bluuebunny/crossref_metadata_2025 huggingface dataset:
ATIM-34. SINGLE-CELL RNA SEQUENCING REVEALS DYNAMIC IMMUNE RESPONSE CHANGES IN GLIOBLASTOMA PATIENT WITH DURABLE COMPLETE RESPONSE TO CMV PP65-LAMP RNA-PULSED DENDRITIC VACCINES
Authors: Yegorov Oleg , Yang Changlin , Rahman Maryam , Ghiaseddin Ashley , Dechkovskaia Anjelika , Cleaver Brian , Hodik Marcia , Amdur Robert , Massini Tara , Kresak Jesse , Mitchell Duane
Published: November 2019

BACKGROUND

The application of single cell sequencing as a novel immune monitoring platform can enhance the ability to interrogate at unprecedented depth the single-cell level dynamic phenotypic and functional attributes of immune cells in patients undergoing cancer immunotherapy treatment. We applied single-cell sequencing analysis of PBMCs in a patient with newly-diagnosed GBM enrolled on the ATTAC II clinical trial (FDA IND BB-16530) who experienced a sustained complete radiographic response to autologous CMV pp65-LAMP RNA-pulsed DC vaccines plus GM-CSF and tetanus-diphtheria booster administered during adjuvant cycles of dose-intensified TMZ.

METHODS

We constructed 5’ gene expression libraries and T cell receptor enriched libraries for 10x Genomics single-cell sequencing, generated from PBMCs collected prior to and during patient immunization using dendritic cells loaded with RNA encoding the CMV matrix protein pp65 conjugated with the lysosomal associated membrane protein (LAMP) sequence.

RESULTS

RNA-Seq revealed dynamic changes in immune cell subsets over course of first three vaccines, including increases in cytotoxic T cells and memory T cell subsets. Increased markers of T cell activation were observed during vaccination including enhanced T cell signaling pathways, proliferative signals, and cytokine production. We found that proportion of cytotoxic T cells increased from 3.42% to 11.74% in whole PBMCs after immunization. Surprisingly, we observed very high level of frequency natural killer T (NKT) cells comprising 4.75 % of this patient’s PBMCs at baseline. After three DC vaccines, the level of NKT cells in PBMC increased up to 10%.

CONCLUSIONS

Single cell RNA sequencing of a patient with sustained complete response to DC vaccination during cycles of dose-intensified TMZ reveals dynamic immune activation and expansion within the cytotoxic T cells and NKT compartments. These results emphasize the importance of subset specific profiling to achieve higher resolution in monitoring immune responses compared with bulk expression profiling in patients receiving immunotherapeutic treatment.
ATIM-37. PHASE II, OPEN-LABEL, SINGLE ARM, MULTICENTER STUDY OF AVELUMAB WITH HYPOFRACTIONATED RADIATION (HFRT) FOR ADULT PATIENTS WITH SECONDARILY TRANSFORMED IDH-MUTANT GLIOBLASTOMA (GBM)
Authors: Kurz Sylvia , Silverman Joshua S , Hochman Tsivia , Nayak Lakshmi , Arrillaga-Romany Isabel , Lee Eudocia , Patel Amie , Delara Malcolm , Hsu Fraustina , Imtiaz Tooba , Magnelli Lori , Taylor Jennie , Cloughesy Timothy , Sulman Erik , Golfinos John , Zagzag David , Snuderl Matija , Goldberg Judith D , Chi Andrew S
Published: November 2019

BACKGROUND

There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a “hypermutator phenotype”. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily transformed IDH-mutant GBMs. Safety-lead-in results will be presented.

METHODS

This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE.

RESULTS

Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5–54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade ≥ 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade ≤ 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4–5.7). Median OS was 10.1 (range 6.8–21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual.

CONCLUSIONS

Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen.
ATIM-38. GLITIPNI: A PHASE 1B CLINICAL TRIAL COMBINING SURGICAL RESECTION WITH DIRECT INTRACEREBRAL INJECTION OF IMMUNE CHECKPOINT INHIBITORS IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Duerinck Johnny , Awada Gil , Katharina Schwarze Julia , Dufait Ines , Peeters Stephanie , Seynave Laura , Van Binst Anne-marie , Everaert Hendrik , Michotte Alex , Rogiers Anne , Van Velthoven Vera , Neyns Bart
Published: November 2019

INTRODUCTION

Intravenous (iv) administration of PD-1 blocking mAb is largely ineffective for the treatment of recurrent glioblastoma (rGB). Combination of iv-ipilimumab (IPI) plus nivolumab (NIVO) is associated with a high incidence of irAE. Intracerebral (ic) administration of immune-checkpoint inhibiting mAb following the resection of rGB could be a more effective and safer alternative to iv-dosing.

METHODS

Patients underwent maximal safe resection of their rGB followed by ic-injection of 10mg IPI (cohort-1) or 5mg IPI plus 10mg NIVO (cohort-2) in the wall of the resection cavity. In both cohorts 10mg nivolumab was administered iv for a max of 6 doses, starting 1 day pre-operatively.

RESULTS

21 pts were included (3 in C-1, 18 in C-2; 8F/13M; median age 56y [range 38–72]; 17 de novo GB, 4 secGB). All patients underwent maximal safe surgical resection followed by ic-injection of IPI and NIVO as planned. Median number of iv-administrations of NIVO was 5 (range 1–8). Treatment was generally well tolerated. Postoperatively, 2 patients experienced a G3 symptomatic increase in perilesional cerebral edema with neurological deterioration, reversible upon steroid treatment. One patient had worsening neurological symptoms related to an inflammatory intracerebral cyst at the resection site, requiring surgical decompression 4 months post-study treatment. Most frequent AEs were fatigue (2pts G3, 8pts G2), postoperative fever (11pts G1) and headache (3pts G2); 1pt developed G3 pneumonitis. No other immune-related AEs or treatment-related deaths occurred. After median follow-up of 60 weeks, median PFS is 14.4 weeks (95% CI 11.2–17.6); 11/21 patients are alive, and 1- and 2y-OS% are respectively 46% (95% CI 19- 73%), and15% (95% CI 0–42%).

CONCLUSION

This is the first study demonstrating the safety and activity of combined surgical resection of rGB with local intracerebral administration of immune checkpoint-inhibiting mAb. Survival compares favorably to historical controls justifying further investigation of this experimental therapy.
ATIM-43. PLASMA EXTRACELLULAR VESICLE MIRNA SIGNATURES IN GBM PATIENTS RECEIVING AN EXPERIMENTAL IMMUNOTHERAPY
Authors: Cumba-Garcia Luz , Dehankar Mrunal , Nair Asha , Parney Ian
Published: November 2019

Patients with glioblastoma (GBM) have a median survival of 15 months despite aggressive treatment. Immunotherapies such as dendritic cell (DC) vaccines have modest clinical efficacy in small clinical trials. Treatment-related pseudo-progression confounds outcome assessment by MRI, particularly in patients receiving immunotherapy. Thus, there is a need for additional non-invasive methods to monitor treatment response. Extracellular vesicles (EVs), especially plasma exosomes, contain tumor-specific microRNA (miRNA) cargo that could serve as a liquid biopsy to distinguish true progression from treatment-related pseudo-progression. Plasma exosomes were isolated by serial density gradient ultracentrifugation from 20 newly diagnosed GBM patients enrolled in a clinical trial of allogeneic tumor lysate-pulsed autologous DC vaccination. Short non-coding RNA sequencing and bioinformatics analysis was performed for each patient at three time points (TP): pre-vaccine (TP1), post-initial vaccine (TP2), and at end of treatment (TP3). miRNA expression analysis revealed a total of 14 upregulated and 12 downregulated miRNAs across time points (p-value < 0.05, |logFC| >1), few of which have been previously reported to be differentially expressed in GBM. Interestingly, patients’ miRNA profile expression differed more at the beginning of treatment (e.g. TP1-vs-TP2) and at subsequent time points (e.g. TP2-vs-TP3). Ingenuity Pathway Analysis is in progress to identify pathways associated with immunotherapy treatment response in malignant gliomas. In conclusion, miRNA sequencing from GBM patients’ plasma exosomes enrolled in our DC clinical trial shows marked differential miRNA expression between time points. These results suggest that as patients progress through treatment, consistent differences in plasma exosomal miRNA expression profile can be identified that could be utilized as predictors of treatment response. Thus, plasma EVs may serve as a robust platform to monitor treatment outcome.
ACTR-09. A PHASE 0 PHARMACODYNAMIC AND PHARMACOKINETIC STUDY OF EVEROLIMUS IN VESTIBULAR SCHWANNOMA (VS) AND MENINGIOMA PATIENTS
Authors: Karajannis Matthias , Goldberg Judith , Thomas Roland J , Sen Chandranath , Placantonakis Dimitris , Golfinos John , Allen Jeffrey , Dunbar Erin , Plotkin Scott , Akshintala Srivandana , Schneider Robert , Deng Jingjing , Neubert Thomas A , Giancotti Filippo , Zagzag David , O Blakeley Jaishri
Published: November 2019

BACKGROUND

Inhibition of mTORC1 signaling has been shown to diminish growth of NF2 deficient tumors in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of adult and pediatric NF2 patients with VS. To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (“phase 0”) clinical trial of everolimus in patients undergoing surgery for VS or meningiomas.

METHODS

Eligible patients with meningioma or VS requiring tumor resection received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively.

RESULTS

Ten patients completed protocol therapy, including 5 patients with NF2-related meningioma, 3 patients with sporadic meningioma, and 2 patients with NF2-related VS. Median pre- and post-operative plasma levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 ng/g (range 9.2–169.2), and median tumor tissue to post-operative plasma drug concentration ratio was 0.39. We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to matched control tissues from untreated patients (p = 0.005). Consistent with prior observations that inhibition of mTORC1 may lead to MAPK pathway activation through a PI3K-dependent feedback loop, we observed a statistically significant increase of phospho-ERK (p < 0.03) versus untreated controls.

CONCLUSIONS

In patients with meningioma or VS, treatment with everolimus leads to incomplete inhibition of mTORC1 signaling and upregulation phospho-ERK. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and identify upregulation of phospho-ERK as a likely resistance mechanism that could be addressed with combination therapies.
ACTR-14. A PROSPECTIVE RANDOMIZED STUDY OF CONCURRENT CHEMORADIOTHERAPY WITH TEMOZOLOMIDE VERSUS RADIOTHERAPY ALONE IN PATIENTS WITH IDH WILD-TYPE/TERT PROMOTER MUTATION GRADE II/III GLIOMAS
Authors: Liu Yanwei , Shan Xia , Qiu Xiaoguang
Published: November 2019

Our previous data showed that WHO grade II/III gliomas with isocitrate dehydrogenase wide-type (IDH-wt) and telomerase reverse transcriptase promoter mutation (TERTp-mut) have dismal prognosis as glioblastoma. This study compared concurrent chemoradiotherapy(CRT) with radiotherapy(RT) alone on the outcome of these patients. Between September 2016 and November 2018, 30 eligible grade II/III glioma patients with IDH-wt and TERTp-mut were randomly assigned to receive either RT (60 Gy in 30 daily fractions for 6 weeks) alone (n=15) or concurrent CRT with daily temozolomide and adjuvant temozolomide (n=15). The median follow-up duration was 15.5 months. The median age was 51 years (range, 24–66 years). The median Karnofsky performance status (KPS) score at randomization was 80 (range, 60–80). Surgery was the primary treatment. The characteristics of the two treatment groups were well balanced at baseline. The 1-year OS rate was significant difference between CRT group (92.3%; 95% CI: 77.8–100) and RT alone group(71.1%; 95% CI: 47.0–95.2) (p = 0.019). Local, distant, and combined tumor recurrence patterns were observed in 4 (26.7%), 1 (6.7%), and 3 patients (20%) in the CRT group and 4 (26.7%), 3 (20%), and 3 patients (20%) in the RT alone group. Those treated with RT alone had shorter median PFS (9 vs 18 months, HR: 0.517; 95% CI: 0.193 to 1.386; p = 0.19). CRT with temozolomide and extent of resection were statistically significant predictors for survival on univariate analysis. Multivariate analysis showed that CRT was associated with a significantly better OS compared with RT alone (OR=0.195; 95% CI, 0.044 to 0.867; p=0.032). Consequently, concurrent CRT with daily temozolomide and adjuvant temozolomide for newly diagnosed IDHwt/TERTp-mut grade II/III gliomas had significantly better OS compared with RT alone. A large multi-center prospective randomized trial is warranted. The trial has been registered at ClinicalTrials.gov (NCT02766270).
ACTR-16. MATRix REGIMEN FOR NEWLY DIAGNOSED PRIMARY DIFFUSE B-CELL LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM: PRELIMINARY RESULTS
Authors: Green Richard , Thornton Colleen
Published: November 2019

We report our preliminary experience treating 9 patients with newly diagnosed primary diffuse B-cell lymphoma of the central nervous system with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 63 y; 5 patients were men and 4 were women. Seven had cerebral mass lesions, 1 a paraspinal mass, and 1 leptomeningeal disease. Five patients underwent biopsy; 2 imaging total resection; 1 subtotal resection; and in 1 the extent of resection was indeterminate. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 4 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Two patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received 2 additional cycles that included cytarabine and thiotepa. Overall, 7 patients completed initial chemotherapy, with 5 complete responses and 2 partial responses. Six of these 7 went on to transplantation and remain alive without disease progression after a median follow-up of 470 days. One patient with initial PR progressed and did not proceed to transplantation. Two patients died after 1 cycle; they were both over 70 y (76 and 84) and succumbed to sepsis with neutropenic fever. No serious acute toxicity occurred in the 6 patients who completed the entire regimen including transplantation; 1 patient has experienced symptomatic leukoencephalopathy. Overall progression free survival was 394 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high early mortality in patients over 70 years in this group suggests that the regimen may be too toxic for very elderly individuals.
ACTR-21. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIAL OF DEPATUXIZUMAB MAFODOTIN (ABT-414) IN EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AMPLIFIED (AMP) NEWLY DIAGNOSED GLIOBLASTOMA (nGBM)
Authors: Lassman Andrew , Pugh Stephanie , Wang Tony , Aldape Kenneth , Gan Hui , Preusser Matthias , Vogelbaum Michael , Sulman Erik , Won Minhee , Zhang Peixin , Moazami Golnaz , Macsai Marian , Gilbert Mark , Bain Earle , Blot Vincent , Ansell Peter , Samanta Suvajit , Kundu Madan , Seidel Clemens , De Vos Filip , Hsu Sigmund , Cardona Andrés , Lombardi Giuseppe , Bentsion Dmitry , Peterson Richard , Gedye Craig , Lebrun-Frénay Christine , Wick Antje , Curran Walter , Mehta Minesh
Published: November 2019

BACKGROUND

Approximately 50% of nGBMs harbor EGFR-amp. Depatuxizumab mafodotin (depatux-m) is an antibody drug conjugate: a monoclonal antibody that binds activated EGFR (wild-type and EGFRvIII mutant) linked to a microtubule-inhibitor toxin. Pre-clinical and earlier clinical trials suggested efficacy.

METHODS

RTOGF 3508/AbbVie M13-813 (INTELLANCE-1, NCT02573324) was a phase 3 academic-industry collaboration (RTOG-Foundation, AbbVie). Eligible adults (KPS ≥ 70, EGFR-amp nGBM, centrally confirmed histology and biomarkers) were randomized 1:1 to radiotherapy (RT) and temozolomide and either depatux-m (2.0 mg/kg during RT, 1.25 mg/kg thereafter, q 14 days) or placebo, stratified by region of world, RPA class, MGMT methylation, and EGFRvIII mutation. Primary endpoint was overall survival (OS), with 640 patients planned for randomization; 441 events yielded 85% power to detect 25% reduction in hazard of death (HR 0.75), one-sided 2.5% level of significance by stratified weighted log-rank.

RESULTS

2229 patients were screened and 639 (median age 60, range 22–84; 394 men, 62%) randomized. Pre-specified interim analysis after 346 events (≥ 75% required) found no OS improvement for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.01, 95% CI 0.82–1.25, one-sided p= 0.63). Progression-free survival (PFS) trended toward depatux-m (median 8.0 vs. 6.3 months; HR 0.84, 95% CI 0.70–1.02), particularly among the ~50% with EGFRvIII mutation (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93) but without an OS improvement (median 19.8 vs. 18.2, HR=0.95, 95% CI 0.71–1.27). Ocular side effects (grade ≥ 1) occurred in 95% of depatux-m treated patients, 61% grade 3–4, causing 12% to discontinue, and were the most common treatment related adverse events.

CONCLUSION

Interim analysis demonstrated no OS benefit for treating EGFR-amp nGBM with depatux-m. PFS trended toward favoring depatux-m, particularly in the EGFRvIII harboring subgroup. No new important safety risks were identified. The trial was stopped for futility. Active patients are permitted to continue treatment.
ACTR-22. INITIAL TREATMENT OF GBM WITH A KETOGENIC DIET ALONG WITH RADIATION AND CHEMOTHERAPY: CLINICAL OUTCOMES
Authors: Schwartz Kenneth , Noel Mary , Nikolae Michele , Olson Karl , Zakem Micheal , Elnabtity Mohamed , Clark Justin , Figueroa Bryan , Chang Howard
Published: November 2019

INTRODUCTION

Combining an adjuvant ketogenic diet (KD) with standard therapy of radiation and chemotherapy right after tissue diagnosis is feasible and safe. We report outcomes of a pilot clinical trial study using a KD combined with radiation and chemotherapy as initial therapy for glioblastoma (GBM).

METHODS

Eligibility criteria included: 1. Tissue diagnosis; 2. Age over 18; 3. ECOG performance status of 2 or better; and 4. Not having diabetes or being pregnant. An isocaloric KD diet with 3:1 weight ratio of fat to combined weight of carbohydrate and protein was supervised by an experienced dietitian and maintained with initial radiation and chemotherapy for 6 weeks.

RESULTS

9 patients (8M, 1F, mean age 45) completed the prescribed 6 week trial. Blood counts, chemistries, lipid profiles and uric acids were not markedly changed. Ketosis was maintained for the 6 week study period with blood ketone and glucose levels checked twice daily. 3 younger patients (mean age 28 at diagnosis) are working and show no progression of their gliomas at 49 (IDH +), 31 (IDH WT with methylated MGMT), and 32 (IDH WT) months since diagnosis. 6 older male patients (mean age 54) have died at 25, 25, 13, 12, 9 and 9 months after diagnosis. A recent report of 6 additional older male pts mean age 53 tx with a KD with daily checks of blood ketones showed limited survival ranging from 12–19 mo. (van der Louw accepted for pub in “Therapeutic Advances in Medical Oncology”).

CONCLUSION

KD may be a helpful in initial treatment of GBM patients, especially in younger patients. Additional studies are needed. However, since 12 older male patients have not substantially benefited from the KD, we suggest that future evaluations of the efficacy of KD for GBM be focused towards younger patients.
ACTR-23. MAINTENANCE TREATMENT WITH IBRUTINIB FOLLOWING FIRST LINE METHOTREXATE-BASED IMMUNO-CHEMOTHERAPY IN ELDERLY PATIENTS WITH PRIMARY CNS LYMPHOMA (PCNSL). A PHASE 2 OPEN-LABEL STUDY
Authors: Bairey Osnat , Benouaich-amiel Alexandra , Yust-Katz Shlomit , Gurion Ronit , Siegal Tali
Published: November 2019

BACKGROUND

Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment prolongs PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas.

METHODS

Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate–based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months.

RESULTS

Of the 16 patients screened for the study 2 were excluded due to relapse while on screening. 14 patients have been enrolled with a median age of 74 (61–80) years. The median interval between PCNSL diagnosis and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed.

CONCLUSIONS

Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-MTX based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.
ACTR-37. ASSOCIATION BETWEEN MGMT PROMOTER METHYLATION SCORE AND SURVIVAL IN PATIENTS WITH GLIOBLASTOMA
Authors: Romo Carlos , Shah Pavan , Sun Yuqing , Ye Xiaobu , Grossman Stuart
Published: November 2019

BACKGROUND

MGMT promoter methylation is associated with longer survival in patients with high-grade gliomas who receive alkylating therapy. Methylation status is commonly determined by methylation-specific PCR and results are reported in two forms: a dichotomization of “present” or “not present,” and as a methylation score (MGMT/beta-actinx1000). The primary objective of this study is to determine the association between the degree of methylation and overall survival (OS) in newly diagnosed patients with glioblastoma.

METHODS

A retrospective IRB-approved study was conducted of 684 patients treated at Johns Hopkins from 2007–2015. Adults with a histologically confirmed glioblastoma treated with standard therapy were included in the analysis. OS was estimated from the date of diagnosis to time of death or last follow up using the Kaplan–Meier method. Cox regression model was used to assess possible positive association between MGMT score and OS. For purposes of this analysis IDH1-mutated patients were excluded.

RESULTS

In 100 evaluable patients, median age at diagnosis was 56 years [45–77]. Fifty-two patients were MGMT promoter methylated (score ≥2.00) and 48 were unmethylated. The median OS was 31 months in the methylated patients and 15 months in the unmethylated (p=0.0001). Methylated patients had MGMT scores ranging from 2.53-1278. The methylated scores were classified into 3 groups; #1: 0-25th percentile, #2: 25-75th percentiles, and #3: >75th percentile. mOS was: 30.8 months for group 1 (n=13); 34.8 months for group 2 (n=27); and 20.9 months for group 3 (n=12) (p=0.19). Difference in mOS between groups 1 and 3 was not statistically significant (HR 0.819 [95% CI, 0.3–2.2], p=0.69).

DISCUSSION

The prognostic value of MGMT promoter methylation in patients with glioblastoma was replicated in our study sample. The degree of methylation reported as a score on routine testing does not appear to be directly related to OS in this patient population.
ACTR-39. PAMIPARIB IN COMBINATION WITH RADIATION THERAPY (RT) AND/OR TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED OR RECURRENT/REFRACTORY (R/R) GLIOBLASTOMA (GBM); PHASE 1B/2 STUDY UPDATE
Authors: Piotrowski Anna , Puduvalli Vinay , Wen Patrick , Campian Jian , Colman Howard , Pearlman Michael , Butowski Nicholas , Battiste James , Glass Jon , Cloughesy Timothy , Schiff David , van den Bent Martin , Walbert Tobias , Ahluwalia Manmeet , Badruddoja Michael , Kalra Amandeep , Aregawi Dawit , Weller Michael , Ramakrishnan Vanitha , Zhang Kathy , Wood Katie , Mellinghoff Ingo , Shih Kent
Published: November 2019

Pamiparib, an investigational, selective PARP1/2 inhibitor that has demonstrated potent PARP trapping and ability to cross the blood-brain barrier, showed synergistic cytotoxicity with TMZ preclinically. We report updated safety and antitumor effects from a phase 1b/2 study of pamiparib + RT and/or TMZ in patients with newly diagnosed or R/R GBM (SNO 2018, ACTR-30). The dose-escalation/expansion study has 3 arms: Arm A, pamiparib (2, 4, or 6 weeks) + RT in newly diagnosed GBM patients with unmethylated MGMT promoter (unmethylated-GBM); Arm B, pamiparib (6 weeks) + RT and increasing TMZ dosed in weeks 1 and 5 of RT in newly diagnosed, unmethylated-GBM patients; and Arm C, pamiparib + increasing TMZ doses in methylated/unmethylated R/R-GBM patients. Arm A and B patients receive maintenance treatment post-RT rest period at the Arm C expansion dose/schedule. As of 10 April 2019, accrual was completed for Arms A and C dose-escalation (A: n=20; C: n=17) and continues in the dose expansion (A: n=28/40; C: n=28/30); accrual was completed in dose escalation for B (n=9). Recommended phase 2 doses were established for Arms A (pamiparib 60 mg BID×6 weeks + 6–7 weeks RT) and C (pamiparib 60 mg BID d1–28 + TMZ 60 mg d1–7/28-d cycle). One dose-limiting toxicity (grade 3 febrile neutropenia) was reported in Arm B. Treatment-related adverse events (≥10%) were (overall/grade 3 [no grade 4/5]): Arm A, nausea (23%/2%); B, decreased WBC count (11%/11%); C (none). Of patients with tumor assessment post-RT: Arm A (n=17), 1 had cPR, 1 uPR, and 9 SD (disease control rate, 64.7% [95% CI, 38.3–85.8]); C (n=26), 1 had cPR (sustained 12 cycles), 1 uPR, and 5 SD (objective response rate, 7.7% [95% CI, 0.9–25.1]). Pamiparib 60 mg BID + RT/TMZ was generally well tolerated in patients with newly diagnosed or R/R GBM. Clinical trial ID: NCT03150862
ACTR-48. CLINICAL DEVELOPMENT TARGETING AXL IN RECURRENT GLIOBLASTOMA
Authors: Nakano Ichiro
Published: November 2019

Glioblastoma (GBM) is a lethal disease without effective therapies. Previously we reported that the TAM receptor tyrosine kinase family member AXL is upregulated in mesenchymal GBM and its knockdown induces apoptosis of mesenchymal but not proneural glioma sphere cultures (GSCs). In this study, we report that BGB324, a novel small molecule inhibitor for AXL, prolongs the survival of immunocompromised mice bearing mesenchymal GSC-derived GBM-like intracranial tumors by inhibition of AXL activation in tumor cells. Mechanistically, we identified that protein S (PROS1), known as a ligand for other TAM receptors, is secreted by tumor-associated macrophages, thereby physically associates and activates AXL in mesenchymal GSCs. The PROS1-driven phosphorylation of AXL resulted in the NF-kB activation in mesenchymal GSCs and this activation was eliminated by BGB324 treatment. In addition, BGB324 downregulated the immune checkpoint protein PD-L1 both in vitro and in vivo. Combination of BGB324 with Nivolumab - the neutralizing antibody for PD-1 (a receptor for PD-L1) was effective to prolong the survival of immunocompetent mice bearing syngeneic GBM models. Clinically, both AXL and PROS1 expression indicated poorer prognosis of GBM patients. These data suggest that the PROS1/AXL pathway regulates intrinsic mesenchymal signaling as well as extrinsic immune microenvironment, contributing to the growth of aggressive GBM tumors. To translate the pre-clinical data to human GBM patients, we designed a surgical PK/PD clinical trial with BGB324 for recurrent GBM. As of May 2019, this trial, termed ABTC1701, is in pending approval by the Brain Malignancy Steering Committee in the National Cancer Institute.
ACTR-56. PHASE II TRIAL OF NILOTINIB IN PDGFR-ALPHA ENRICHED RECURRENT GLIOBLASTOMA
Authors: Picconi David , Juarez Tiffany , Kesari Santosh
Published: November 2019

BACKGROUND

This phase II study was designed to determine the efficacy of nilotinib in a biomarker-selected population of recurrent glioblastoma (GBM), enriched for platelet-derived growth factor receptor-alpha (PDGFR-alpha) activation. Nilotinib is a multi-kinase inhibitor approved as treatment for Philadelphia-chromosome/Bcr-Abl chronic myelogenous leukemia. In addition to targeting Bcr-Abl tyrosine kinase, it also inhibits PDGFR-alpha signaling.

METHODS

Patients with recurrent GBM, with either PDGFR-alpha amplification or PDGFR-alpha overexpression by immunohistochemistry (IHC) were enrolled in a single-arm, single institution phase II study. Nilotinib was administered at 400 mg twice a day. The primary end point was progression-free survival at 6 months (PFS6). Secondary end points were safety, overall survival (OS) and Objective Response Rate (ORR).

RESULTS

34 patients were treated (22 IDH-wild type GBM, 2 IDH-mutant GBM, 10 GBM NOS). 26 were male and 8 were female. Median age was 55.5 (range 22–78 years). Four patients had PDGFR-alpha amplification, and 30 had overexpression by IHC. Median lines of prior therapy were 1 (range 1–7). 6/34 patients (18%) experienced related adverse events grade ≥ 3. There were no grade 5 events. The PFS6 was 9% (3/34), and PFS12 was 6% (2/34). Median PFS was 1.3 months and the median OS was 6.6 months. Best response was stable disease (SD) for 8 patients and complete response (CR) for one patient. ORR was 1/34 patients (3%). The patient with a CR was IDH-wild type, unmethylated, had PDGFR-alpha overexpression by IHC, and had a durable response > 5 years.

CONCLUSION

Nilotinib had limited activity in recurrent GBM enriched for PDGFR-alpha, although there were a small number of durable responders. Further molecular characterization is warranted to determine additional biomarkers of response that could be used to select patients that may benefit from nilotinib.
SURG-02. STAGED SURGERY FOR SELECTED GIANT ADULT PITUITARY ADENOMA
Authors: Ma Jun , Ma Shunchang , Jia Guijun , Yao Fei , Jia Wang
Published: November 2019

PURPOSE

Combined surgical strategy with both trans-cranial surgery and trans-sphenoid surgery is necessary for selected giant pituitary adenoma with both intra-cranial and intra-sphenoidal invasion. Cases of staged surgery were reviewed retrospectively to deeply investigate this treatment strategy.

METHODS

Adult cases received staged surgery were reviewed. Data regarding clinical presentation, laboratory tests, image examination, surgery details, and outcome were analyzed. The size and invasion was evaluated by pre-op MR and intra-op observation. Diagnosis was confirmed by histology examination. Literatures were reviewed.

RESULTS

8 NFPAs were included. 4 received trans-cranial resection first while the other 4 received trans-sphenoidal resection first. Time interval between two operations was 1–2 months. After the first surgery, the rate of visual defects and of pituitary hypofunction improvement were higher in trans-cranial first group. 1 apoplexy and 1 CSF rhinorrhea were observed in trans-sphenoidal first group. After the second surgery, the extend of resection and the rate of complete visual symptoms improvement were higher in trans-cranial first group. All pituitary hypofunction resolved completely in long-term follow-up. 11 literatures were reviewed.

CONCLUSIONS

An appropriate surgical strategy is essential for selective pituitary adenoma requiring combined resection. For staged surgery cases, taking trans-cranial approach for first stage with trans-sphenoidal subsequently, comparing to the inverse resection order, would offer higher extent of resection with less recurrence, earlier and better symptom improvement, and less post-op complications after first stage. Further investigation is necessary.
SURG-07. STEREOTACTIC LASER ABLATION AS A THERAPEUTIC OPTION FOR RECURRENT GLIOBLASTOMA: A LARGE SINGLE INSTITUTIONAL EXPERIENCE
Authors: Hwang Lee , Barnett Gene , Mohammadi Alireza
Published: November 2019

INTRODUCTION

The prognosis of patients diagnosed with recurrent glioblastoma remains dismal, and therapeutic options are limited. The median survival is only 3 to 5 months. Stereotactic laser ablation is a minimally invasive neurosurgical technique used as an ablative treatment. We report outcomes of a large single institutional patient database of recurrent glioblastoma treated with laser ablation.

METHODS

Patients with recurrent glioblastoma, previously treated with biopsy or surgical resection plus standard radiation/temozolomide (and any other additional therapies), who underwent laser ablation with the NeuroBlate system at The Cleveland Clinic were retrospectively reviewed from 2011 through 2017. Primary endpoints were progression free survival (PFS) and overall survival (OS).

RESULTS

Between 2011 and 2017, 31 patients with recurrent glioblastoma were treated with laser ablation out of more than 250 laser ablation cases for brain tumors. This population included 17 males and 14 females. Age at the time of diagnosis ranged from 27 to 77. 84% underwent surgical resection as the initial treatment. 65% were treated with laser ablation after the first recurrence of previously treated glioblastoma. The average number of postoperative hospital days was 2.8, and most patients went home. 54% remained neurologically stable without new postoperative deficits, and 52% had no reported change in Karnofsky Performance Scale from before to after laser ablation. Median PFS was 5 months, and median OS was 13 months.

CONCLUSIONS

Laser ablation has been used to treat various intracranial lesions at The Cleveland Clinic, particularly recurrent glioblastoma. This treatment modality can be utilized at any point of recurrence in patients with appropriate clinical and radiographic characteristics. In addition, the minimally invasive nature and relatively short hospital stay in comparison to surgical tumor resection make laser ablation favorable. Laser ablation is becoming a valuable tool in a multidisciplinary approach to treat recurrent glioblastoma.
SURG-13. DAY-CASE IMAGE-GUIDED BIOPSY FOR BRAIN TUMOURS: A DECADE OF EXPERIENCE FROM A SINGLE NEUROSURGICAL UNIT IN THE UNITED KINGDOM
Authors: Wykes Victoria , McElligott Simon , Roach Joy , Duffill Jonathan , Weidmann Crispin , Grundy Paul
Published: November 2019

In the United Kingdom widespread adoption of day-case image-guided biopsy (DIB) for brain tumour has yet to develop. We review a decade of experience of DIB for suspected supra-tentorial brain tumour and recommend discharge criteria for patients post-operatively. 30-day complications, post-operative admissions into hospital and patient satisfaction are examined.

METHODS

Published protocols and procedures for DIB of brain tumours were used. Tissue samples were sent for fixed histological preparation without intraoperative neuropathological assessment. All patients undergoing an image-guided biopsy for tumour were retrospectively identified from operative logbooks (01/10/2006–30/09/2016), and information recorded from online records. Patients completed satisfaction questionnaires.

RESULTS

706 image-guided biopsies for supratentorial tumour were performed of which approximately 60% were identified pre-operatively as candidates for DIB. 92% of DIB patients were successfully discharged 6 hours postoperatively. 4.5% of DIB patients were admitted directly from the day-case unit following identification of a postoperative haematoma >2 cm diameter on CT head performed at 4 hours. 3/401 DIB patients (< 1%) required surgical evacuation for the haematoma, all made a full recovery, with no delay to commencing their oncological management. A diagnostic accuracy of 98% was achieved. Overall 90% of patients were satisfied about the timing of their discharge from hospital and 92.5 % felt they had enough medical support following discharge.

DISCUSSION

Conscious sedation with enhanced recovery techniques, lack of intra-operative neuropathological analysis and a stream lined service with robust communication between patients, carers/families and the oncology allied medical professionals has ensured that DIB for diagnosis of tumour is safe, reliable and feasible for most patients and is not associated with increased morbidity or mortality. The procedure is well tolerated with good patient satisfaction. We recommend that patients with a good pre-operative functional baseline, requiring a supra-tentorial biopsy are offered day-case surgery in a dedicated unit specialising in this procedure.
SURG-26. READMISSION FOLLOWING RESECTION FOR PATIENTS WITH BRAIN METASTASES IN THE UNITED STATES
Authors: Kotecha Rupesh , Rubens Muni , Gonzalez-Arias Sergio , Siomin Vitaly , Hall Matthew , Odia Yazmin , Vogelbaum Michael , Mehta Minesh
Published: November 2019

OBJECTIVE

Up to 30% of cancer patients will develop brain metastasis during the course of their systemic disease with a significant proportion undergoing resection of at least one lesion. The objective of the present study was to characterize the rates, predictors, and costs of 30-day readmissions following craniotomy for brain metastases using a nationally representative database.

METHODS

This study was a retrospective analysis of data from the Nationwide Readmissions Database (NRD) from 2010–2014. We included patients who underwent craniotomy for brain metastasis, identified using ICD-9-CM diagnosis (198.3) and procedure (01.59) codes. The primary outcome of the study was unplanned 30-day all-cause readmission rates. Secondary outcomes included predictors and costs of readmissions.

RESULTS

During the study period, there were 44,846 index hospitalizations for patients who underwent resection of brain metastasis. Among this cohort, 17.8% (n=7,965) had unplanned readmissions within the first 30 days after discharge from the index hospitalization. The readmission rate did not change significantly during the study period (P=0.286). The odds of unplanned readmission were significantly greater in patients with thromboembolic complications (aOR, 1.53; 95% CI: 1.18–2.01), patients with Elixhauser comorbidities >3 (aOR, 1.35; 95% CI: 1.22–1.50), male patients (adjusted odds ratio [aOR], 1.29; 95% CI: 1.17–1.42), patients with an initial length of stay ≥5 days (aOR, 1.02; 95% CI: 1.01–1.03). The median per-patient cost for 30-day unplanned readmission was $11,109 and this accounted for a total cost of $132.1 million during the study period.

CONCLUSIONS

Unplanned readmissions after resection for brain metastases involve substantial healthcare expenditures. Though there have been many interventions for improving surgical quality, post-operative care, and cost metrics, unplanned readmission rates have not changed. Key patient-specific variables and high rates of comorbidities should be considered to focus our efforts on patient selection for resection, and for strengthening existing interventions for high-risk patients.
SURG-33. IMMUNO-STIMULATION THROUGH SURGICALLY ADMINISTERED MECHANICAL HIGH INTENSITY FOCUSED ULTRASOUND
Authors: Wang James , Huang Chin-Hsin , Echeagaray Oscar , Amirfakhri Siamak , Blair Sarah , Trogler William , Kummel Andrew , Chen Clark
Published: November 2019

INTRODUCTION

While immunotherapy through anti-PD1 checkpoint inhibition has demonstrated impressive clinical efficacy against a number of tumor types, its application has been ineffective against glioblastomas.

METHODS

We wished to determine whether high intensity focused ultrasound (HIFU) augment the efficacy of anti-PD1 checkpoint inhibition against glioblastomas. HIFU can be surgically administered through low-duty cycle to induce subcellular fragmentation without causing temperature elevation (termed mechanical HIFU). Alternatively, HIFU delivered through high duty cycle can induce foci of temperature elevation and thermal ablation (termed thermal HIFU). We tested the impact of mechanical and thermal HIFU on the anti-glioblastoma effects of the immune checkpoint inhibitor, ipililumab.

RESULTS

In an in vivomurine glioblastoma model, sites targeted by mechanical HIFU exhibited a 10–100 fold increase in accumulation in tumor infiltrating lymphocytes and interferon-γ (IFN-γ) in the presence of PD-1 blockade. At least 75% of mice engrafted with glioblastomas achieved remission when treated with mechanical HIFU and PD-1 blockade. In contrast, none of the mice treated with single therapies achieved durable remission. Likelihood of remission correlated with the abundance of tumor infiltrating lymphocytes (p< 0.001) and IFN- γ levels (p=0.001). The synergy observed between mechanical HIFU and PD-1 blockade was not seen when combining thermal HIFU and PD-1 blockade, suggesting thermal protein denaturation is prohibitive to immune-stimulatory effects of HIFU.

CONCLUSION

Mechanical HIFU, but not thermal HIFU, augments the anti-glioblastoma effects of PD-1 blockade. Our findings inform the utility of HIFU as an immune-adjuvant in glioblastoma therapy that can be surgically administered.
TMIC-04. CANCER STEM CELL GENETIC AND GENOMIC ALTERATIONS DIFFERENTIALLY DICTATE STROMAL CELL REGULATION OF LOW-GRADE GLIOMA GROWTH
Authors: Guo Xiaofan , Pan Yuan , Gutmann David
Published: November 2019

BACKGROUND

Children with the Neurofibromatosis type 1 (NF1) brain tumor predisposition syndrome are prone to the formation of low-grade gliomas (LGGs) of the optic pathway (optic pathway glioma; OPG). While all tumors harbor bi-allelic NF1 gene inactivation, there is significant clinical variability in affected children with respect to tumor growth, associated neurologic deficits, and response to therapy. In order to identify the potential factors that contribute to glioma biological variability, we leveraged a series of Nf1 mutant optic glioma mouse strains with different germline Nf1 gene mutations and secondary genomic alterations.

METHODS

Cancer stem cells (optic glioma stem cells; o-GSCs) were isolated from these Nf1 mutant optic glioma mouse strains, and their intrinsic growth properties and chemokine expression profiles determined.

RESULTS

Differences in the intrinsic o-GSC growth properties did not account for the observed differences in Nf1 optic glioma tumor growth. Instead, Nf1 optic glioma tumor growth correlated with the differential recruitment of T cells and microglia by chemokines produced by the o-GSCs. As such, the collective action of T cells and microglia dictated the level of Ccl5 expression, the key stromal factor that determines murine NF1-associated optic glioma growth.

CONCLUSIONS

Taken together, these observations demonstrate that genomic and genetic differences within the cancer cells create unique Nf1 optic glioma growth patterns through the differential elaboration of chemokines that attract T cells and microglia. GRANT SUPPORT: This work was funded by grants from the National Cancer Institute (1-R01-CA195692-01) and the National Institute of Neurological Disorders and Stroke (1-R35-NS07211-01) to D.H.G, as well as to the Hope Center Viral Vectors Core and the Genome Technology Access Center (UL1-TR000448). Y.P. was supported by a fellowship grant from the James S. McDonnell Foundation.
TMIC-21. TARGETING INVADOPODIA TO BLOCK IONIZING RADIATION-INDUCED GLIOBLASTOMA CELL INVASION
Authors: Decotret Lisa , Bennewith Kevin
Published: November 2019

BACKGROUND

Glioblastoma multiforme (GBM) is a highly heterogeneous and aggressive brain tumour that is considered incurable. The majority of GBM patients have a median survival of 15 months despite undergoing extensive treatment. The principal reason for poor outcome is a high rate of recurrence, often due to the tumours cells escaping therapy by infiltrating into the surrounding healthy brain tissue. Previous work from our lab suggests tumour cells that survive radiation therapy (RT) exhibit a more aggressively metastatic phenotype. We hypothesize that RT may increase GBM cell invasion by promoting the activity of invadopodia. Invadopodia are protrusions of the plasma membrane that secrete matrix metalloproteinases to degrade surrounding tissue. Further understanding of the mechanisms by which RT regulates invadopodial biology may lead to new therapeutic strategies to slow or halt the invasion of GBM cells and extend the lives of patients.

RESULTS

Three human GBM cell lines were exposed to 0, 2, or 5 Gy of ionizing radiation (IR) prior to quantification of cell viability by clonogenic survival assays. Invasion was investigated using a Transwell Matrigel Invasion Assay 48 hours post-IR. Exposure to 2 Gy IR increased invasion of LN229 and U87-MG cells but not LN18 cells. These data suggest that clinically relevant levels of radiation (2 Gy) increases the invasiveness of a subset of GBM cells in vitro. We are currently analyzing proteomic changes in LN229, U87-MG, and LN18 cells post-IR to identify novel drivers of IR-induced GBM cell invasion. Future work will involve genetically or pharmacologically inhibiting the proteins identified via mass spectrometry to determine their role in therapy induced invadopodia-mediated GBM cell invasion. SIGNIFICANCE: Recent evidence suggests tumour cells that survive RT exhibit a more aggressive phenotype. Identifying novel therapeutic targets to limit IR-induced GBM invasion may help to increasing the efficacy of current brain cancer therapy.