesics, anticonvulsants, and alcohol. The odds of major effect/death in both groups were also greater in 2019-2022, with suicide attempt cases in advanced ages showing higher odds. The co-use of antidepressants, prescription opioids, atypical antipsychotics, anticonvulsants, and other analgesics were associated with a higher likelihood of major effect/death in both exposure groups. For instance, adjusted odds ratios for co-used prescription opioids were 2.20 (95 percent confidence intervals: 2.09-2.31) among suicide attempt cases and 3.51 (95 percent confidence intervals: 3.10-3.97) among other intentional misuse cases. DISCUSSION: Healthcare providers need to screen for suicidal ideation among benzodiazepine users, with special attention to an increased risk of suicide attempt among those who co-use antidepressants and opioids and to decreasing adverse outcomes in all misuse cases. Assessments of underlying mental health and substance use problems and medication regimens to minimize polypharmacy and drug interactions are needed to reduce adverse outcomes. CONCLUSIONS: Though the numbers of benzodiazepine-involved suicide attempt and other intentional misuse cases reported to United States poison centers decreased in recent years, the likelihood of major medical effect/death among these cases have increased.

Radical surgical resection with molecular margins is associated with improved survival in IDH wild-type glioblastoma.

BACKGROUND: Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of postsurgical progressive events are failures within 2 cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown. METHODS: We developed a predictive model to identify which IDH wild-type GBMs are amenable to radiographic gross-total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation. RESULTS: Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an area under the curve of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found that 89% of patients were correctly predicted to achieve a residual volume (RV) < 4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a GTR (RV < 1cc). In these 5 patients at 30 months follow-up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (P = .02). CONCLUSIONS: These findings identify a subset of patients with GBM that may derive local control benefits from radical resection to undetectable molecular margins.

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.

Mediation of the Association Between Physical Exercise and Depressive/Anxiety Symptoms by Pain and Sleep Problems Among Older Adults.

In this study, based on the 2022 National Health and Aging Trend Study (N = 5,593, age 65+), we examined direct associations between moderate and vigorous physical exercise (PE) and depressive/anxiety symptoms as well as bothersome pain and sleep problems. We then examined if the association between PE and depressive/anxiety symptoms would be partially mediated by the effects of PE on bothersome pain and sleep problems. Results from a path model showed that controlling for sociodemographic and health statuses, PE was negatively associated with depressive/anxiety symptoms and bothersome pain, but it was not significantly associated with sleep problems. The mediation analysis showed that 10% of the total effects of PE on depressive/anxiety symptoms was indirect effects of PE on bothersome pain. This study is important as it examined the associations among PE, pain, sleep, and depression/anxiety in community-dwelling older adults in their natural environments. Healthcare and social service providers for older adults need to emphasize the importance and benefits of PE for older adults' physical and mental health. Easy access to venues for PE is also important.

Challenges in Global Access to CAR-T cells: an Asian Perspective.

The use of cell therapy for clinical applications has seen a dramatic increase in recent years, primarily in oncology, especially with the use of chimeric antigen receptor (CAR) T-cell therapies. However, there are some barriers to the widespread adoption of CAR-T cell therapies globally, primarily because of the high cost of manufacturing these cells and clinical infrastructure considerations. We reviewed the different strategies adopted across Asia to implement CAR-T cell therapy and found that these included patient assistance programs, close engagement with funders, cost-effectiveness studies, on-site manufacturing of CAR-T cells, and joint ventures between local partners and foreign pharmaceutical companies. Although on-site manufacturing can reduce the cost of genetic engineering and expansion, it does not address many other hidden costs and quality considerations. Future growth in large-scale regional manufacturing, facilitated by cutting-edge science and innovation, could reduce costs through economies of scale and facilitate the eagerly needed global access.

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.).

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.

Fluorescence and immune-cell infiltration of nonneoplastic, postbrachytherapy brain tissue in 5-ALA-guided resection of recurrent anaplastic meningioma: illustrative case.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) fluorescence-guided surgery is a well-established technique for resecting high-grade gliomas. However, its application in meningiomas, especially those previously treated with radiation therapy, remains under investigation. OBSERVATIONS: A 48-year-old female with recurrent anaplastic meningioma, World Health Organization grade 3, underwent a right-sided craniotomy using off-label 5-ALA as a surgical adjunct. The patient had previously undergone brachytherapy seed implantation (20 × cesium 131) for tumor management. During the surgery, a large fluorescent tumor mass adjacent to the brachytherapy-treated area was resected, and the prior brachytherapy seeds were removed. Interestingly, the surrounding brain tissue in the irradiated area showed robust 5-ALA fluorescence. Pathological examination confirmed that the fluorescent brain tissue was nonneoplastic and associated with lymphocyte and macrophage infiltration. LESSONS: This case report presents unique 5-ALA fluorescence in nonneoplastic tissue following brachytherapy, which was found during the resection of recurrent anaplastic meningioma. This phenomenon may reflect an intricate interplay among radiation therapy, immune cells, the tumor microenvironment, and 5-ALA metabolism. Given that false-positive findings in fluorescence-guided surgery can lead to unnecessary tissue resection and increased surgical morbidity, further research is warranted to elucidate the mechanisms underlying this phenomenon and its implications for meningioma surgery.

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.

Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population.

Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications. SIGNIFICANCE: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897.