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1.
Clin Cancer Res ; 30(7): 1327-1337, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38252427

ABSTRACT

PURPOSE: Adverse clinical events cause significant morbidity in patients with GBM (GBM). We examined whether genomic alterations were associated with AE (AE) in patients with GBM. EXPERIMENTAL DESIGN: We identified adults with histologically confirmed IDH-wild-type GBM with targeted next-generation sequencing (OncoPanel) at Dana Farber Cancer Institute from 2013 to 2019. Seizure at presentation, lymphopenia, thromboembolic events, pseudoprogression, and early progression (within 6 months of diagnosis) were identified as AE. The biologic function of genetic variants was categorized as loss-of-function (LoF), no change in function, or gain-of-function (GoF) using a somatic tumor mutation knowledge base (OncoKB) and consensus protein function predictions. Associations between functional genomic alterations and AE were examined using univariate logistic regressions and multivariable regressions adjusted for additional clinical predictors. RESULTS: Our study included 470 patients diagnosed with GBM who met the study criteria. We focused on 105 genes that had sequencing data available for ≥ 90% of the patients and were altered in ≥10% of the cohort. Following false-discovery rate (FDR) correction and multivariable adjustment, the TP53, RB1, IGF1R, and DIS3 LoF alterations were associated with lower odds of seizures, while EGFR, SMARCA4, GNA11, BRD4, and TCF3 GoF and SETD2 LoF alterations were associated with higher odds of seizures. For all other AE of interest, no significant associations were found with genomic alterations following FDR correction. CONCLUSIONS: Genomic biomarkers based on functional variant analysis of a routine clinical panel may help identify AE in GBM, particularly seizures. Identifying these risk factors could improve the management of patients through better supportive care and consideration of prophylactic therapies.


Subject(s)
Brain Neoplasms , Glioblastoma , Adult , Humans , Glioblastoma/genetics , Glioblastoma/pathology , Nuclear Proteins/genetics , Transcription Factors/genetics , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Genomics , Seizures/genetics , Mutation , DNA Helicases/genetics , Bromodomain Containing Proteins , Cell Cycle Proteins/genetics
2.
Neuro Oncol ; 26(4): 596-608, 2024 04 05.
Article in English | MEDLINE | ID: mdl-38071654

ABSTRACT

Despite major strides in cancer research and therapy, these advances have not been equitable across race and ethnicity. Historically marginalized groups (HMG) are more likely to have inadequate preventive screening, increased delays in diagnosis, and poor representation in clinical trials. Notably, Black, Hispanic, and Indigenous people represent 30% of the population but only 9% of oncology clinical trial participants. As a result, HMGs lack equitable access to novel therapies, contradicting the principle of distributive justice, as enshrined in the Belmont report, which demands the equitable selection of subjects in research involving human subjects. The lack of clinical trial diversity also leads to low generalizability and potentially harmful medical practices. Specifically, patients with brain cancer face unique barriers to clinical trial enrollment and completion due to disease-specific neurologic and treatment-induced conditions. Collectively, the intersection of these disease-specific conditions with social determinants of health fosters a lack of diversity in clinical trials. To ameliorate this disparity in neuro-oncology clinical trial participation, we present interventions focused on improving engagement of HMGs. Proposals range from inclusive trial design, decreasing barriers to care, expanding trial eligibility, access to tumor profiling for personalized medical trials, setting reasonable metrics and goals for accrual, working with patient community stakeholders, diversifying the neuro-oncology workforce, and development of tools to overcome biases with options to incentivize equity. The diversification of participation amongst neuro-oncology clinical trials is imperative. Equitable access and inclusion of HMG patients with brain tumors will not only enhance research discoveries but will also improve patient care.


Subject(s)
Brain Neoplasms , Humans , Brain Neoplasms/therapy , Medical Oncology , Ethnicity
3.
Cancer Cytopathol ; 132(4): 214-223, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37812603

ABSTRACT

BACKGROUND: Leptomeningeal metastases occur across multiple solid and lymphoid cancers, and patients typically undergo cytopathologic assessment of cerebrospinal fluid (CSF) in this setting. For patients diagnosed with metastatic cancer, the detection of actionable somatic mutations in CSF can provide clinically valuable information for treatment without the need for additional tissue collection. METHODS: The authors validated a targeted next-generation sequencing assay for the detection of somatic variants in cancer (OncoPanel) on cell-free DNA (cfDNA) isolated from archival CSF specimens in a cohort of 25 patients who had undergone molecular testing of a prior tumor specimen. RESULTS: CSF storage time and volume had no impact on cfDNA concentration or mean target coverage of the assay. Previously identified somatic variants in CSF cfDNA were detected in 88%, 50%, and 27% of specimens diagnosed cytologically as positive, suspicious/atypical, and negative for malignancy, respectively. Somatic variants were identified in 81% of CSF specimens from patients who had leptomeningeal enhancement on magnetic resonance imaging compared with 31% from patients without such enhancement. CONCLUSIONS: These data highlight the stability of cfDNA in CSF, which allows for cytopathologic evaluation before triage for next-generation sequencing assays. For a subset of cases in which clinical suspicion is high but cytologic or radiographic studies are inconclusive, the detection of pathogenic somatic variants in CSF cfDNA may aid in the diagnosis of leptomeningeal metastases.


Subject(s)
Cell-Free Nucleic Acids , Neoplasms , Humans , Cell-Free Nucleic Acids/genetics , Mutation , Neoplasms/diagnostic imaging , Neoplasms/genetics , High-Throughput Nucleotide Sequencing/methods
4.
Clin Transl Radiat Oncol ; 44: 100697, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38046107

ABSTRACT

Introduction and background: While recurrent glioblastoma patients are often treated with re-irradiation, there is limited data on the use of re-irradiation in the setting of bevacizumab (BEV), temozolomide (TMZ) re-challenge, or immune checkpoint inhibition (ICI). We describe target delineation in patients with prior anti-angiogenic therapy, assess safety and efficacy of re-irradiation, and evaluate patterns of recurrence. Materials and methods: Patients with a histologically confirmed diagnosis of glioblastoma treated at a single institution between 2013 and 2021 with re-irradiation were included. Tumor, treatment and clinical data were collected. Logistic and Cox regression analysis were used for statistical analysis. Results: One hundred and seventeen recurrent glioblastoma patients were identified, receiving 129 courses of re-irradiation. In 66 % (85/129) of cases, patients had prior BEV. In the 80 patients (62 %) with available re-irradiation plans, 20 (25 %) had all T2/FLAIR abnormality included in the gross tumor volume (GTV). Median overall survival (OS) for the cohort was 7.3 months, and median progression-free survival (PFS) was 3.6 months. Acute CTCAE grade ≥ 3 toxicity occurred in 8 % of cases. Concurrent use of TMZ or ICI was not associated with improved OS nor PFS. On multivariable analysis, higher KPS was significantly associated with longer OS (p < 0.01). On subgroup analysis, patients with prior BEV had significantly more marginal recurrences than those without (26 % vs. 13 %, p < 0.01). Conclusion: Re-irradiation can be safely employed in recurrent glioblastoma patients. Marginal recurrence was more frequent in patients with prior BEV, suggesting a need to consider more inclusive treatment volumes incorporating T2/FLAIR abnormality.

5.
Curr Neurol Neurosci Rep ; 23(12): 815-825, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37889427

ABSTRACT

PURPOSEOF REVIEW: Health disparities are preventable differences in the diagnosis, treatment, and outcomes of many diseases, including central nervous system (CNS) tumors. This review will summarize and compile the existing literature on health disparities in neuro-oncology and provide directions for future research and interventions. RECENT FINDINGS: Patients from historically marginalized groups are more likely to receive inadequate treatment, develop complications, and experience a shorter life expectancy. Financial toxicity can be particularly severe for patients with CNS tumors due to the high costs of treatment. Additionally, CNS clinical trials and research lack diverse representation.


Subject(s)
Central Nervous System Neoplasms , Humans , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/therapy , Medical Oncology , Forecasting
6.
Nature ; 623(7985): 157-166, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37853118

ABSTRACT

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 ).


Subject(s)
Brain Neoplasms , Glioblastoma , Herpesvirus 1, Human , Oncolytic Virotherapy , Oncolytic Viruses , Humans , Brain Neoplasms/immunology , Brain Neoplasms/pathology , Glioblastoma/immunology , Glioblastoma/pathology , Nestin/genetics , Oncolytic Virotherapy/adverse effects , Oncolytic Viruses/genetics , Oncolytic Viruses/immunology , Oncolytic Viruses/physiology , Reproducibility of Results , Survival Analysis , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Treatment Outcome , Tumor Microenvironment/immunology , Herpesvirus 1, Human/genetics , Herpesvirus 1, Human/immunology , Herpesvirus 1, Human/physiology
7.
J Clin Oncol ; 41(36): 5524-5535, 2023 Dec 20.
Article in English | MEDLINE | ID: mdl-37722087

ABSTRACT

PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.


Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/pathology , Random Allocation , Bayes Theorem , Brain Neoplasms/therapy , ErbB Receptors/genetics , Biomarkers
8.
Br J Haematol ; 203(5): 774-780, 2023 12.
Article in English | MEDLINE | ID: mdl-37584155

ABSTRACT

Data describing outcomes of chimeric antigen receptor (CAR) T-cell therapy in patients with secondary central nervous system (SCNS) involvement of mantle cell lymphoma (MCL) are limited. We identified 10 patients with MCL and SCNS involvement treated with anti-CD19 CAR T-cell therapy at three US academic centres. Frequent objective responses were observed in the CNS (86%) and systemically (90%), and the 1-year progression-free survival was 47%. Seven patients developed immune-effector-cell-associated-neurotoxicity-syndrome (n = 2 Grade 1, n = 5 Grade 3). Our results suggest that anti-CD19 CAR T-cell therapy in this setting is feasible and additional data regarding neurotoxicity in this population may be warranted.


Subject(s)
Lymphoma, Mantle-Cell , Neurotoxicity Syndromes , Receptors, Chimeric Antigen , Adult , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Lymphoma, Mantle-Cell/drug therapy , Receptors, Chimeric Antigen/therapeutic use , Receptors, Antigen, T-Cell/therapeutic use , T-Lymphocytes , Treatment Outcome , Antigens, CD19 , Central Nervous System , Neurotoxicity Syndromes/drug therapy , Cell- and Tissue-Based Therapy
9.
Neurooncol Adv ; 5(1): vdad083, 2023.
Article in English | MEDLINE | ID: mdl-37554224

ABSTRACT

Background: Glioblastoma (GBM) patients are treated with radiation therapy, chemotherapy, and corticosteroids, which can cause myelosuppression. To understand the relative prognostic utility of blood-based biomarkers in GBM and its implications for clinical trial design, we examined the incidence, predictors, and prognostic value of lymphopenia, neutrophil-to-lymphocyte ratio (NLR), and platelet count during chemoradiation (CRT) and recurrence. Methods: This cohort study included 764 newly diagnosed glioblastoma patients treated from 2005 to 2019 with blood counts prior to surgery, within 6 weeks of CRT, and at first recurrence available for automatic extraction from the medical record. Logistic regression was used to evaluate exposures and Kaplan-Meier was used to evaluate outcomes. Results: Among the cohort, median age was 60.3 years; 87% had Karnofsky performance status ≥ 70, 37.5% had gross total resection, and 90% received temozolomide (TMZ). During CRT, 37.8% (248/656) of patients developed grade 3 or higher lymphopenia. On multivariable analysis (MVA), high NLR during CRT remained an independent predictor for inferior survival (Adjusted Hazard Ratio [AHR] = 1.57, 95% CI = 1.14-2.15) and shorter progression-free survival (AHR = 1.42, 95% CI = 1.05-1.90). Steroid use was associated with lymphopenia (OR = 2.66,1.20-6.00) and high NLR (OR = 3.54,2.08-6.11). Female sex was associated with lymphopenia (OR = 2.33,1.03-5.33). At first recurrence, 28% of patients exhibited grade 3 or higher lymphopenia. High NLR at recurrence was associated with worse subsequent survival on MVA (AHR = 1.69, 95% CI = 1.25-2.27). Conclusions: High NLR is associated with worse outcomes in newly diagnosed and recurrent glioblastoma. Appropriate eligibility criteria and accounting and reporting of blood-based biomarkers are important in the design and interpretation of newly diagnosed and recurrent glioblastoma trials.

10.
Clin Cancer Res ; 29(16): 3017-3025, 2023 Aug 15.
Article in English | MEDLINE | ID: mdl-37327319

ABSTRACT

PURPOSE: We evaluated the efficacy of bavituximab-a mAb with anti-angiogenic and immunomodulatory properties-in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916). PATIENTS AND METHODS: Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiotherapy, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSC) and macrophages. RESULTS: The study met its primary endpoint with an OS-12 of 73% (95% confidence interval, 59%-90%). Decreased pre-C1 rCBF (HR, 4.63; P = 0.029) and increased pre-C1 Ktrans were associated with improved overall survival (HR, 0.09; P = 0.005). Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment tumor specimens contained fewer immunosuppressive MDSCs (P = 0.01). CONCLUSIONS: Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.

11.
JAMA Oncol ; 8(10): 1493-1501, 2022 10 01.
Article in English | MEDLINE | ID: mdl-36006639

ABSTRACT

Importance: Previous histologic classifications of brain tumors have been limited by discrepancies in diagnoses reported by neuropathologists and variability in outcomes and response to therapies. Such diagnostic discrepancies have impaired clinicians' ability to select the most appropriate therapies for patients and have allowed heterogeneous populations of patients to be enrolled in clinical trials, hindering the development of more effective therapies. In adult-type diffuse gliomas, histologic classification has a particularly important effect on clinical care. Observations: In 2021, the World Health Organization published the fifth edition of the Classification of Tumors of the Central Nervous System. This classification incorporates advances in understanding the molecular pathogenesis of brain tumors with histopathology in order to group tumors into more biologically and molecularly defined entities. As such, tumor classification is significantly improved through better characterized natural histories. These changes have particularly important implications for gliomas. For the first time, adult- and pediatric-type gliomas are classified separately on the basis of differences in molecular pathogenesis and prognosis. Furthermore, the previous broad category of adult-type diffuse gliomas has been consolidated into 3 types: astrocytoma, isocitrate dehydrogenase (IDH) mutant; oligodendroglioma, IDH mutant and 1p/19q codeleted; and glioblastoma, IDH wild type. These major changes are driven by IDH mutation status and include the restriction of the diagnosis of glioblastoma to tumors that are IDH wild type; the reclassification of tumors previously diagnosed as IDH-mutated glioblastomas as astrocytomas IDH mutated, grade 4; and the requirement for the presence of IDH mutations to classify tumors as astrocytomas or oligodendrogliomas. Conclusions and Relevance: The 2021 World Health Organization central nervous system tumor classification is a major advance toward improving the diagnosis of brain tumors. It will provide clinicians with more accurate guidance on prognosis and optimal therapy for patients and ensure that more homogenous patient populations are enrolled in clinical trials, potentially facilitating the development of more effective therapies.


Subject(s)
Astrocytoma , Brain Neoplasms , Central Nervous System Neoplasms , Glioblastoma , Glioma , Oligodendroglioma , Humans , Adult , Child , Isocitrate Dehydrogenase/genetics , Glioma/genetics , Glioma/therapy , Oligodendroglioma/genetics , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Astrocytoma/genetics , Central Nervous System Neoplasms/therapy , World Health Organization , Mutation
12.
Nat Commun ; 13(1): 1325, 2022 03 14.
Article in English | MEDLINE | ID: mdl-35289329

ABSTRACT

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4-12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.


Subject(s)
Meningeal Neoplasms , Meningioma , Antibodies, Monoclonal, Humanized/adverse effects , Disease Progression , Humans , Meningeal Neoplasms/drug therapy , Meningioma/drug therapy , Tumor Microenvironment
13.
Neuro Oncol ; 24(8): 1341-1349, 2022 08 01.
Article in English | MEDLINE | ID: mdl-34999844

ABSTRACT

BACKGROUND: The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate progress made in all phase therapeutic clinical trials for neuroepithelial CNS tumors stratified by demographic-specific age-adjusted disease incidence and mortality. Additionally, we identify workforce characteristics associated with clinical trials meeting established accrual benchmarks. METHODS: Registry study of published clinical trials for World Health Organization defined neuroepithelial CNS tumors between January 2000 and December 2019. Study participants were obtained from PubMed and ClinicalTrials.gov. Population-based data originated from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and χ 2 tests were used for data analysis. RESULTS: Among 662 published clinical trials representing 49 907 participants, 62.5% of participants were men and 37.5% women (P < .0001) representing a mortality specific over-accrual for men (P = .001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with mortality, Blacks (47% of expected mortality, P = .008), Hispanics (17% of expected mortality, P < .001) and Asians (33% of expected mortality, P < .001) were underrepresented compared with Whites (114% of expected mortality, P < .001). Clinical trials meeting accrual benchmarks for race included minority authorship. CONCLUSIONS: Following the Revitalization Act, minorities and women remain underrepresented in therapeutic clinical trials for neuroepithelial tumors, relative to disease incidence and mortality. Study accrual has improved with time. This study provides a framework for clinical trial accrual efforts and offers guidance regarding workforce considerations associated with enrollment of underserved patients.


Subject(s)
Clinical Trials as Topic , Neoplasms , Patient Selection , Female , Humans , Male , Minority Groups , National Institutes of Health (U.S.) , Neoplasms/therapy , Research Design , United States
14.
Neuro Oncol ; 24(1): 101-113, 2022 01 05.
Article in English | MEDLINE | ID: mdl-34015129

ABSTRACT

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.


Subject(s)
Meningeal Neoplasms , Meningioma , B7-H1 Antigen , Humans , Meningeal Neoplasms/drug therapy , Meningioma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Nivolumab/therapeutic use , Programmed Cell Death 1 Receptor
15.
Neuro Oncol ; 24(7): 1140-1149, 2022 07 01.
Article in English | MEDLINE | ID: mdl-34878541

ABSTRACT

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 1011 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 posthoc 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.


Subject(s)
Glioblastoma , Adult , Clinical Trials as Topic , Glioblastoma/diagnosis , Glioblastoma/genetics , Glioblastoma/therapy , High-Throughput Nucleotide Sequencing/methods , Humans , Mutation , Pathology, Molecular , Retrospective Studies
16.
Hematol Oncol Clin North Am ; 36(1): 147-159, 2022 02.
Article in English | MEDLINE | ID: mdl-34801161

ABSTRACT

Primary central nervous system lymphoma is a rare and aggressive extranodal non-Hodgkin lymphoma restricted to the brain, spinal cord, cerebrospinal fluid, and eyes. Optimization of treatment including high-dose methotrexate-based chemotherapy followed by consolidation therapy in the form of autologous stem cell transplant or whole-brain radiation leads to improved survival. However, several patients do not respond to upfront therapy and the relapse risk is high. Additionally, there is a risk of delayed neurotoxicity, particularly in older patients. Recent molecular insights underlying the pathophysiology of PCNSL have led to the development of clinical trials involving targeted therapies and immunotherapies for salvage.


Subject(s)
Central Nervous System Neoplasms , Lymphoma, Non-Hodgkin , Aged , Antineoplastic Combined Chemotherapy Protocols , Central Nervous System , Central Nervous System Neoplasms/therapy , Combined Modality Therapy , Humans , Lymphoma, Non-Hodgkin/drug therapy , Methotrexate/therapeutic use , Neoplasm Recurrence, Local , Stem Cell Transplantation
17.
Hematol Oncol Clin North Am ; 36(1): e1-e8, 2022 02.
Article in English | MEDLINE | ID: mdl-34801164

ABSTRACT

Since the 2002 Institute of Medicine report, which many cite as a landmark in first defining and calling attention to the concept of health disparities in medicine, much work has been dedicated to characterizing health disparities in medical care with the aim of eliminating them. Importantly, this report, "Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care," laid bare the differences in quality of health care that are based on race, ethnicity, and socioeconomic status. Here, the authors elaborate on these issues and discuss the role of the neuro-oncologic workforce in potentially mitigating these disparities.


Subject(s)
Central Nervous System Neoplasms , Ethnicity , Central Nervous System Neoplasms/epidemiology , Central Nervous System Neoplasms/therapy , Delivery of Health Care , Humans , Socioeconomic Factors , United States
19.
Nat Commun ; 12(1): 5955, 2021 10 12.
Article in English | MEDLINE | ID: mdl-34642316

ABSTRACT

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.


Subject(s)
Brain Neoplasms/drug therapy , CTLA-4 Antigen/immunology , Immune Checkpoint Inhibitors/therapeutic use , Meningeal Carcinomatosis/drug therapy , Meningeal Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/immunology , Tumor Microenvironment/drug effects , Adult , Aged , Antibodies, Monoclonal, Humanized/therapeutic use , Brain Neoplasms/immunology , Brain Neoplasms/mortality , Brain Neoplasms/secondary , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/genetics , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/immunology , Female , Gene Expression Regulation, Neoplastic , Humans , Immunotherapy , Interferon-gamma/genetics , Interferon-gamma/immunology , Ipilimumab/therapeutic use , Male , Meningeal Carcinomatosis/immunology , Meningeal Carcinomatosis/mortality , Meningeal Carcinomatosis/pathology , Meningeal Neoplasms/immunology , Meningeal Neoplasms/mortality , Meningeal Neoplasms/pathology , Middle Aged , Nivolumab/therapeutic use , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/genetics , Single-Cell Analysis , Survival Analysis , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology
20.
Nat Commun ; 12(1): 5954, 2021 10 12.
Article in English | MEDLINE | ID: mdl-34642329

ABSTRACT

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.


Subject(s)
Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Combined Chemotherapy Protocols , Brain Neoplasms/drug therapy , Ipilimumab/administration & dosage , Meningeal Carcinomatosis/drug therapy , Meningeal Neoplasms/drug therapy , Nivolumab/administration & dosage , Adult , Aged , Anorexia/chemically induced , Anorexia/mortality , Anorexia/pathology , Antineoplastic Agents, Immunological/adverse effects , Brain Neoplasms/mortality , Brain Neoplasms/secondary , Colitis/chemically induced , Colitis/mortality , Colitis/pathology , Exanthema/chemically induced , Exanthema/mortality , Exanthema/pathology , Fatigue/chemically induced , Fatigue/mortality , Fatigue/pathology , Female , Fever/chemically induced , Fever/mortality , Fever/pathology , Hepatitis/etiology , Hepatitis/mortality , Hepatitis/pathology , Humans , Ipilimumab/adverse effects , Male , Meningeal Carcinomatosis/mortality , Meningeal Carcinomatosis/pathology , Meningeal Neoplasms/mortality , Meningeal Neoplasms/pathology , Middle Aged , Nausea/chemically induced , Nausea/mortality , Nausea/pathology , Nivolumab/adverse effects , Survival Analysis
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