Publications by authors named "David A Reardon"

319 Publications

Clinical Trial Enrollment Among Adolescent and Young Adults with Primary Central Nervous System Tumors Treated at the Dana-Farber Cancer Institute.

J Adolesc Young Adult Oncol 2022 Jan 18. Epub 2022 Jan 18.

Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA.

In recent decades, the survival outcomes among adolescent and young adults (AYAs, 15-39 years) have not improved substantially, especially among AYAs with primary central nervous system (CNS) tumors. While this is likely multifactorial, low participation in clinical trials among AYAs is thought to be a critical contributing factor. In this study, we describe the pattern of clinical trial enrollment among AYAs with primary CNS tumors at our institution. We performed a retrospective, IRB-approved chart review of AYAs with CNS tumors treated at the Dana-Farber Cancer Institute (DFCI) between January 2009 and December 2018. We used logistic regression analyses and descriptive statistics to analyze this sample and determine the clinical trial enrollment at the pediatric affiliate (Dana-Farber/Boston Children's Cancer and Blood Disorders Center) and adult affiliate (Dana-Farber/Brigham and Women's Cancer Center). Ninety-three AYA patients with primary CNS tumors were treated at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, while 507 patients with primary CNS gliomas were treated at the Dana-Farber/Brigham and Women's Cancer Center. At the pediatric affiliate, 35.4% (33/93) of AYAs were enrolled in a therapeutic clinical trial, while at the adult affiliate, 15.8% (80/507) of AYAs were enrolled in a clinical trial. High-grade gliomas were associated with significantly higher rates of enrollment in the adult affiliate. Clinical trial enrollment remains poor among AYAs with CNS tumors, and clinical trial enrollment participation is modestly higher in the pediatric setting. Our study demonstrates the continued need to evaluate and address factors associated with clinical trial enrollment among AYAs with CNS tumors.
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http://dx.doi.org/10.1089/jayao.2021.0187DOI Listing
January 2022

Clinical utility of targeted next generation sequencing assay in IDH-wildtype glioblastoma for therapy decision-making.

Neuro Oncol 2021 Dec 8. Epub 2021 Dec 8.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Targeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center.

Methods: We identified 1,011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013-2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results.

Results: Of the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a post hoc analysis.

Conclusions: While NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.
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http://dx.doi.org/10.1093/neuonc/noab282DOI Listing
December 2021

Combined immunotherapy with controlled Interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: an open-label, multi-institutional phase 1 trial.

Neuro Oncol 2021 Nov 26. Epub 2021 Nov 26.

Northwestern Memorial Hospital, Chicago, IL.

Background: Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8 + T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition.

Methods: An open-label, multi-institutional, dose-escalation phase 1 trial in rGBM subjects (NCT03636477) accrued 21 subjects in 3 dose-escalating cohorts: 1- neo-adjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n= 3); 2- neo-adjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n=3); and 3- neo-adjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n=15). Nivolumab was administered 7 (+/- 3) days before resection of the rGBM followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and then for 14 days after surgery. Nivolumab was administered every two weeks after surgery.

Results: Toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable, dose-related and reversible upon withholding doses of VDX and/or nivolumab. VDX plasma pharmacokinetics demonstrate a dose-response relationship with effective brain tumor tissue VDX penetration and production of IL-12. IL-12 levels in serum peaked in all subjects at about Day 3 after surgery. Tumor IFNγ increased in post treatment biopsies. Median overall survival (mOS) for VDX 10 mg with nivolumab was 16.9 months and for all subjects was 9.8 months.

Conclusion: The safety of this combination immunotherapy was established and has led to an ongoing phase 2 clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).
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http://dx.doi.org/10.1093/neuonc/noab271DOI Listing
November 2021

Authors:
David A Reardon

Hematol Oncol Clin North Am 2022 02;36(1):xv-xvi

Harvard Medical School, Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

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http://dx.doi.org/10.1016/j.hoc.2021.10.001DOI Listing
February 2022

Is There a Role for Immunotherapy in Central Nervous System Cancers?

Hematol Oncol Clin North Am 2022 02;36(1):237-252

Harvard Medical School, Boston, MA, USA; Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

Glioblastoma has emerged as an immunotherapy-refractory tumor based on negative phase III studies of anti-programmed cell death-1 therapy among newly diagnosed as well as recurrent patients. In addition, although much work on vaccine and cellular approaches is ongoing, therapeutic benefit with these approaches has been underwhelming. Much scientific insight into the multitiered layers of immunosuppression exploited by glioblastoma tumors is emerging that sheds light on the explanation for the disappointing results to date and highlights possible therapeutic avenues that may offer a better likelihood of therapeutic benefit for immune-based therapies.
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http://dx.doi.org/10.1016/j.hoc.2021.09.002DOI Listing
February 2022

Long-term outcomes of patients with active melanoma brain metastases treated with combination nivolumab plus ipilimumab (CheckMate 204): final results of an open-label, multicentre, phase 2 study.

Lancet Oncol 2021 12 10;22(12):1692-1704. Epub 2021 Nov 10.

Department of Medical Oncology, City of Hope, Duarte, CA, USA.

Background: Combination nivolumab plus ipilimumab was efficacious in patients with asymptomatic melanoma brain metastases (MBM) in CheckMate 204, but showed low efficacy in patients with symptomatic MBM. Here, we provide final 3-year follow-up data from the trial.

Methods: This open-label, multicentre, phase 2 study (CheckMate 204) included adults (aged ≥18 years) with measurable MBM (0·5-3·0 cm in diameter). Asymptomatic patients (cohort A) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no neurological symptoms or baseline corticosteroid use; symptomatic patients (cohort B) had an ECOG performance status of 0-2 with stable neurological symptoms and could be receiving low-dose dexamethasone. Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg was given intravenously every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks for up to 2 years, until disease progression or unacceptable toxicity. The primary endpoint was intracranial clinical benefit rate (complete responses, partial responses, or stable disease lasting ≥6 months) assessed in all treated patients. Intracranial progression-free survival and overall survival were key secondary endpoints. This study is registered with ClinicalTrials.gov, NCT02320058.

Findings: Between Feb 19, 2015, and Nov 1, 2017, 119 (72%) of 165 screened patients were enrolled and treated: 101 patients were asymptomatic (cohort A; median follow-up 34·3 months [IQR 14·7-36·4]) and 18 were symptomatic (cohort B; median follow-up 7·5 months [1·2-35·2]). Investigator-assessed intracranial clinical benefit was observed in 58 (57·4% [95% CI 47·2-67·2]) of 101 patients in cohort A and three (16·7% [3·6-41·4]) of 18 patients in cohort B; investigator-assessed objective response was observed in 54 (53·5% [43·3-63·5]) patients in cohort A and three (16·7% [3·6-41·4]) patients in cohort B. 33 (33%) patients in cohort A and three (17%) patients in cohort B had an investigator-assessed intracranial complete response. For patients in cohort A, 36-month intracranial progression-free survival was 54·1% (95% CI 42·7-64·1) and overall survival was 71·9% (61·8-79·8). For patients in cohort B, 36-month intracranial progression-free survival was 18·9% (95% CI 4·6-40·5) and overall survival was 36·6% (14·0-59·8). The most common grade 3-4 treatment-related adverse events (TRAEs) were increased alanine aminotransferase and aspartate aminotransferase (15 [15%] of 101 patients each) in cohort A; no grade 3 TRAEs occurred in more than one patient each in cohort B, and no grade 4 events occurred. The most common serious TRAEs were colitis, diarrhoea, hypophysitis, and increased alanine aminotransferase (five [5%] of each among the 101 patients in cohort A); no serious TRAE occurred in more than one patient each in cohort B. There was one treatment-related death (myocarditis in cohort A).

Interpretation: The durable 3-year response, overall survival, and progression-free survival rates for asymptomatic patients support first-line use of nivolumab plus ipilimumab. Symptomatic disease in patients with MBM remains difficult to treat, but some patients achieve a long-term response with the combination.

Funding: Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(21)00545-3DOI Listing
December 2021

Temporal Muscle Thickness as a Prognostic Marker in Patients with Newly Diagnosed Glioblastoma: Translational Imaging Analysis of the CENTRIC EORTC 26071-22072 and CORE Trials.

Clin Cancer Res 2022 01 19;28(1):129-136. Epub 2021 Oct 19.

Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center and Departments of Neurological Surgery and Neurology, Feinberg School of Medicine, Northwestern University, Chicago.

Purpose: To investigate the prognostic relevance of temporal muscle thickness (TMT) as a surrogate parameter of skeletal muscle status in patients with newly diagnosed glioblastoma.

Experimental Design: We assessed TMT in cranial MRI of 755 patients enrolled in the CENTRIC EORTC 26071-22072 study ( = 508) and CORE study ( = 247). We used predefined sex-specific TMT cut-off values to categorize "patients at risk of sarcopenia" and "patients with normal muscle status" at baseline. Furthermore, we categorized patients according to the extent of TMT loss over time. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using the Cox model adjusted for other exploratory variables.

Results: Patients at risk of sarcopenia (CENTRIC; = 158/508, 31.1%; CORE; = 87/247, 35.2%) at baseline had significantly higher risk of progression and death than patients with normal muscle status in both study cohorts [CENTRIC: PFS = HR 0.16; 95% confidence interval (CI), 0.12-0.21; < 0.001; OS = HR 0.341; 95% CI, 0.27-0.44; < 0.001; CORE: PFS = HR 0.29; 95% CI, 0.21-0.39; < 0.001; OS = HR, 0.365; 95% CI, 0.27-0.49; < 0.001]. Similar results were obtained in multivariate Cox models adjusted for other important prognostic parameters. The extent of TMT loss over time showed a significant inverse correlation with median OS times in patients at risk for sarcopenia (CENTRIC: < 0.001; CORE: = 0.005), but not in patients with normal baseline muscle mass (CENTRIC: = 0.538; CORE: = 0.28).

Conclusions: TMT identifies ambulatory patients with newly diagnosed glioblastoma at risk for progressive sarcopenia and adverse outcomes. Early intervention may prevent skeletal muscle loss and improve patient outcome.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1987DOI Listing
January 2022

Glioblastoma as an age-related neurological disorder in adults.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab125. Epub 2021 Sep 4.

Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDH GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDH GBM have a median age of diagnosis at 68-70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM.

Methods: The Surveillance, Epidemiology, and End Results, The Cancer Genome Atlas, and the Chinese Glioma Genome Atlas databases were analyzed for mortality indices. Meta-analysis of 80 clinical trials was evaluated for log hazard ratio for aging to tumor survivorship.

Results: Despite significant advances in the understanding of intratumoral genetic alterations, molecular characteristics of tumor microenvironments, and relationships between tumor molecular characteristics and the use of targeted therapeutics, life expectancy for older adults with GBM has yet to improve.

Conclusions: Based upon the results of our analysis, we propose that age-dependent factors that are yet to be fully elucidated, contribute to IDH GBM patient outcomes.
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http://dx.doi.org/10.1093/noajnl/vdab125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500689PMC
September 2021

Glial and myeloid heterogeneity in the brain tumour microenvironment.

Nat Rev Cancer 2021 Dec 28;21(12):786-802. Epub 2021 Sep 28.

Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Brain cancers carry bleak prognoses, with therapeutic advances helping only a minority of patients over the past decade. The brain tumour microenvironment (TME) is highly immunosuppressive and differs from that of other malignancies as a result of the glial, neural and immune cell populations that constitute it. Until recently, the study of the brain TME was limited by the lack of methods to de-convolute this complex system at the single-cell level. However, novel technical approaches have begun to reveal the immunosuppressive and tumour-promoting properties of distinct glial and myeloid cell populations in the TME, identifying new therapeutic opportunities. Here, we discuss the immune modulatory functions of microglia, monocyte-derived macrophages and astrocytes in brain metastases and glioma, highlighting their disease-associated heterogeneity and drawing from the insights gained by studying these malignancies and other neurological disorders. Lastly, we consider potential approaches for the therapeutic modulation of the brain TME.
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http://dx.doi.org/10.1038/s41568-021-00397-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616823PMC
December 2021

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

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

Duke University, Durham, North Carolina.

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 preclinical 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

A Molecularly Integrated Grade for Meningioma.

Neuro Oncol 2021 Sep 11. Epub 2021 Sep 11.

Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Background: Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a three-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.

Methods: We evaluated whether chromosomal copy-number data improved prediction of time to recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in two independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.

Results: We developed a three-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent AUC, average precision, and the Brier score.

Conclusion: We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.
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http://dx.doi.org/10.1093/neuonc/noab213DOI Listing
September 2021

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

J Immunother Cancer 2021 07;9(7)

Harvard Medical School, Boston, Massachusetts, USA.

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.
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http://dx.doi.org/10.1136/jitc-2021-002890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291304PMC
July 2021

A Comparative Retrospective Study of Immunotherapy RANO Standard RANO Criteria in Glioblastoma Patients Receiving Immune Checkpoint Inhibitor Therapy.

Front Oncol 2021 25;11:679331. Epub 2021 Jun 25.

Department of Radiology, Brigham and Women's Hospital, Boston, MA, United States.

Objectives: Real-time assessment of treatment response in glioblastoma (GBM) patients on immune checkpoint blockade (ICB) remains challenging because inflammatory effects of therapy may mimic progressive disease, and the temporal evolution of these inflammatory findings is poorly understood. We compare GBM patient response during ICB as assessed with the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) and the standard Response Assessment in Neuro-Oncology (RANO) radiological criteria.

Methods: 49 GBM patients (seven newly diagnosed and 42 recurrent) treated with ICBs at a single institution were identified. Tumor burden was quantified on serial MR scans according to RANO criteria during ICB. Radiographic response assessment by iRANO and RANO were compared.

Results: 82% (40/49) of patients received anti-PD-1, 16% (8/49) received anti-PD-L1, and 2% (1/49) received anti-PD-1 and anti-CTLA4 treatment. Change in tumor burden and best overall response ranged from -100 to +557% (median: +48%). 12% (6/49) of patients were classified as concordant non-progressors by both RANO and iRANO (best response: one CR, one PR, and four SD). Another12% (6/49) had discordant assessments: 15% (6/41) of RANO grade progressive disease (PD) patients had iRANO grade of progressive disease unconfirmed (PDU). The final classification of these discordant patients was pseudoprogression (PsP) in three of six, PD in two of six, and PDU in one of six who went off study before the iRANO assessment of PDU. iRANO delayed diagnosis of PD by 42 and 93 days in the two PD patients. 76% (37/49) patients were classified as concordant PD by both RANO and iRANO. 12% (6/49) of all patients were classified as PsP, starting at a median of 12 weeks (range, 4-30 weeks) after ICB initiation.

Conclusions: Standard RANO and iRANO have high concordance for assessing PD in patients within 6 months of ICB initiation. iRANO was beneficial in 6% (3/49) cases later proven to be PsP, but delayed confirmation of PD by <3 months in 4% (2/49). PsP occurred in 12% of patients, starting at up to 7 months after initiation of ICB. Further study to define the utility of modified RANO compared with iRANO in ICB GBM patients is needed.
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http://dx.doi.org/10.3389/fonc.2021.679331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268004PMC
June 2021

Systematic review of combinations of targeted or immunotherapy in advanced solid tumors.

J Immunother Cancer 2021 07;9(7)

Duke Cancer Institute, Duke University, Durham, North Carolina, USA

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
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http://dx.doi.org/10.1136/jitc-2021-002459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256733PMC
July 2021

Bintrafusp alfa (M7824), a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase I expansion cohort in patients with recurrent glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab058. Epub 2021 Apr 9.

Austin Brain Tumor Center, Austin, Texas, USA.

Background: For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 antibody blocking PD-L1.

Methods: In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety.

Results: As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with -mutant GBM ( = 6) and 13.8% (3.9-31.7%) for patients with -wild-type GBM ( = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [ = 6]).

Conclusions: The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.
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http://dx.doi.org/10.1093/noajnl/vdab058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156979PMC
April 2021

Adolescent and young adult neuro-oncology: a comprehensive review.

Neurooncol Pract 2021 Jun 18;8(3):236-246. Epub 2021 Feb 18.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Adolescent and young adult (AYA; ages 15-39) patients represent a population that experiences significant challenges in cancer care and research, exemplified by poorer clinical outcomes as well as unmet psychosocial and reproductive health needs. Despite central nervous system (CNS) tumors being one of the most common malignancies diagnosed in the age group, there is a clear paucity of AYA CNS tumor-specific publications, especially those related to the unique psychosocial and reproductive health needs of this population of patients. In this review, we examine various aspects of AYA oncological care including tumor biology, clinical outcome, clinical trials enrollment rate, site of care, unique psychosocial needs, and oncofertility. We assess the current state of these issues, highlight areas of deficiencies, and outline the steps needed to address these concerns. We emphasize the importance of comprehensive molecular testing as part of the diagnostic work-up, expansion of clinical trial availability, access to psychosocial care and oncofertility expertise, and the development of AYA-specific clinical research to define best practices and advancing care for this population.
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http://dx.doi.org/10.1093/nop/npab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153805PMC
June 2021

Activity of PD-1 blockade with nivolumab among patients with recurrent atypical/anaplastic meningioma: phase II trial results.

Neuro Oncol 2022 01;24(1):101-113

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Background: Programmed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy.

Methods: Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale.

Results: Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO.

Conclusion: Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.
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http://dx.doi.org/10.1093/neuonc/noab118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730772PMC
January 2022

Safety and efficacy of the combination of nivolumab plus ipilimumab in patients with melanoma and asymptomatic or symptomatic brain metastases (CheckMate 204).

Neuro Oncol 2021 11;23(11):1961-1973

Department of Medical Oncology, City of Hope, Duarte, California, USA.

Background: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present the first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients.

Methods: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks ×4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months).

Results: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed.

Conclusions: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids. Clinical trial registration. ClinicalTrials.gov, NCT02320058.
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http://dx.doi.org/10.1093/neuonc/noab094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563325PMC
November 2021

Improved outcomes associated with maximal extent of resection for butterfly glioblastoma: insights from institutional and national data.

Acta Neurochir (Wien) 2021 07 19;163(7):1883-1894. Epub 2021 Apr 19.

Computational Neuroscience Outcomes Center, Department of Neurosurgery, Brigham and Women's Hospital, 60 Fenwood Rd., Boston, MA, , 02115, USA.

Background: Butterfly glioblastomas (bGBMs) are grade IV gliomas that infiltrate the corpus callosum and spread to bilateral cerebral hemispheres. Due to the rarity of cases, there is a dearth of information in existing literature. Herein, we evaluate clinical and genetic characteristics, associated predictors, and survival outcomes in an institutional series and compare them to a national cohort.

Methods: We identified all adult patients with bGBM treated at Brigham & Women's Hospital (2008-2018). The National Cancer Database (NCDB) was also queried for bGBM patients. Survival was analyzed with Kaplan-Meier methods, and Cox models were built to assess for predictive factors.

Results: Of 993 glioblastoma patients, 62 cases (6.2%) of bGBM were identified. Craniotomy for resection was attempted in 26 patients (41.9%), with a median volumetric extent of resection (vEOR) of 72.3% (95% confidence interval [95%CI] 58.3-82.1). The IDH1 R132H mutation was detected in two patients (3.2%), and MGMT promoter was methylated in 55.5% of the assessed cases. In multivariable regression, factors predictive of longer OS were increased vEOR, MGMT promoter methylation, and receipt of adjuvant therapy. Median OS for the resected cases was 11.5 months (95%CI 7.7-18.8) vs. 6.3 (95%CI 5.1-8.9) for the biopsied. Of 21,353 GBMs, 719 (3.37%) bGBM patients were identified in the NCDB. Resection was more likely to be pursued in recent years, and GTR was independently associated with prolonged OS (p < 0.01).

Conclusion: Surgical resection followed by adjuvant chemoradiation is associated with significant survival gains and should be pursued in carefully selected bGBM patients.
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http://dx.doi.org/10.1007/s00701-021-04844-wDOI Listing
July 2021

Assessment of tumor hypoxia and perfusion in recurrent glioblastoma following bevacizumab failure using MRI and F-FMISO PET.

Sci Rep 2021 04 7;11(1):7632. Epub 2021 Apr 7.

Mays Cancer Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.

Tumoral hypoxia correlates with worse outcomes in glioblastoma (GBM). While bevacizumab is routinely used to treat recurrent GBM, it may exacerbate hypoxia. Evofosfamide is a hypoxia-targeting prodrug being tested for recurrent GBM. To characterize resistance to bevacizumab and identify those with recurrent GBM who may benefit from evofosfamide, we ascertained MRI features and hypoxia in patients with GBM progression receiving both agents. Thirty-three patients with recurrent GBM refractory to bevacizumab were enrolled. Patients underwent MR and F-FMISO PET imaging at baseline and 28 days. Tumor volumes were determined, MRI and F-FMISO PET-derived parameters calculated, and Spearman correlations between parameters assessed. Progression-free survival decreased significantly with hypoxic volume [hazard ratio (HR) = 1.67, 95% confidence interval (CI) 1.14 to 2.46, P = 0.009] and increased significantly with time to the maximum value of the residue (Tmax) (HR = 0.54, 95% CI 0.34 to 0.88, P = 0.01). Overall survival decreased significantly with hypoxic volume (HR = 1.71, 95% CI 1.12 to 12.61, p = 0.01), standardized relative cerebral blood volume (srCBV) (HR = 1.61, 95% CI 1.09 to 2.38, p = 0.02), and increased significantly with Tmax (HR = 0.31, 95% CI 0.15 to 0.62, p < 0.001). Decreases in hypoxic volume correlated with longer overall and progression-free survival, and increases correlated with shorter overall and progression-free survival. Hypoxic volume and volume ratio were positively correlated (r = 0.77, P < 0.0001), as were hypoxia volume and T1 enhancing tumor volume (r = 0.75, P < 0.0001). Hypoxia is a key biomarker in patients with bevacizumab-refractory GBM. Hypoxia and srCBV were inversely correlated with patient outcomes. These radiographic features may be useful in evaluating treatment and guiding treatment considerations.
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http://dx.doi.org/10.1038/s41598-021-84331-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027395PMC
April 2021

The Current Landscape of Immune Checkpoint Blockade in Glioblastoma.

Neurosurg Clin N Am 2021 Apr;32(2):235-248

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215-5450, USA.

The glioblastoma tumor microenvironment is highly immunosuppressed. This immunosuppressive state is engineered by inhibitory molecules secreted by tumor cells that limit activation of immune effector cells, drive T-cell exhaustion, and enhance the immunosuppressive action of tumor-associated myeloid cells. Immunotherapeutic approaches have sought to combat glioblastoma microenvironment immunosuppression with agents such as immune checkpoint inhibitors. Although immune checkpoint blockade in glioblastoma has yielded disappointing results thus far, there is significant interest in the combination of immune checkpoint blockade with other approaches to enhance response.
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http://dx.doi.org/10.1016/j.nec.2020.12.003DOI Listing
April 2021

IDH-mutant gliomas with additional class-defining molecular events.

Mod Pathol 2021 07 26;34(7):1236-1244. Epub 2021 Mar 26.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

The 2016 WHO classifies IDH-mutant gliomas into oligodendroglioma or diffuse astrocytoma based on co-occurring genetic events. Recent literature addresses the concept of stratifying IDH-mutant gliomas based on prognostically significant molecular events. However, the presence of a second class-defining driver alteration in IDH-mutant gliomas has not been systematically described. We searched the sequencing database at our institutions as well as The Cancer Genome Atlas (TCGA) and cBioPortal for IDH-mutant gliomas with other potentially significant alterations. For each case, we reviewed the clinical information, histology and genetic profile. Of 1702 gliomas tested on our targeted exome sequencing panel, we identified 364 IDH-mutated gliomas, four of which had pathogenic FGFR alterations and one with BRAF V600E mutation. Five additional IDH-mutant gliomas with NTRK fusions were identified through collaboration with an outside institution. Also, a search in the glioma database in cBioPortal (5379 total glioma samples, 1515 cases [28.1%] with IDH1/2 mutation) revealed eight IDH-mutated gliomas with FGFR, NTRK or BRAF pathogenic alterations. All IDH-mutant gliomas with dual mutations identified were hemispheric and had a mean age at diagnosis of 36.2 years (range 16-55 years old). Co-occurring genetic events involved MYCN, RB and PTEN. Notable outcomes included a patient with an IDH1/FGFR1-mutated anaplastic oligodendroglioma who has survived 20 years after diagnosis. We describe a series of 18 IDH-mutant gliomas with co-occurring genetic events that have been described as independent class-defining drivers in other gliomas. While these tumors are rare and the significance of these alterations needs further exploration, alterations in FGFR, NTRK, and BRAF could have potential therapeutic implications and affect clinical trial design and results in IDH-mutant studies. Our data highlights that single gene testing for IDH1 in diffuse gliomas may be insufficient for detection of targets with potential important prognostic and treatment value.
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http://dx.doi.org/10.1038/s41379-021-00795-wDOI Listing
July 2021

Clinical, radiological and genomic features and targeted therapy in BRAF V600E mutant adult glioblastoma.

J Neurooncol 2021 May 1;152(3):515-522. Epub 2021 Mar 1.

Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.

Purpose: Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors.

Methods: We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women's Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed.

Results: Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22-69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2-11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7-38.9).

Conclusion: Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.
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http://dx.doi.org/10.1007/s11060-021-03719-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415171PMC
May 2021

The combined use of steroids and immune checkpoint inhibitors in brain metastasis patients: a systematic review and meta-analysis.

Neuro Oncol 2021 08;23(8):1261-1272

Computational Neuroscience Outcomes Center (CNOC), Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Immune checkpoint inhibitors (ICI) have been a breakthrough for selected cancer patients, including those with brain metastases (BMs). Likewise, steroids have been an integral component of symptomatic management of BM patients. However, clinical evidence on the interaction between ICI and steroids in BM patients is conflicting and has not adequately been summarized thus far. Hence, the aim of this study was to perform a systematic literature review and meta-analysis on the association between steroid use and overall survival (OS) in BM patients receiving ICI.

Methods: A systematic literature search was performed. Pooled effect estimates were calculated using random-effects models across included studies.

Results: After screening 1145 abstracts, 15 observational studies were included. Fourteen studies reported sufficient data for meta-analysis, comprising 1102 BM patients of which 32.1% received steroids. In the steroid group, median OS ranged from 2.9 to 10.2 months. In the nonsteroid group, median OS ranged from 4.9 to 25.1 months. Pooled results demonstrated significantly worse OS (HR = 1.84, 95% CI 1.22-2.77) and systemic progression-free survival (PFS; HR = 2.00, 95% CI 1.37-2.91) in the steroid group. Stratified analysis showed a consistent effect across the melanoma subgroup; not in the lung cancer subgroup. No significant association was shown between steroid use and intracranial PFS (HR = 1.31, 95% CI 0.42-4.07).

Conclusions: Administration of steroids was associated with significantly worse OS and PFS in BM patients receiving ICI. Further research on dose, timing, and duration of steroids is needed to elucidate the cause of this association and optimize outcomes in BM patients receiving ICI.
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http://dx.doi.org/10.1093/neuonc/noab046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328028PMC
August 2021

Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis.

Cell 2021 03 15;184(5):1281-1298.e26. Epub 2021 Feb 15.

Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 USA.

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.
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http://dx.doi.org/10.1016/j.cell.2021.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935772PMC
March 2021

Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial.

Cancer 2021 05 26;127(10):1620-1629. Epub 2021 Jan 26.

Institut Gustave Roussy, Villejuif, France.

Background: Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma.

Methods: Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively).

Results: After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression-free survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%).

Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.
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http://dx.doi.org/10.1002/cncr.33378DOI Listing
May 2021

Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank.

Neuro Oncol 2021 03;23(3):356-375

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California.

Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.
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http://dx.doi.org/10.1093/neuonc/noaa277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992879PMC
March 2021

Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma.

Clin Cancer Res 2021 01 25;27(1):276-287. Epub 2020 Nov 25.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Dexamethasone, a uniquely potent corticosteroid, is frequently administered to patients with brain tumors to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in patients with glioblastoma (GBM), particularly in the context of immunotherapy.

Experimental Design: We evaluated the dose-dependent effects of dexamethasone when administered with programmed cell death 1 (PD-1) blockade and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 and CT-2A GBM tumors. Clinically, the effect of dexamethasone on survival was evaluated in 181 patients with isocitrate dehydrogenase (IDH) wild-type GBM treated with PD-(L)1 blockade, with adjustment for relevant prognostic factors.

Results: Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival [reference, no dexamethasone; <2 mg HR, 2.16; 95% confidence interval (CI), 1.30-3.68; = 0.003 and ≥2 mg HR, 1.97; 95% CI, 1.23-3.16; = 0.005].

Conclusions: Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034990PMC
January 2021

Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma.

Clin Cancer Res 2021 02 16;27(4):1048-1057. Epub 2020 Nov 16.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.

Patients And Methods: Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, = 50) or pembrolizumab monotherapy (cohort B, = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.

Results: Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant , unmethylated , and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.

Conclusions: Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284901PMC
February 2021
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