bluuebunny/crossref_metadata_2025_split huggingface dataset:
ATIM-15. SUSTAINED COMPLETE RADIOGRAPHIC RESPONSE AND PROLONGED SYSTEMIC IMMUNE ACTIVATION IN A PATIENT WITH MGMT UNMETHYLATED MIDLINE GLIOBLASTOMA RECEIVING CMV pp65-LAMP RNA-PULSED DENDRITIC CELL VACCINES
Authors: Rahman Maryam , Ghiaseddin Ashley , Yegorov Oleg , Yang Changlin , Dechkovskaia Anjelika , Tran David , Massini Tara , Kresak Jesse , Mitchell Duane 
Published: November 2019

Abstract

BACKGROUND
We initiated a Phase 2, randomized, placebo-controlled, clinical trial evaluating the efficacy of autologous CMV pp65-LAMP RNA pulsed dendritic cell vaccines mixed with GM-CSF and administered during cycles of adjuvant dose-intensified temozolomide (ATTAC II, NCT02465268).

STUDY OBJECTIVE
A patient with partially resected GBM experienced a sustained complete radiographic response after receiving five DC vaccines. Peripheral blood responses were characterized to examine possible immunologic biomarkers concordant with a sustained clinical response.

METHODS
Patients with newly diagnosed glioblastoma undergoing surgical resection are eligible and randomized 2:1 to DC vaccine arms vs placebo (PBMCs in saline). DC vaccines consist of CMV pp65 RNA conjugated either to the full-length lysosomal associated membrane protein (LAMP) or to the short LAMP signal sequence. Patients undergo leukapheresis for DC generation prior to standard chemoradiation and receive cycle 1 of dose-intensified temozolomide (100 mg/m^2 x 21 days) before first three biweekly intradermal DC vaccines admixed with GM-CSF. Subsequent DC vaccines (total of 10) are given monthly with each diTMZ cycle with an intradermal tetanus-diphtheria booster given 6-24hrs before the third, fifth, seventh, and ninth DC vaccines. PBMCs and serum are collected for immune monitoring.

RESULTS
A 58-year old white male with partially-resected, MGMT-unmethlyated, p53 mutant, H3.3 mutant, midline glioblastoma was enrolled on the ATTAC II study and experienced a complete radiographic response after the fifth DC vaccine that has been sustained > 10 months. Immune monitoring by Elispot, cytokine array, and single-cell RNA sequencing have revealed significant expansion of CMV pp65-specific immune responses, increased circulating IFNg, and marked systemic expansion of cytotoxic T cells and iNKT cells during vaccination. These responses were sustained through cycles of diTMZ despite profound lymphopenia.

CONCLUSIONS
CMV pp65-LAMP RNA-pulsed DC vaccination was associated with profound immunologic and clinical response in a patient with MGMT unmethylated midline glioblastoma.
ATIM-27. TUMOR MUTATIONAL BURDEN PREDICTS RESPONSE TO ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) IN MALIGNANT GLIOMA PATIENTS: ASSESSMENT OF TRANSCRIPTIONAL AND IMMUNOLOGICAL CORRELATES
Authors: Gromeier Matthias , Brown Michael , Beuabier Nike , Yan Hai , He Yiping , Zhang Gao , Desjardins Annick , Herndon James , Bolognesi Dani , Friedman Allan , Friedman Henry , McSherry Frances , Lin Xiang , Wei Zhi , Nair Smita , Peters Katherine , Randazzo Dina , Sampson John , McLendon Roger , Bigner Darell , Ashley David 
Published: November 2019

Abstract

BACKGROUND
The live attenuated oral poliovirus vaccine was modified to contain a heterologous internal ribosomal entry site stemming from human rhinovirus type 2, creating PVSRIPO. PVSRIPO recognizes CD155, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We have previously reported that deep sequencing of biopsy material obtained prior to PVSRIPO infusion confirmed that a very low mutational load is associated with longer survival.

METHODS
Patient tumor material from both phase I and 2 clinical trials was collected pre PVSRIPO. When available, post-treatment tissue from longitudinal samples were also collected. Tissue was subjected to RNA sequencing, histological analysis, and flow cytometry analysis. RNAseq analyses were performed comparing pre- and post- treatment expression profiles and computational predictions of tumor immune composition deciphered changes after PVSRIPO therapy. Histology and flow cytometry quantitated myeloid, CD8/4/regulatory T cell densities, and other immune cell types after treatment and compared to baseline tissue similarly analyzed to detect changes.

RESULTS
To date, analysis of phase 1 trial data has demonstrated a correlation between low TMB and increased markers of immunological gene expression profiles. This trend was not observed in TCGA samples that were almost exclusively primary GBM suggesting and interplay with prior therapy or evolution with recurrence.

CONCLUSION
Our findings presented here suggest that response to PVSRIPO therapy, and possibly that of other modalities engaging innate antiviral signatures in situ, may be dependent upon prevailing tumor microenvironment composition/status at the time of treatment.
ATIM-28. PHASE II TRIAL OF AV-GBM-1 (AUTOLOGOUS DENDRITIC CELLS LOADED WITH TUMOR ASSOCIATED ANTIGENS) AS ADJUNCTIVE THERAPY FOLLOWING SURGERY PLUS CONCURRENT CHEMORADIATION IN NEWLY DIAGNOSED GBM PATIENTS
Authors: Bota Daniela , Taylor Thomas , Picconi David , Duma Christopher , Aiken Robert , LaRocca Renato , Xiao-Tang Kong , Fu Beverly , Alsharif Mohamad , Hsieh Candace , Nistor Gabriel , Dillman Robert 
Published: November 2019

Abstract
Newly-diagnosed glioblastoma (GBM) patients have a limited survival (18–24 months). In the last decade immunotherapy has improved survival for patients with other malignancies, but not GBM. Herein we present the design and initial enrollment results for the AV-GBM-1 single-arm phase 2 trial. The study enrolls patients with primary GBM who have undergone craniotomy, have a tumor cell culture established, and complete satisfactory leukapheresis prior to planned concurrent chemotherapy and radiation. Patients are scheduled to receive up to 8 vaccine injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Blood samples are collected just prior to each injection. The primary endpoint is overall survival from date of enrollment for intent-to-treat with AV-GBM-1. The study has fully enrolled 26 of planned 55 patients. The cell line success rate is 30/32, with 6 in progress; successful completion of leukapheresis is 28/29. Two patients have completed all 8 doses, two discontinued after dose 3 and dose 6 because of progressive disease; 15 are currently in treatment, and 6 are about to start treatment. There have been seven SAE, all for hospitalizations related to GBM. For the first 8 treated patients, plasma samples from baseline and weeks 2, 3, and 8 have been analyzed for immune markers by RayBiotech Life Inc. using quantitative multiplex ELISA array. Markers reflecting Th1, Th2, Th17 pathways and B-cells, natural killer cells and cytotoxic T-lymphocytes increased in 7/8 patients. Principal component analysis demonstrates correlative marker groupings with early dominance of Th1/Th17 (weeks 1 and 2) followed by Th2/immunoglobulins at week 8. These findings show that these patient-specific dendritic cell vaccines are inducing pro-inflammatory responses similar to what was observed in a previous trial in melanoma. The study is progressing efficiently. Full enrollment data may be available for presentation at the time of the annual meeting.
ATIM-32. PREDICTORS OF IMPROVED SURVIVAL FOLLOWING ONCOLYTIC VIRUS TREATMENT IN PATIENTS WITH RECURRENT GLIOBLASTOMA: GENE EXPRESSION ANALYSIS FROM THE PHASE IB G207 CLINICAL TRIAL
Authors: Cassady Kevin , Miller Katherine , Prasad Nripesh , Maric Dragan , Bernstock Josh , Roth Justin , Barker Naomi , Coleman Jennifer , Schieffer Kathleen , Leraas Kristen , Miller Anthony , Leavenworth Jianmei , Cutter Gary , Whitley Richard , Roizman Bernard , Yancey Gillespie G , Mardis Elaine , Markert James 
Published: November 2019

Abstract
Our Phase I trials of experimental virotherapy for recurrent glioblastoma (GBM) have shown that inoculation with a conditionally replication-competent early generation oncolytic herpes simplex virus (oHSV), G207, is safe. However, while 17 of 37 subjects experienced objective clinical responses, the highly attenuated oHSV did not uniformly improve survival. We sought to identify predictors that would identify mechanisms contributing to survival and improve future trial design, by studying accrued samples. We analyzed pre-treatment biopsy and post-G207-treatment tumor samples (collected D2-5 post injection) banked from the patients enrolled in the phase IB G207 trial. The key findings from these patients suggest that productive G207 infection and G207-induced changes in gene expression were predictive of oHSV therapeutic success. RNAseq-based transcriptome analysis of these samples revealed that both the intrinsic IFN mediated antiviral response and adaptive immune functional response in patients correlated significantly with improved survival following G207 inoculation. Further, GBM tissue stained using multiplex fluorescent immunohistochemistry supported differences in the tumor microenvironments that were identified from RNAseq data analysis. Our data indicate that both viral gene expression and the resulting intrinsic anti-viral and recruited adaptive response were critical for survival after G207 inoculation and predict survival with this early generation oHSV in patients with recurrent malignant glioma.
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

Abstract

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

Abstract

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

Abstract

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

Abstract
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

Abstract

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

Abstract
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).