Publications by authors named "John Sampson"

320 Publications

Designing Clinical Trials for Combination Immunotherapy: A Framework for Glioblastoma.

Clin Cancer Res 2021 Sep 24. Epub 2021 Sep 24.

Duke University Medical Center, Duke University

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both pre-clinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2681DOI Listing
September 2021

Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement.

Clin Cancer Res 2021 Sep 24. Epub 2021 Sep 24.

Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as "recruiting" or "not yet recruiting" as of February 2021.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2750DOI Listing
September 2021

Monitoring work and training load in military settings - what's in the toolbox?

Eur J Sport Sci 2021 Sep 21:1-14. Epub 2021 Sep 21.

Land Division, Defence Science and Technology Group, Melbourne, Australia.

Military personnel are required to complete physically demanding tasks when performing work and training, which may be quantified through the physical stress imposed (external load) or the resultant physiological strain (internal load). The aim of this narrative review is to provide an overview of the techniques used to monitor work and training load in military settings, summarise key findings, and discuss important practical, analytical, and conceptual considerations. Most investigations have focused upon measuring external and internal load in military training environments; however, limited data exist in operational settings. Accelerometry has been the primary tool used to estimate external load, with heart rate commonly used to quantify internal load. Supplemental to heart rate, psychophysiological and biochemical measures have also been investigated to elucidate aspects of internal load. Broadly, investigations have revealed that military training requires personnel to perform relatively large volumes of physical activity (e.g. averaging ∼15,000 steps·day) of typically low-moderate intensity activity (<6 MET), although considerable temporal and inter-individual variability is observed from these gross mean estimates. There are limitations associated with these measures and, at best, estimates of external and internal load can only be inferred. These limitations are particularly pertinent for military tasks such as load carriage and manual material handling, which often involve complex activities performed individually or in teams, in a range of operational environments, with multiple layers of protection, over a protracted duration. Comprehensively quantifying external and internal loads during these functional activities poses substantial practical and analytical challenges.
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http://dx.doi.org/10.1080/17461391.2021.1971774DOI Listing
September 2021

Association of Vasopressor Choice with Clinical and Functional Outcomes Following Moderate to Severe Traumatic Brain Injury: A TRACK-TBI Study.

Neurocrit Care 2021 Aug 2. Epub 2021 Aug 2.

Critical Care and Perioperative Population Health Research Unit, Department of Anesthesiology, Duke University, Durham, NC, USA.

Background: Early hypotension following moderate to severe traumatic brain injury (TBI) is associated with increased mortality and poor long-term outcomes. Current guidelines suggest the use of intravenous vasopressors to support blood pressure following TBI; however, guidelines do not specify vasopressor type, resulting in variation in clinical practice. Minimal data are available to guide clinicians on optimal early vasopressor choice to support blood pressure following TBI. Therefore, we conducted a multicenter study to examine initial vasopressor choice for the support of blood pressure following TBI and its association with clinical and functional outcomes after injury.

Methods: We conducted a retrospective cohort study of patients enrolled in the transforming research and clinical knowledge in traumatic brain injury (TRACK-TBI) study, an 18-center prospective cohort study of patients with TBI evaluated in participating level I trauma centers. We examined adults with moderate to severe TBI (defined as Glasgow Coma Scale score < 13) who were admitted to the intensive care unit and received an intravenous vasopressor within 48 h of admission. The primary exposure was initial vasopressor choice (phenylephrine versus norepinephrine), and the primary outcome was 6-month Glasgow Outcomes Scale Extended (GOSE), with the following secondary outcomes: length of hospital stay, length of intensive care unit stay, in-hospital mortality, new requirement for dialysis, and 6-month Disability Rating Scale. Regression analysis was used to assess differences in outcomes between patients exposed to norepinephrine versus phenylephrine, with propensity weighting to address selection bias due to the nonrandom allocation of the treatment groups and patient dropout.

Results: The final study sample included 156 patients, of whom 79 (51%) received norepinephrine, 69 (44%) received phenylephrine, and 8 (5%) received an alternate drug as their initial vasopressor. 121 (77%) of patients were men, with a mean age of 43.1 years. Of patients receiving norepinephrine as their initial vasopressor, 32% had a favorable outcome (GOSE 5-8), whereas 40% of patients receiving phenylephrine as their initial vasopressor had a favorable outcome. Compared with phenylephrine, exposure to norepinephrine was not significantly associated with improved 6-month GOSE (weighted odds ratio 1.40, 95% confidence interval 0.66-2.96, p = 0.37) or any secondary outcome.

Conclusions: The majority of patients with moderate to severe TBI received either phenylephrine or norepinephrine as first-line agents for blood pressure support following brain injury. Initial choice of norepinephrine, compared with phenylephrine, was not associated with improved clinical or functional outcomes.
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http://dx.doi.org/10.1007/s12028-021-01280-7DOI Listing
August 2021

Targeting Immunometabolism in Glioblastoma.

Front Oncol 2021 16;11:696402. Epub 2021 Jun 16.

Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States.

We have only recently begun to understand how cancer metabolism affects antitumor responses and immunotherapy outcomes. Certain immunometabolic targets have been actively pursued in other tumor types, however, glioblastoma research has been slow to exploit the therapeutic vulnerabilities of immunometabolism. In this review, we highlight the pathways that are most relevant to glioblastoma and focus on how these immunometabolic pathways influence tumor growth and immune suppression. We discuss hypoxia, glycolysis, tryptophan metabolism, arginine metabolism, 2-Hydroxyglutarate (2HG) metabolism, adenosine metabolism, and altered phospholipid metabolism, in order to provide an analysis and overview of the field of glioblastoma immunometabolism.
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http://dx.doi.org/10.3389/fonc.2021.696402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242259PMC
June 2021

The Association Between Alterations in Redox Homeostasis, Cortisol, and Commonly Used Objective and Subjective Markers of Fatigue in American Collegiate Football.

Int J Sports Physiol Perform 2021 May 29:1-7. Epub 2021 May 29.

Purpose: To assess associations between a free oxygen radical test (FORT), free oxygen radical defense test (FORD), oxidative stress index, urinary cortisol, countermovement jump (CMJ), and subjective wellness in American college football.

Methods: Twenty-three male student athlete American college football players were assessed over 10 weeks: off-season conditioning (3 wk), preseason camp (4 wk), and in season (3 wk). Assessments included a once-weekly FORT and FORD blood sample, urinary cortisol sample, CMJ assessment including flight time, reactive strength index modified and concentric impulse, and a daily subjective wellness questionnaire. Linear mixed models analyzed the effect of a 2 within-subject SD change in the predictor variable on the dependent variable. The effects were interpreted using magnitude-based inference and are presented as standardized effect size (ES) ± 90% confidence intervals.

Results: Small negative associations were observed between FORT-flight time, FORT-fatigue, FORT-soreness (ES range = -0.30 to -0.48), FORD-sleep (ES = 0.42 ± 0.29), and oxidative stress index soreness (ES = 0.56 ± 0.29). Small positive associations were observed between FORT-cortisol (ES = 0.36 ± 0.35), FORD-flight time, FORD reactive strength index modified and FORD-soreness (0.37-0.41), oxidative stress index concentric impulse (ES = 0.37 ± 0.28), and with soreness-concentric impulse, soreness-flight time, and soreness reactive strength index modified (0.33-0.59). Moderate positive associations were observed between cortisol-concentric impulse and cortisol-sleep (0.57-0.60).

Conclusion: FORT/FORD was associated with CMJ variables and subjective wellness. Greater amounts of subjective soreness were associated with decreased CMJ performance, increased FORT and cortisol, and decreased FORD.
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http://dx.doi.org/10.1123/ijspp.2020-0933DOI Listing
May 2021

Association of Early Multiple Organ Dysfunction With Clinical and Functional Outcomes Over the Year Following Traumatic Brain Injury: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Study.

Crit Care Med 2021 10;49(10):1769-1778

Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA.

Objectives: Traumatic brain injury is a leading cause of death and disability in the United States. While the impact of early multiple organ dysfunction syndrome has been studied in many critical care paradigms, the clinical impact of early multiple organ dysfunction syndrome in traumatic brain injury is poorly understood. We examined the incidence and impact of early multiple organ dysfunction syndrome on clinical, functional, and disability outcomes over the year following traumatic brain injury.

Design: Retrospective cohort study.

Setting: Patients enrolled in the Transforming Clinical Research and Knowledge in Traumatic Brain Injury study, an 18-center prospective cohort study of traumatic brain injury patients evaluated in participating level 1 trauma centers.

Subjects: Adult (age > 17 yr) patients with moderate-severe traumatic brain injury (Glasgow Coma Scale < 13). We excluded patients with major extracranial injury (Abbreviated Injury Scale score ≥ 3).

Interventions: Development of early multiple organ dysfunction syndrome, defined as a maximum modified Sequential Organ Failure Assessment score greater than 7 during the initial 72 hours following admission.

Measurements And Main Results: The main outcomes were: hospital mortality, length of stay, 6-month functional and disability domains (Glasgow Outcome Scale-Extended and Disability Rating Scale), and 1-year mortality. Secondary outcomes included: ICU length of stay, 3-month Glasgow Outcome Scale-Extended, 3-month Disability Rating Scale, 1-year Glasgow Outcome Scale-Extended, and 1-year Disability Rating Scale. We examined 373 subjects with moderate-severe traumatic brain injury. The mean (sd) Glasgow Coma Scale in the emergency department was 5.8 (3.2), with 280 subjects (75%) classified as severe traumatic brain injury (Glasgow Coma Scale 3-8). Among subjects with moderate-severe traumatic brain injury, 252 (68%) developed early multiple organ dysfunction syndrome. Subjects that developed early multiple organ dysfunction syndrome had a 75% decreased odds of a favorable outcome (Glasgow Outcome Scale-Extended 5-8) at 6 months (adjusted odds ratio, 0.25; 95% CI, 0.12-0.51) and increased disability (higher Disability Rating Scale score) at 6 months (adjusted mean difference, 2.04; 95% CI, 0.92-3.17). Subjects that developed early multiple organ dysfunction syndrome experienced an increased hospital length of stay (adjusted mean difference, 11.4 d; 95% CI, 7.1-15.8), with a nonsignificantly decreased survival to hospital discharge (odds ratio, 0.47; 95% CI, 0.18-1.2).

Conclusions: Early multiple organ dysfunction following moderate-severe traumatic brain injury is common and independently impacts multiple domains (mortality, function, and disability) over the year following injury. Further research is necessary to understand underlying mechanisms, improve early recognition, and optimize management strategies.
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http://dx.doi.org/10.1097/CCM.0000000000005055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448900PMC
October 2021

Modified RANO, Immunotherapy RANO, and Standard RANO Response to Convection-Enhanced Delivery of IL4R-Targeted Immunotoxin MDNA55 in Recurrent Glioblastoma.

Clin Cancer Res 2021 Jul 16;27(14):3916-3925. Epub 2021 Apr 16.

Medicenna BioPharma, Houston, Texas.

Purpose: The current study compared the standard response assessment in neuro-oncology (RANO), immunotherapy RANO (iRANO), and modified RANO (mRANO) criteria as well as quantified the association between progression-free (PFS) and overall survival (OS) in an immunotherapy trial in recurrent glioblastoma (rGBM).

Patients And Methods: A total of 47 patients with rGBM were enrolled in a prospective phase II convection-enhanced delivery of an IL4R-targeted immunotoxin (MDNA55-05, NCT02858895). Bidirectional tumor measurements were created by local sites and centrally by an independent radiologic faculty, then standard RANO, iRANO, and mRANO criteria were applied.

Results: A total of 41 of 47 patients (mean age 56 ± 11.7) were evaluable for response. PFS was significantly shorter using standard RANO compared with iRANO (log-rank, < 0.0001; = 0.3) and mRANO ( < 0.0001; = 0.3). In patients who died and had confirmed progression on standard RANO, no correlation was observed between PFS and OS (local, = 0.47; central, = 0.34). Using iRANO, a weak association was observed between confirmed PFS and OS via local site measurements ( = 0.017), but not central measurements ( = 0.18). A total of 24 of 41 patients (59%) were censored using iRANO and because they lacked confirmation of progression 3 months after initial progression. A strong correlation was observed between mRANO PFS and OS for both local ( = 0.66, < 0.0001) and centrally determined reads ( = 0.57, = 0.0007).

Conclusions: No correlation between radiographic PFS and OS was observed for standard RANO or iRANO, but a correlation was observed between PFS and OS using the mRANO criteria. Also, the iRANO criteria was difficult to implement due to need to confirm progression 3 months after initial progression, censoring more than half the patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282697PMC
July 2021

Evaluating Rapid-cycle Deliberate Practice Versus Mastery Learning in Training Nurse Anesthetists on the Universal Anaesthesia Machine Ventilator in Sierra Leone.

J Educ Perioper Med 2021 Jan-Mar;23(1):E658. Epub 2021 Jan 1.

Background: Underserved sub-Saharan countries have 0.1 to 1.4 anesthesia providers per 100 000 citizens, below the Lancet Commission's target of 20 per 100 000 needed for safe surgery. Most of these anesthesia providers are nurse anesthetists, with anesthesiologists numbering as few as zero in some nations and 2 per 7 million in others, such as Sierra Leone. In this study, we compared 2 simulation-based techniques for training nurse anesthetists on the Universal Anaesthesia Machine Ventilator-rapid-cycle deliberate practice and mastery learning.

Methods: A 2-week Universal Anaesthesia Machine Ventilator course was administered to 17 participants in Sierra Leone. Seven were randomized to the rapid-cycle deliberate practice group and 10 to the mastery learning group. Participants underwent baseline and posttraining evaluations in 3 scenarios: general anesthesia, intraoperative power failure, and postoperative pulmonary edema. Performance was analyzed based on checklist performance scores and the number of times participants were stopped for a mistake. Statistical significance to 0.05 was determined with the Mann-Whitney Test.

Results: Checklist performance scores did not differ significantly between the 2 groups. When the groups were combined, simulation-based training resulted in a statistically significant improvement in performance. The highest-frequency problem areas were preoxygenation, switching from spontaneous to mechanical ventilation, and executing appropriate treatment interventions for a postoperative emergency.

Conclusion: Both rapid-cycle deliberate practice and mastery learning are effective methods for simulation-based training to improve nurse anesthetist performance with the Universal Anaesthesia Machine Ventilator in 3 separate scenarios. The data did not indicate any difference between these methods; however, a larger sample size may support or refute our findings.
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http://dx.doi.org/10.46374/volxxiii_issue1_sampsonDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983184PMC
January 2021

A conjoined universal helper epitope can unveil antitumor effects of a neoantigen vaccine targeting an MHC class I-restricted neoepitope.

NPJ Vaccines 2021 Jan 18;6(1):12. Epub 2021 Jan 18.

Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

Personalized cancer vaccines targeting neoantigens arising from somatic missense mutations are currently being evaluated for the treatment of various cancers due to their potential to elicit a multivalent, tumor-specific immune response. Several cancers express a low number of neoantigens; in these cases, ensuring the immunotherapeutic potential of each neoantigen-derived epitope (neoepitope) is crucial. In this study, we discovered that therapeutic vaccines targeting immunodominant major histocompatibility complex (MHC) I-restricted neoepitopes require a conjoined helper epitope in order to induce a cytotoxic, neoepitope-specific CD8+ T-cell response. Furthermore, we show that the universally immunogenic helper epitope P30 can fulfill this requisite helper function. Remarkably, conjoined P30 was able to unveil immune and antitumor responses to subdominant MHC I-restricted neoepitopes that were, otherwise, poorly immunogenic. Together, these data provide key insights into effective neoantigen vaccine design and demonstrate a translatable strategy using a universal helper epitope that can improve therapeutic responses to MHC I-restricted neoepitopes.
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http://dx.doi.org/10.1038/s41541-020-00273-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814002PMC
January 2021

Association of Severe Acute Kidney Injury with Mortality and Healthcare Utilization Following Isolated Traumatic Brain Injury.

Neurocrit Care 2021 Jan 13. Epub 2021 Jan 13.

Duke University Medical Center, Department of Anesthesiology, DUMC 3094, Duke University, Durham, NC, 27710, USA.

Background/objective: Traumatic brain injury (TBI) is a leading cause of morbidity, mortality, and disability in the USA. While cardiopulmonary dysfunction can result in poor outcomes following severe TBI, the impact of acute kidney injury (AKI) is poorly understood. We examined the association of severe AKI with hospital mortality and healthcare utilization following isolate severe TBI.

Methods: We conducted a retrospective cohort study using the National Trauma Data Bank from 2007 to 2014. We identified a cohort of adult patients with isolated severe TBI and described the incidence of severe AKI, corresponding to Acute Kidney Injury Network stage 3 disease or greater. We examined the association of severe AKI with the primary outcome of hospital mortality using multivariable logistic regression models. In secondary analyses, we examined the association of severe AKI with dialysis catheter placement, tracheostomy and gastrostomy utilization, and hospital length of stay.

Results: There were 37,851 patients who experienced isolated severe TBI during the study period. Among these patients, 787 (2.1%) experienced severe (Stage 3 or greater) AKI. In multivariable models, the development of severe AKI in the hospital was associated with in-hospital mortality (OR 2.03, 95% CI 1.64-2.52), need for tracheostomy (OR 2.10, 95% CI 1.52-2.89), PEG tube placement (OR 1.88, 95% CI 1.45-2.45), and increased hospital length of stay (p < 0.001).

Conclusions: The overall incidence of severe AKI is relatively low (2.1%), but is associated with increased mortality and multiple markers of increased healthcare utilization following severe TBI.
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http://dx.doi.org/10.1007/s12028-020-01183-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275693PMC
January 2021

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

Nat Commun 2021 01 13;12(1):352. Epub 2021 Jan 13.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, 27710, USA.

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
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http://dx.doi.org/10.1038/s41467-020-20469-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806846PMC
January 2021

The 11+ of the future: a primary injury prevention framework for sub-elite football.

Br J Sports Med 2020 Oct 15. Epub 2020 Oct 15.

Centre of Medical and Exercise Physiology, School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia.

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http://dx.doi.org/10.1136/bjsports-2020-102788DOI Listing
October 2020

Determinants of Intraparenchymal Infusion Distributions: Modeling and Analyses of Human Glioblastoma Trials.

Pharmaceutics 2020 Sep 21;12(9). Epub 2020 Sep 21.

Department of Neurosurgery, Duke University, Durham, NC 27710, USA.

Intra-parenchymal injection and delivery of therapeutic agents have been used in clinical trials for brain cancer and other neurodegenerative diseases. The complexity of transport pathways in tissue makes it difficult to envision therapeutic agent distribution from clinical MR images. Computer-assisted planning has been proposed to mitigate risk for inadequate delivery through quantitative understanding of infusion characteristics. We present results from human studies and simulations of intratumoral infusions of immunotoxins in glioblastoma patients. Gd-DTPA and I-labeled human serum albumin (I-HSA) were co-infused with the therapeutic, and their distributions measured in MRI and PET. Simulations were created by modeling tissue fluid mechanics and physiology and suggested that reduced distribution of tracer molecules within tumor is primarily related to elevated loss rates computed from DCE. PET-tracer on the other hand shows that the larger albumin molecule had longer but heterogeneous residence times within the tumor. We found over two orders of magnitude variation in distribution volumes for the same infusion volumes, with relative error ~20%, allowing understanding of even anomalous infusions. Modeling and measurement revealed that key determinants of flow include infusion-induced expansion and loss through compromised BBB. Opportunities are described to improve computer-assisted CED through iterative feedback between simulations and imaging.
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http://dx.doi.org/10.3390/pharmaceutics12090895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559135PMC
September 2020

Checkpoint inhibitor immunotherapy for glioblastoma: current progress, challenges and future outlook.

Expert Rev Clin Pharmacol 2020 Oct 11;13(10):1147-1158. Epub 2020 Sep 11.

Department of Neurosurgery, Duke University Medical Center , Durham, NC, USA.

Introduction: Despite maximal surgical resection and chemoradiation, glioblastoma (GBM) continues to be associated with significant morbidity and mortality. Novel therapeutic strategies are urgently needed. Given success in treating multiple other forms of cancer, checkpoint inhibitor immunotherapy remains foremost amongst novel therapeutic strategies that are currently under investigation.

Areas Covered: Through a systematic review of both published literature and the latest preliminary data available from ongoing clinical studies, we provide an up-to-date discussion on the immune system in the CNS, a detailed mechanistic evaluation of checkpoint biology in the CNS along with evidence for disruption of these pathways in GBM, and a summary of available preclinical and clinical data for checkpoint blockade in GBM. We also include a discussion of novel, emerging targets for checkpoint blockade which may play an important role in GBM immunotherapy.

Expert Opinion: Evidence indicates that while clinical success of checkpoint blockade for the treatment of GBM has been limited to date, through improved preclinical models, optimization in the context of standard of care therapies, assay standardization and harmonization, and combinatorial approaches which may include novel targets for checkpoint blockade, checkpoint inhibitor immunotherapy may yield a safe and effective therapeutic option for the treatment of GBM.
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http://dx.doi.org/10.1080/17512433.2020.1817737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658017PMC
October 2020

Temozolomide treatment outcomes and immunotherapy efficacy in brain tumor.

J Neurooncol 2021 Jan 19;151(1):55-62. Epub 2020 Aug 19.

Duke University, Durham, NC, USA.

Introduction: Glioblastoma (GBM) has a survival rate of around 2 years with aggressive current standard of care. While other tumors have responded favorably to trials combining immunotherapy and chemotherapy, GBM remains uniformly deadly with minimal increases in overall survival. GBM differ from others due to being isolated behind the blood brain barrier, increased heterogeneity and mutational burden, and immunosuppression from the brain environment and tumor itself.

Methods: We have reviewed clinical and preclinical studies investigating how different doses (dose intense (DI) and metronomic) and timing of immunotherapy following TMZ treatment can eradicate tumor cells, alter tumor mutational burden, and change immune cells.

Results: Recent clinical trials with standard of care (SoC), DI and metronomic TMZ regimes are no able to completely eradicate GBM. Elevated TMZ levels in DI treatment can overcome MGMT resistance but may result in hypermutation of surviving tumor cells. Higher levels of TMZ will also generate a higher degree of lymphopenia compared to SoC and metronomic regimes in preclinical studies.

Conclusion: The different levels of lymphopenia and tumor eradication discussed in this review suggest possible beneficial pairings between immunotherapy and TMZ treatment. Treatments resulting in profound lymphopenia will allow for expansion of vaccine specific T cells or of CAT T cells. Clinical and preclinical studies are currently comparing different combinations of TMZ and immunotherapy timing to treat GBM through a balance between tumor killing and immune cell expansion. More frequent immune monitoring time points in ongoing clinical trials are crucial for further development of these combinations.
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http://dx.doi.org/10.1007/s11060-020-03598-2DOI Listing
January 2021

A pilot study using a small-sided games program to modify cardiovascular health in sedentary Indigenous men.

Health Promot J Austr 2021 Oct 14;32 Suppl 2:72-77. Epub 2020 Sep 14.

Centre of Medical and Exercise Physiology, School of Medicine, University of Wollongong, Wollongong, NSW, Australia.

Issues Addressed: To determine cardiovascular health benefits in Indigenous men following short-duration small-sided games.

Methods: Fourteen sedentary Indigenous males (35.6 SD 7.2 years), randomly assigned to a small-sided games (SSG) or a non-exercising control. Small-sided 20-minute (4 × 5 minute bouts) games of touch football were played 2 x/week for 9 weeks. Waist and hip circumferences, height, total body mass (kg), fat (%), fat free mass (kg), muscle mass (kg), resting heart rate (bpm), systolic blood pressure (mmHg), total cholesterol and high-density lipid concentrations were measured and waist-hip ratios, body mass index (BMI), heart rate variability (HRV), metabolic age and Framingham risk calculated before and after the exercise intervention. Between group differences were examined using unpaired t tests (welch corrected) and described using Cohen's effect size (ES) differences (corrected to determine hedges g).

Results: Significant between group differences favouring the SSG group were observed in body mass (P = .039, ES = 0.18), BMI (P = .031, ES = 0.22) and metabolic age (P = .033, ES = 0.29) and in HRV parameters of approximate entropy (ApEN; P = .01, ES = 1.65) and sample entropy (SampEN; P = .0193, ES = 1.40).

Conclusion: Middle-aged Indigenous men can gain cardiovascular health benefits following short bouts of small-sided game play accumulating in 40-minutes of exercise each week. SO WHAT?: Short-duration SSG may address many exercise barriers, and offer a sustainable form of exercise to improve cardiovascular health amongst Indigenous men.
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http://dx.doi.org/10.1002/hpja.409DOI Listing
October 2021

GLP toxicology study of a fully-human T cell redirecting CD3:EGFRvIII binding immunotherapeutic bispecific antibody.

PLoS One 2020 31;15(7):e0236374. Epub 2020 Jul 31.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States of America.

We recently reported the development of a fully-human, CD3-binding bispecific antibody for immunotherapy of malignant glioma. To translate this therapeutic (hEGFRvIII-CD3- bi-scFv) to clinical trials and to help further the translation of other similar CD3-binding therapeutics, some of which are associated with neurologic toxicities, we performed a good laboratory practice (GLP) toxicity study to assess for potential behavioral, chemical, hematologic, and pathologic toxicities including evaluation for experimental autoimmune encephalomyelitis (EAE). To perform this study, male and female C57/BL6 mice heterozygous for the human CD3 transgene (20/sex) were allocated to one of four designated groups. All animals were administered one dose level of hEGFRvIII-CD3 bi-scFv or vehicle control. Test groups were monitored for feed consumption, changes in body weight, and behavioral disturbances including signs of EAE. Urinalysis, hematologic, and clinical chemistry analysis were also performed. Vehicle and test chemical-treated groups were humanely euthanized 48 hours or 14 days following dose administration. Complete gross necropsy of all tissues was performed, and selected tissues plus all observed gross lesions were collected and evaluated for microscopic changes. This included hematoxylin-eosin histopathological evaluation and Fe-ECR staining for myelin sheath enumeration. There were no abnormal clinical observations or signs of EAE noted during the study. There were no statistical changes in food consumption, body weight gain, or final body weight among groups exposed to hEGFRvIII-CD3 bi-scFv compared to the control groups for the 2- and 14-day timepoints. There were statistical differences in some clinical chemistry, hematologic and urinalysis endpoints, primarily in the females at the 14-day timepoint (hematocrit, calcium, phosphorous, and total protein). No pathological findings related to hEGFRvIII-CD3 bi-scFv administration were observed. A number of gross and microscopic observations were noted but all were considered to be incidental background findings. The results of this study allow for further translation of this and other important CD3 modulating bispecific antibodies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236374PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394377PMC
September 2020

Once, Twice, Three Times a Finding: Reproducibility of Dendritic Cell Vaccine Trials Targeting Cytomegalovirus in Glioblastoma.

Clin Cancer Res 2020 10 27;26(20):5297-5303. Epub 2020 Jul 27.

The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina.

Despite standard of care for glioblastoma, including gross total resection, high-dose radiation, and dose-limited chemotherapy, this tumor remains one of the most aggressive and therapeutically challenging. The relatively small number of patients with this diagnosis compared with more common solid tumors in clinical trials commits new glioblastoma therapies to testing in small, underpowered, nonrandomized settings. Among approximately 200 registered glioblastoma trials identified between 2005 and 2015, nearly half were single-arm studies with sample sizes not exceeding 50 patients. These constraints have made demonstrating efficacy for novel therapies difficult in glioblastoma and other rare and aggressive cancers. Novel immunotherapies for glioblastoma such as vaccination with dendritic cells (DC) have yielded mixed results in clinical trials. To address limited numbers, we sequentially conducted three separate clinical trials utilizing cytomegalovirus (CMV)-specific DC vaccines in patients with newly diagnosed glioblastoma whereby each follow-up study had nearly doubled in sample size. Follow-up data from the first blinded, randomized phase II clinical trial (NCT00639639) revealed that nearly one third of this cohort is without tumor recurrence at 5 years from diagnosis. A second clinical trial (NCT00639639) resulted in a 36% survival rate at 5 years from diagnosis. Results of the first two-arm trial (NCT00639639) showed increased migration of the DC vaccine to draining lymph nodes, and this increased migration has been recapitulated in our larger confirmatory clinical study (NCT02366728). We have now observed that nearly one third of the glioblastoma study patient population receiving CMV-specific DC vaccines results in exceptional long-term survivors.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1082DOI Listing
October 2020

Influence of Training Schedules on Objective Measures of Sleep in Adolescent Academy Football Players.

J Strength Cond Res 2020 Sep;34(9):2515-2521

School of Sport, Exercise and Rehabilitation, Faculty of Health, University of Technology Sydney, Sydney, Australia; and.

Brown, GA, Veith, S, Sampson, JA, Whalan, M, and Fullagar, HHK. Influence of training schedules on objective measures of sleep in adolescent academy football players. J Strength Cond Res 34(9): 2515-2521, 2020-Football academy settings may pose risks to adolescent athletes achieving sufficient sleep because of the contextual challenges these players face (e.g., psychosocial pressure, changes in training, competition, and academic stress). Given the importance of sleep to overall health as well as physical athletic development and injury risk, this study aimed to investigate whether differences in training schedules (morning vs. evening training sessions) affected objective measures of sleep in adolescent academy football (soccer) players. Twelve academy players (mean age 14.18 ± 1.36 years) wore an ActiGraph accelerometer on nights before, and nights of, training days in 2 separate weeks where morning (09:00-11:00 hours) and evening (18:00-20:00 hours) training occurred. Objective sleep parameters and training load data were collected. Night-time sleep periods were categorized as sleep preceding morning training, preceding evening training, or after evening training. One-way univariate and multivariate analyses of variance for repeated measures were performed to determine the impact of the training schedule on sleep. Significance levels were set at p < 0.05. The total sleep time was below the recommended guidelines (<8 hours) across conditions. A large significant effect of the training schedule on time attempted to fall asleep (p = 0.004, effect size [ES] = 0.40) and time of sleep (p = 0.003, ES = 0.41) was present, with post-evening sessions resulting in the latest times. Overall, the players' sleep behavior was resilient to changes in training schedules. However, the low sleep durations (and potential risks to physical performance/injury) suggest that sleep education coupled with practical interventions are required in this cohort.
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http://dx.doi.org/10.1519/JSC.0000000000003724DOI Listing
September 2020

Oncolytic virus-derived type I interferon restricts CAR T cell therapy.

Nat Commun 2020 06 24;11(1):3187. Epub 2020 Jun 24.

Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.

The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNβ infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNβ. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.
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http://dx.doi.org/10.1038/s41467-020-17011-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314766PMC
June 2020

PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma?

Clin Cancer Res 2020 10 11;26(20):5287-5296. Epub 2020 Jun 11.

Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Glioblastoma (WHO grade IV glioma) is the most common malignant primary brain tumor in adults. Survival has remained largely static for decades, despite significant efforts to develop new effective therapies. Immunotherapy and especially immune checkpoint inhibitors and programmed cell death (PD)-1/PD-L1 inhibitors have transformed the landscape of cancer treatment and improved patient survival in a number of different cancer types. With the exception of few select cases (e.g., patients with Lynch syndrome) the neuro-oncology community is still awaiting evidence that PD-1 blockade can lead to meaningful clinical benefit in glioblastoma. This lack of progress in the field is likely to be due to multiple reasons, including inherent challenges in brain tumor drug development, the blood-brain barrier, the unique immune environment in the brain, the impact of corticosteroids, as well as inter- and intratumoral heterogeneity. Here we critically review the clinical literature, address the unique aspects of glioma immunobiology and potential immunobiological barriers to progress, and contextualize new approaches to increase the efficacy of PD-1/PD-L1 inhibitors in glioblastoma that may identify gaps and testable relevant hypotheses for future basic and clinical research and to provide a novel perspective to further stimulate preclinical and clinical research to ultimately help patients with glioma, including glioblastoma, which is arguably one of the greatest areas of unmet need in cancer. Moving forward, we need to build on our existing knowledge by conducting further fundamental glioma immunobiology research in parallel with innovative and methodologically sound clinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682636PMC
October 2020

Comparative study of α-helical and β-sheet self-assembled peptide nanofiber vaccine platforms: influence of integrated T-cell epitopes.

Biomater Sci 2020 Jun 26;8(12):3522-3535. Epub 2020 May 26.

Biomedical Engineering Department, Duke University, Durham, NC 27708, USA.

Several different self-assembling peptide systems that form nanofibers have been investigated as vaccine platforms, but design principles for adjusting the character of the immune responses they raise have yet to be well articulated. Here we compared the immune responses raised by two structurally dissimilar peptide nanofibers, one a β-sheet fibrillar system (Q11), and one an α-helical nanofiber system (Coil29), hypothesizing that integrated T-cell epitopes within the latter would promote T follicular helper (Tfh) cell engagement and lead to improved antibody titers and quality. Despite significantly different internal structures, nanofibers of the two peptides exhibited surprisingly similar nanoscale morphologies, and both were capable of raising strong antibody responses to conjugated peptide epitopes in mice without adjuvant. Both were minimally inflammatory, but as hypothesized Coil29 nanofibers elicited antibody responses with higher titers and avidities against a conjugated model epitope (OVA) and a candidate peptide epitope for vaccination against S. aureus. Subsequent investigation indicated that Coil29 nanofibers possessed internal CD4+ T cell epitopes: whereas Q11 nanofibers required co-assembly of additional CD4+ T cell epitopes to be immunogenic, Coil29 nanofibers did not. Coil29 nanofibers also raised stronger germinal center B cell responses and follicular helper T cell (Tfh) responses relative to Q11 nanofibers, likely facilitating the improvement of the antibody response. These findings illustrate design strategies for improving humoral responses raised by self-assembled peptide nanofibers.
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http://dx.doi.org/10.1039/d0bm00521eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665831PMC
June 2020

Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial.

JAMA Oncol 2020 07;6(7):1003-1010

Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.

Importance: Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported.

Objective: To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab.

Design, Setting, And Participants: In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites.

Interventions: Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death.

Main Outcomes And Measures: The primary end point was overall survival (OS).

Results: A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). The MGMT promoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30); P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs.

Conclusions And Relevance: Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types.

Trial Registration: ClinicalTrials.gov Identifier: NCT02017717.
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http://dx.doi.org/10.1001/jamaoncol.2020.1024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243167PMC
July 2020

Effect of a novel low volume, high intensity concurrent training regimen on recruit fitness and resilience.

J Sci Med Sport 2020 Oct 14;23(10):979-984. Epub 2020 Mar 14.

Centre for Medical and Exercise Physiology, Faculty of Science, Medicine and Health, University of Wollongong, Australia. Electronic address:

Objectives: To determine the effect of a novel low volume high intensity concurrent training regimen and warm-up on physiological performance and musculoskeletal injury in Australian recruits.

Design: Controlled longitudinal intervention.

Methods: Military recruits completed 12 weeks of either experimental (EXP: n=78, 6-8RM resistance loads, and high intensity intervals) or basic military (CON: n=69, usual practice) matched for total sessions and time. Endurance (3.2km 22kg-load carriage, V˙O, multi-stage fitness test (MSFT)), 1RM strength and local muscle endurance (bench, squat, box-lift and push-ups) and power (squat jump) were assessed at Weeks 1,6,12. Body composition, physical activity (PAC·min) and heart rate reserve (HRR%), were assessed at Weeks 2,7,9. Musculoskeletal injury and mechanism were recorded. Two-way repeated measures ANOVA interaction (group×time), mean difference and effect size (ES) are reported p≤0.05.

Results: A significant interaction over 12 weeks was observed for load carriage (ES -0.30), squat jump (ES 0.65), V˙O (ES 0.58), MSFT (ES 0.41), push-ups (ES 0.26), 1RM bench (ES 0.26), squat (ES 1.05) and box lift (ES 0.27) in EXP compared to CON. At Week 12 significantly greater squat (38.9kg), MSFT (2.1mL·kg·min), and faster load carriage (49.9s) was observed in EXP than CON, but no difference in body composition. EXP had a lower PAC·min (641.1±63.1) but higher HRR% (21.8±4.0) compared to CON. EXP had a lower number of injuries (6) compared to CON (17).

Conclusions: The inclusion of compound-specific resistance exercise and high intensity intervals improved physical function and was associated with reduced musculoskeletal injury.
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http://dx.doi.org/10.1016/j.jsams.2020.03.005DOI Listing
October 2020

First in human dose calculation of a single-chain bispecific antibody targeting glioma using the MABEL approach.

J Immunother Cancer 2020 04;8(1)

Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, United States

Background: First-in-human (FIH) clinical trials require careful selection of a safe yet biologically relevant starting dose. Typically, such starting doses are selected based on toxicity studies in a pharmacologically relevant animal model. However, with the advent of target-specific and highly active immunotherapeutics, both the Food and Drug Administration and the European Medicines Agency have provided guidance that recommend determining a safe starting dose based on a minimum anticipated biological effect level (MABEL) approach.

Methods: We recently developed a T cell activating bispecific antibody that effectively treats orthotopic patient-derived malignant glioma and syngeneic glioblastoma in mice (hEGFRvIII:CD3 bi-scFv). hEGFRvIII:CD3 bi-scFv is comprized of two single chain antibody fragments (bi-scFvs) that bind mutant epidermal growth factor receptor variant III (EGFRvIII), a mutation frequently seen in malignant glioma, and human CD3ε on T cells, respectively. In order to establish a FIH dose, we used a MABEL approach to select a safe starting dose for hEGFRvIII:CD3 bi-scFv, based on a combination of in vitro data, in vivo animal studies, and theoretical human receptor occupancy modeling.

Results: Using the most conservative approach to the MABEL assessment, a dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/kg body weight was selected as a safe starting dose for a FIH clinical study.

Conclusions: The comparison of our MABEL-based starting dose to our in vivo efficacious dose and the theoretical human receptor occupancy strongly supports that our human starting dose of 57.4 ng hEGFRvIII:CD3 bi-scFv/patient kg will be safe.
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http://dx.doi.org/10.1136/jitc-2019-000213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254109PMC
April 2020

Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial.

Clin Cancer Res 2020 04 7;26(7):1586-1594. Epub 2020 Feb 7.

Celldex Therapeutics, Inc., Hampton, New Jersey.

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma.

Patients And Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.

Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control ( = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; < 0.0001).

Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1140DOI Listing
April 2020

CAR T cells and checkpoint inhibition for the treatment of glioblastoma.

Expert Opin Biol Ther 2020 06 17;20(6):579-591. Epub 2020 Feb 17.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

: Glioblastoma (GBM) is a highly aggressive brain tumor and is one of the most lethal human cancers. Chimeric antigen receptor (CAR) T cell therapy has markedly improved survival in previously incurable disease; however, this vanguard treatment still faces challenges in GBM. Likewise, checkpoint blockade therapies have not enjoyed the same victories against GBM. As it becomes increasingly evident that a mono-therapeutic approach is unlikely to provide anti-tumor efficacy, there evolves a critical need for combined treatment strategies.: This review highlights the clinical successes observed with CAR T cell therapy as well the current efforts to overcome its perceived limitations. The review also explores employed combinations of CAR T cell approaches with immune checkpoint blockade strategies, which aim to potentiate immunotherapeutic benefits while restricting the impact of tumor heterogeneity and T cell exhaustion.: Barriers such as tumor heterogeneity and T cell exhaustion have exposed the weaknesses of various mono-immunotherapeutic approaches to GBM, including CAR T cell and checkpoint blockade strategies. Combining these potentially complementary strategies, however, may proffer a rational means of mitigating these barriers and advancing therapeutic successes against GBM and other solid tumors.
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http://dx.doi.org/10.1080/14712598.2020.1727436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202971PMC
June 2020

Current multidisciplinary management of brain metastases.

Cancer 2020 04 23;126(7):1390-1406. Epub 2020 Jan 23.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late-stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, laser-interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune-checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.
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http://dx.doi.org/10.1002/cncr.32714DOI Listing
April 2020

Brain immunology and immunotherapy in brain tumours.

Nat Rev Cancer 2020 01 5;20(1):12-25. Epub 2019 Dec 5.

The Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

Gliomas, the most common malignant primary brain tumours, remain universally lethal. Yet, seminal discoveries in the past 5 years have clarified the anatomy, genetics and function of the immune system within the central nervous system (CNS) and altered the paradigm for successful immunotherapy. The impact of standard therapies on the response to immunotherapy is now better understood, as well. This new knowledge has implications for a broad range of tumours that develop within the CNS. Nevertheless, the requirements for successful therapy remain effective delivery and target specificity, while the dramatic heterogeneity of malignant gliomas at the genetic and immunological levels remains a profound challenge.
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http://dx.doi.org/10.1038/s41568-019-0224-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327710PMC
January 2020
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