bluuebunny/crossref_metadata_2025 huggingface dataset:
Inter-plant communication via parasitic bridging
Authors: Banerjee Arjan
Published: November 2019

This article comments on:

Li S, Zhang J, Liu H, Liu N, Shen G, Zhuang H, Wu J. 2020. Dodder-transmitted mobile signals prime host plants for enhanced salt tolerance. Journal of Experimental Botany 71, 1171–1184.
Decidability of affine solution problems
Authors: Hetzl Stefan , Zivota Sebastian
Published: November 2019

We present formula equations—first-order formulas with unknowns standing for predicates—as a general formalism for treating certain questions in logic and computer science, like the Auflösungsproblem and loop invariant generation. In the case of the language of affine terms over $\mathbb{Q}$, we translate a quantifier-free formula equation into an equivalent statement about affine spaces over $\mathbb{Q}$, which can then be decided by an iteration procedure.
The first six months of the Advanced LIGO’s and Advanced Virgo’s third observing run with GRANDMA
Authors: Antier S , Agayeva S , Aivazyan V , Alishov S , Arbouch E , Baransky A , Barynova K , Bai J M , Basa S , Beradze S , Bertin E , Berthier J , Blažek M , Boër M , Burkhonov O , Burrell A , Cailleau A , Chabert B , Chen J C , Christensen N , Coleiro A , Cordier B , Corre D , Coughlin M W , Coward D , Crisp H , Delattre C , Dietrich T , Ducoin J-G , Duverne P-A , Marchal-Duval G , Gendre B , Eymar L , Fock-Hang P , Han X , Hello P , Howell E J , Inasaridze R , Ismailov N , Kann D A , Kapanadze G , Klotz A , Kochiashvili N , Lachaud C , Leroy N , Le Van Su A , Lin W L , Li W X , Lognone P , Marron R , Mo J , Moore J , Natsvlishvili R , Noysena K , Perrigault S , Peyrot A , Samadov D , Sadibekova T , Simon A , Stachie C , Teng J P , Thierry P , Thöne C C , Tillayev Y , Turpin D , de Ugarte Postigo A , Vachier F , Vardosanidze M , Vasylenko V , Vidadi Z , Wang X F , Wang C J , Wei J , Yan S Y , Zhang J C , Zhang J J , Zhang X H
Published: November 2019

We present the Global Rapid Advanced Network Devoted to the Multi-messenger Addicts (GRANDMA). The network consists of 21 telescopes with both photometric and spectroscopic facilities. They are connected together thanks to a dedicated infrastructure. The network aims at coordinating the observations of large sky position estimates of transient events to enhance their follow-up and reduce the delay between the initial detection and optical confirmation. The GRANDMA programme mainly focuses on follow-up of gravitational-wave alerts to find and characterize the electromagnetic counterpart during the third observational campaign of the Advanced LIGO and Advanced Virgo detectors. But it allows for follow-up of any transient alerts involving neutrinos or gamma-ray bursts, even those with poor spatial localization. We present the different facilities, tools, and methods we developed for this network and show its efficiency using observations of LIGO/Virgo S190425z, a binary neutron star merger candidate. We furthermore report on all GRANDMA follow-up observations performed during the first six months of the LIGO–Virgo observational campaign, and we derive constraints on the kilonova properties assuming that the events’ locations were imaged by our telescopes.
General relativistic magnetohydrodynamic dynamo in thick accretion disks: fully nonlinear simulations
Authors: Tomei N , Del Zanna L , Bugli M , Bucciantini N
Published: November 2019

The recent imaging of the M87 black hole at millimeter wavelengths by the Event Horizon Telescope (EHT) collaboration has triggered a renewed interest in numerical models for the accretion of magnetized plasma in the regime of general relativistic magnetohydrodynamics (GRMHD). Here non-ideal simulations, including both the resistive effects and, above all, the mean-field dynamo action due to sub-scale, unresolved turbulence, are applied for the first time to such systems in the fully nonlinear regime. Combined with the differential rotation of the disk, the dynamo process is able to produce an exponential growth of any initial seed magnetic field up to the values required to explain the observations, when the instability tends to saturate even in the absence of artificial quenching effects. Before reaching the final saturation stage we observe a secondary regime of exponential growing, where the magnetic field increases more slowly due to accretion, which is modifying the underlying equilibrium. By varying the dynamo coefficient we obtain different growth rates, though the field seems to saturate at approximately the same level, at least for the limited range of parameters explored here, providing substantial values for the MAD parameter for magnetized accretion. For reasonable values of the central mass density and the commonly employed recipes for synchrotron emission by relativistically hot electrons, our model is able to reproduce naturally the observed flux of Sgr A*, the next target for EHT.
Scale-invariance in the repeating fast radio burst 121102
Authors: Lin Hai-Nan , Sang Yu
Published: November 2019

The statistical properties of the repeating fast radio burst FRB 121102 are investigated. We find that the cumulative distributions of fluence, flux density, total energy and waiting time can be well fitted by the bent power law. In addition, the probability density functions of fluctuations of fluence, flux density and total energy well follow the Tsallis q-Gaussian distribution. The q values keep steady around q ∼ 2 for different scale intervals, indicating a scale-invariant structure of the bursts. The statistical properties of FRB 121102 are very similar to that of the soft gamma repeater SGR J1550-5418. The underlying physical implications need to be further investigated.
Stress response pathways in the male germ cells and gametes
Authors: Santiago J , Santos M A S , Fardilha M , Silva J V
Published: November 2019

The unfolded protein response (UPR) is a conserved and essential cellular pathway involved in protein quality control that is activated in response to several cellular stressors such as diseases states, ageing, infection and toxins. The cytosol, endoplasmic reticulum (ER) and mitochondria are continuously exposed to new proteins and in situations of aberrant protein folding; one of three lines of defence may be activated: (i) heat-shock response, (ii) mitochondrial UPR and (iii) ER UPR. These pathways lead to different signal transduction mechanisms that activate or upregulate transcription factors that, in turn, regulate genes that increase the cell's ability to correct the conformation of poorly folded proteins or, ultimately, lead to apoptosis. Despite the recent progress in understanding such biological processes, few studies have focused on the implications of the UPR in male infertility, highlighting the need for a first approach concerning the presence of these components in the male reproductive system. In testis, there is a high rate of protein synthesis, and the UPR mechanisms are well described. However, the presence of these mechanisms in spermatozoa, apparently transcriptionally inactive cells, is contentious, and it is unclear how sperm cells deal with stress. Here, we review current concepts and mechanisms of the UPR and highlight the relevance of these stress response pathways in male fertility, especially the presence and functional activation of those components in male germinal cells and spermatozoa.
Exposome-Explorer 2.0: an update incorporating candidate dietary biomarkers and dietary associations with cancer risk
Authors: Neveu Vanessa , Nicolas Geneviève , Salek Reza M , Wishart David S , Scalbert Augustin
Published: November 2019

Exposome-Explorer (http://exposome-explorer.iarc.fr) is a database of dietary and pollutant biomarkers measured in population studies. In its first release, Exposome-Explorer contained comprehensive information on 692 biomarkers of dietary and pollution exposures extracted from the analysis of 480 peer-reviewed publications. Today, Exposome-Explorer has been further expanded and contains a total of 908 biomarkers. Two additional types of information have been collected. First, 185 candidate dietary biomarkers having 403 associations with food intake (as measured by metabolomic studies) have been identified and added. Second, 1356 associations between dietary biomarkers and cancer risk in epidemiological studies, which were collected from 313 publications, have also been added to the database. Classifications for both foods and compounds have been revised, and new classifications for biospecimens, analytical methods and cancers have been implemented. Finally, the web interface has been redesigned to significantly improve the user experience.
Exploring trophoblast-specific Tead4 enhancers through chromatin conformation capture assays followed by functional screening
Authors: Tomikawa Junko , Takada Shuji , Okamura Kohji , Terao Miho , Ogata-Kawata Hiroko , Akutsu Hidenori , Tanaka Satoshi , Hata Kenichiro , Nakabayashi Kazuhiko
Published: November 2019

Tead4 is critical for blastocyst development and trophoblast differentiation. We assayed long-range chromosomal interactions on the Tead4 promoter in mouse embryonic stem (ES) cells and trophoblast stem (TS) cells. Using luciferase reporter assays with ES and TS cells for 34 candidate enhancer regions, we identified five genomic fragments that increased Tead4 promoter activity in a TS-specific manner. The five loci consisted of three intra- and two inter-chromosomal loci relative to Tead4 on chromosome 6. We established five mouse lines with one of the five enhancer elements deleted and evaluated the effect of each deletion on Tead4 expression in blastocysts. By quantitative RT-PCR, we measured a 42% decrease in Tead4 expression in the blastocysts with a homozygous deletion with a 1.5 kb genomic interval on chromosome 19 (n = 14) than in wild-type blastocysts. By conducting RNA-seq analysis, we confirmed the trans effect of this enhancer deletion on Tead4 without significant cis effects on its neighbor genes at least within a 1.7 Mb distance. Our results demonstrated that the genomic interval on chromosome 19 is required for the appropriate level of Tead4 expression in blastocysts and suggested that an inter-chromosomal enhancer-promoter interaction may be the underlying mechanism.
ATIM-04. PHASE I IMMUNOVIROTHERAPY TRIAL OF IL-12 EXPRESSING HSV-1 (M032) IN PET DOGS WITH SPONTANEOUS HIGH GRADE GLIOMAS: A PRELIMINARY REPORT
Authors: Renee Chambers M , Crossman David , Foote Jeremy , Koehler Jey , Markert James , Platt Simon , Mitchell Self D , Shores Andy , Waters Alicia , Yanke Amy , Yancey Gillespie G
Published: November 2019

Malignant gliomas are the most common primary brain tumors in humans, accounting for approximately 30% of all primary central nervous system (CNS) tumors in adults. Incidence and outcomes of gliomas in pet dogs are similar to humans. Previous methods of studying gliomas in rodent models do not adequately represent several features that define human cancers, most notably the sporadic nature of tumor development. Murine models lack intra-tumoral heterogeneity or hosts do not have an intact immune system. To overcome these rodent model deficiencies, many investigators have used canine models to study human diseases. We describe a prospective, phase I clinical trial in canine patients with sporadic high-grade gliomas to evaluate M032, a mutant HSV-1 expressing IL-12, alone or combined with a checkpoint inhibitor (Indoximod) to assess safety, tolerability and efficacy. M032 has been shown to infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; will provide an increased adjuvant effect from released viral DNA recognized by TLR-9 receptors; and express IL-12 locally, stimulating activation of TH1 lymphocytes. The intratumoral inflammatory cell infiltration is expected to result in immune-related anti-viral responses with cross-epitope spreading to tumor antigens. Indoximod immunomodulation will be tested in latter cohorts to prolong anti-tumor responses. To date, six canines with high-grade gliomas have received intratumoral M032 without virus-related toxicities. Resected tumor and serial blood samples are being cryopreserved for analysis of lymphoid and monocyte/myeloid subset markers. This same virus is being tested in a phase 1 clinical trial in humans with high-grade malignant gliomas; eight human patients have received treatment at this writing without virus-related toxicities. The concurrent prosecution of both trials allows unprecedented real time comparison of safety and efficacy of immunovirotherapy as a stringent test of suitability of the dog as a valid and informative model of human brain tumors.
ATIM-06. TREATMENT OF RECURRENT/REFRACTORY (R/R) ANAPLASTIC ASTROCYTOMA (AA, WHO GRADE 3) PATIENTS WITH ANTI-TGFß2 RNA THERAPEUTIC OT-101 VERSUS TEMOZOLOMIDE IS ASSOCIATED WITH IMPROVED OVERALL SURVIVAL
Authors: Uckun Fatih , Qazi Sanjive , Nam David , Hwang Larn , Trieu Vuong
Published: November 2019

BACKGROUND

OT-101 is a first-in-class RNA therapeutic designed to disrupt the immunosuppressive action of TGFß2. During Phase 1 clinical trials, OT-101 induced partial responses in R/R AA patients. We now report our clinical results from a randomized Phase IIB study (NCT00431561) that further evaluated its single agent activity in R/R AA patients in side-by-side comparison with the standard chemotherapy drug temozolomide (TMZ).

METHODS

OT-101 was administered via high-flow microperfusion with an intratumoral catheter using a convection enhanced delivery (CED) system. 26 AA patients (12: 2.5 mg/cycle; 14: 19.8 mg/cycle) received 7-day cycles of OT-101 every other week via continuous infusion for 4–11 cycles. Response determinations were based on central review of MRI scans by an independent review committee according to standard as well as modified McDonald criteria. 11 patients in the active control arm were treated with TMZ (150–200 mg/m2, 5 days/28-day cycles x up to 6 treatment cycles). Standard statistical methods were applied for the analysis of data.

RESULTS

14 of 26 patients (53.8%) treated with 4–11 cycles of OT-101 had either a CR (N=2) or PR (N=12) as their best overall response. The average time until 99% reduction of their tumor volumes ranged from 9.9 to 115.4 (median: 23.7) months. In contrast, only 1 of 10 evaluable patients (10%) treated with TMZ achieved an objective response which was a PR (Fisher’s exact test, 2-tailed, P-value = 0.0002). The median overall survival (OS) was 1154 days (95% CI: 811 - >1743) for the OT-101 group and 590 days (95% CI: 287 - >1137) days for the TMZ group (Log Rank Chi Square = 7.55, P-value = 0.006).

CONCLUSION

Our results confirm and extend previous studies and provide early evidence that the anti-TGFß2 RNA therapeutic OT-101 is at least as active as TMZ in salvage therapy of R/R AA patients.
ATIM-08. TRIAL IN PROGRESS: CA209-9Y8 PHASE 2 TRIAL OF TUMOR TREATING FIELDS (TTFS), NIVOLUMAB PLUS/MINUS IPILIMUMAB FOR BEVACIZUMAB-NAÏVE, RECURRENT GLIOBLASTOMA
Authors: Odia Yazmin , Iwamoto Fabio
Published: November 2019

Recurrent glioblastoma has limited therapeutic options. The EF11 trial of TTFs vs. physician’s choice chemotherapy showed an objective response rate (ORR) of 14%, but no survival (OS) benefit. CheckMate 143 randomized phase 3, open-label trial of nivolumab vs. bevacizumab failed to show an OS benefit, though nivolumab led to ORR of 7.8% with more durable response than bevacizumab (11.1 vs. 5.3 months). Preclinical studies suggest synergism between TTFs and immunotherapy. TTFs expose calreticulin on cell surfaces, causing HMGB1 and ATP secretion—hallmarks of anticancer immunogenic cell death. Observed trends in a glioma cohort also suggest synergism: 77% of glioma patients treated with TTFs received concurrent temozolomide (16, 31%), nitrosourea (4,8%), bevacizumab (19,37%), or immunotherapy (28,54%). Only 2 (4%) experienced skin toxicity requiring TTFs hold. For TTFs plus immunotherapy vs. chemotherapy, there was a trend toward increased OS (8.3 vs. 6.5 months,p=0.32) and ORR (26% vs. 13%), with significant increase in PFS for glioblastomas (4.6 vs. 3.5 months,p=0.04). ORR was >14% in EF11 or < 5- 10% in meta-analyses of immunotherapy for recurrent glioblastoma. This open-label, phase 2 trial with 2 parallel arms uses a 2-stage Minimax design with stopping rules for futility. We will enroll 30 (15/Arm) to 60 (30/Arm) evaluable subjects. The primary endpoint is ORR by modified RANO. Secondary objectives are OS, PFS, safety, compliance, and biomarker correlations. Adults with glioblastoma at first or second recurrence and no prior CTLA inhibitor or bevacizumab are eligible. All receive TTFs with nivolumab for ≤24 months and ipilimumab for ≤4 doses. Arm A (no prior PD1/PDL1 inhibitor) receive nivolumab only and add ipiliumumab at progression. Arm B (prior PD1/PDL1 inhibitor) receive nivolumab and ipilumimab. Nivolumab is dosed IV q2weeks 240mg as monotherapy and 3mg/kg with ipilumimab IV 1mg/kg q6weeks. TTFs starts by 1 month and worn for ≥75% over ≤24 months.
ATIM-09. CLINICAL TRIAL IN PROGRESS: A STUDY OF NEOADJUVANT AND ADJUVANT VB-111 FOR TREATMENT OF RECURRENT GBM
Authors: Cloughesy Timothy , Butowski Nicholas , Harats Dror , Rachmilewitz Minei Tamar , Wen Patrick
Published: November 2019

BACKGOUND

Ofranergene obadenovec (VB-111) is a targeted anti-cancer viral based gene therapy with a dual mechanism: a broad antiangiogenic effect and induction of a tumor directed immune response. Previous study demonstrated a survival benefit for patients with recurrent glioblastoma (rGBM) treated with VB-111 monotherapy that was continued upon progression with combination treatment of VB-111 and bevacizumab. Glioblastoma is an immunologically “cold” microenvironment which fosters immunosuppression and antagonizes anti-tumor immune responses. The role of T-cell infiltration in combating cancer has been increasingly recognized and associated with improved participant outcomes. Based on these observations, this study will assess the hypothesis that neoadjuvant use of VB-111 will lead to a statistically significant increase in tumor infiltrating T lymphocyte (TIL) density within the tumor and enhanced systemic tumor-specific T cell responses.

METHODS

This is a multicenter, randomized, blinded, placebo-controlled, phase 2 surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral cancer therapy VB-111 in rGBM. 45 participants with rGBM indicated for resection will randomized to one of three treatment arms: Neoadjuvant Arm: intravenous VB-111 prior to resection, and VB-111 every 6 weeks after resection. Adjuvant Arm: placebo prior to resection, and VB-111 every 6 weeks afterwards. The control arm will receive placebo prior to resection followed by standard of care. Upon evidence of contrast-enhancing progression, bevacizumab may be initiated as needed for supportive care and VB-111 will continue until progression is supported at two consecutive time points. Tumor samples will be obtained and archived at the time of surgery, and blood samples will be obtained as pharmacodynamic markers throughout the study to allow DNA sequencing of T cells. The primary endpoint is influence of neoadjuvant VB-111 on TIL density. Other endpoints include safety and tolerability, peripheral T cell response, tumor/microenvironment transcriptomic alteration, and PFS/OS. Study will open for enrolment in 2019.
ATIM-11. TUMOR-INFILTRATING LYMPHOCYTES EXPRESSING ANTI-PD-1 ANTIBODY EXHIBIT A PROMISING EFFICACY AND SURVIVAL BENEFIT IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Tang Chao , Zhang Zhi , Chen Di , Ji Kai , Ji Chunxia , Liu Xiao , Chen Ling , Lu Qiqi , Chu Wen , Qin Wen , Xu Fei , Jin Hua , Qian Qi , Yao Yu , Zhou Liang
Published: November 2019

Adoptive cell therapies utilizing autologous tumor-infiltrating lymphocytes (TIL) have been demonstrated to be safe and promising in anti-tumor activities; However, their efficiency was still low in treating glioblastoma multiforme (GBM) because of immunosuppression microenvironment. In this study, we proposed a new strategy to enhance the anti-tumor immune response by using modified TIL expressing anti-PD-1 antibody (anti-PD1-TIL), which could reverse immunosuppression in tumor microenviroment. From April 2017 to April 2018，a total of 8 patients with recurrent GBM were enrolled and received more than one cycles of anti-PD1-TIL immunotherapy after surgery and chemotherapy with a median follow-up of 20 months. The anti-PD1-TIL immunotherapy was well tolerated. Two patients suffered grade 1 and 2 adverse events, including fatigue, mucosal/cutaneous toxicities. The median overall survival time was 16.1（95% CL: 15.4–16.7）months. By iRANO criteria, one patient experienced a partial response (PR), and three patients experienced stable disease (SD) after anti-PD-1-TIL immunotherapy. Genomic analysis by whole exome sequencing revealed an enrichment of MUC12 mutation in responders (p< 0.01), and an enrichment of TMEM125 (p< 0.01) and HIST2H3A/C amplification (p< 0.05) associated with immunosuppressive signature in non-responders. Taken together, the anti-PD1-TIL immunotherapy is a safe and promising strategy with durable efficacy to treat patients with recurrent GBM. Clinicaltrials.gov identifier: NCT 03347097.
ATIM-17. A PHASE I TRIAL OF HYPOFRACTIONATED STEREOTACTIC IRRADIATION (HFSRT) COMBINED WITH NIVOLUMAB (NIVO), IPILIMUMAB (IPI) AND BEVACIZUMAB (BEV) IN PATIENTS (PTS) WITH RECURRENT HIGH GRADE GLIOMAS
Authors: Sahebjam Solmaz , Forsyth Peter , Tran Nam , Etame Arnold , Arrington John , Jaglal Michael , Mokhtari Sepideh , MacAulay Robert , Wicklund Melissa , Evernden Brittany , Gatewood Tyra , Robinson Timothy , Raval Raju , Yu Michael
Published: November 2019

BACKGROUND

There is strong pre-clinical evidence that combining CTLA4 and PD-1/PDL-1 blockade with antiangiogenic agents and HFSRT independently enhance anti-tumor immune responses and tumor regression.

METHODS

This phase I study includes a safety cohort of 6 pts followed by dose expansion cohort of 26 pts. Pts with Bev naïve recurrent WHO grade III or IV gliomas (maximum diameter of enhancing brain lesion ≤ 4 cm) are eligible. An interval of at least 6 months after the end of prior RT is required unless there is a new recurrence outside of the previous RT treatment field. Eligible pts are treated with HFSRT to the recurrent tumor (30 Gy in 5 fractions) and 4 cycles of Nivo (3 mg/kg), Ipi (1 mg/kg) and Bev (15 mg/kg) every 3 weeks followed by Nivo 240 mg and Bev 10 mg/kg every 2 weeks for 4 months. After 4 months, Nivo is administered every 4 weeks at 480 mg flat dose and Bev is continued at every 2 week schedule. The primary study objectives are to determine safety and tolerability of above treatment. Secondary endpoints include response rate, 6 and 9-months survival rates, and exploring tissue and imaging biomarkers.

RESULTS

As of June 2019, safety cohort has been completed and accrual to dose expansion cohort is ongoing. Combination of HFSRT, Nivo, Ipi and Bev as above is well tolerated. The most common toxicities were grade 1 anorexia, grade 1 diarrhea, grade 1 elevation of alanine aminotransferase, grade 1 elevation of lipase and grade 1 infusion related reaction. One patient had grade 3 confusion which was reversible with use of corticosteroids. No dose limiting toxicity has been observed.

CONCLUSIONS

Combination of HFSRT with Nivo, Ipi and Bev was considered safe to be studied in expansion cohort. Updated safety and efficacy data will be presented.
ATIM-18. SURVIVAL OF SUBJECTS WITH RECURRENT GLIOBLASTOMA RECEIVING INTRA-TUMORAL ADMINISTRATION OF IL-12 MANAGED WITH LOW-DOSE DEXAMETHASONE
Authors: Lukas Rimas , Chiocca Ennio , Kurz Sylvia , Yu John , Landolfi Joseph , Rao Ganesh , Buck Jill , Demars Nathan , Smith Amy , Miao John , Zhou John , Wang Yunxia , Gelb Arnold , Cooper Laurence
Published: November 2019

Ad-RTS-hIL-12 (Ad) is a novel gene therapy, conditionally expressing IL-12 via the RheoSwitch Therapeutic System® (RTS®) gene switch under control of an oral activator ligand, veledimex (V). We previously reported results from 51 subjects (NCT02026271 and NCT03679754) describing biological activity of controlled IL-12, safety and survival data. Previously, subjects who received Ad+V (20 mg) managed with low-dose dexamethasone in the Main study achieved a mOS of 17.8 months, which is approximately twice the anticipated survival compared to historical controls. The mechanism of action of Ad+V is based on controlled secretion of recombinant IL-12 (measured in peripheral blood as a surrogate for intra-tumor-production), downstream upregulation of endogenous IFN-g (measured in peripheral blood), and an increase in the “cytoindex” (ratio of circulating CD8+ T cells to FoxP3+ regulatory T cells), an emerging biomarker of overall survival. Herein we provide an update of subject characteristics, survival and biomarker analysis from the ongoing Phase 1 and expansion substudy. assessing safety and tolerability of local, inducible IL-12 by single intratumoral injection of Ad (2 x 1011 viral particles) + V (20 mg PO QD x15 doses Days 0–14) in subjects, including a subset receiving low-dose corticosteroids (≤20 mg cumulative dexamethasone Days 0–14). Drug-related toxicities were predictable, dose-related, and promptly reversible upon discontinuation of V with no drug-related deaths. Biomarker studies related to production of IL-12 and IFN-g, as well as cytoindex remain encouraging. As of 04Jun19, mOS in the Expansion substudy had not yet been reached (patient enrollment occurred from September 2018-February 2019). Most subjects (65%) received low-dose dexamethasone (cumulative ≤20mg Days 0–14); initial impact of this and other subject characteristics on survival will be presented.
ATIM-22. PHASE I TRIAL OF DRUG RESISTANT IMMUNOTHERAPY: A FIRST-IN-CLASS COMBINATION OF MGMT-MODIFIEDγδ T CELLS AND TEMOZOLOMIDE CHEMOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME
Authors: Lamb Lawrence , Markert James , Yancey Gillespie G , Beelen Melissa , Langford Catherine , Pereboeva Larisa , Youngblood Samantha , Nabors Louis
Published: November 2019

INTRODUCTION

Alkylating agents such as Temozolomide (TMZ) significantly upregulate stress-induced NKG2D ligands targeted by innate immune effector cells. Genetic modification of γδT cells with an MGMT-expressing lentivector abrogates TMZ-induced lymphodepletion allowing simultaneous chemotherapy and γδT cell therapy in a process we have termed Drug Resistant Immunotherapy (DRI) resulting in a significant improvement in long-term survival in patient-derived xenograft (PDXT) models of primary and recurrent GBM. We have now initiated a Phase I clinical trial of DRI in primary GBM (BB-IND-17928) to determine the safety of this approach.

METHODS

Effector γδT cells are manufactured from a fractional apheresis product obtained immediately prior to post-resection chemo/radiotherapy. Cultures are propagated in a Miltenyi Prodigy® bioreactor using media containing Zoledronic Acid and rhIL-12, transduced with a P140K-MGMT lentivector, maintained for up to 14 days, harvested, and cryopreserved. At the initiation of maintenance TMZ therapy, patients receive 150mg/m2 intravenous TMZ and 1 x 107 γδT cells delivered through a Rickham reservoir inserted into the tumor cavity at primary resection. Treatment frequency escalates from one to three 28-day cycles in a standard 3 x 3 design.

RESULTS

Closed system manufacturing in the Prodigy bioreactor produced 4.5 – 11.9 x 108 γδT cells (44–103 fold expansion) from the apheresis starting material (0.6–1.9% γδT cells) with vector copy numbers of 0.9 - 2.1 copies/cell and in vitro cytotoxicity against K562 44.3% - 77.9% at E:T 40:1. Products were successfully cryopreserved and retained in vivo potency against GBM PDXT in mice over single-agent TMZ (p= 0.0286). All cell products met sterility and identity criteria.

CONCLUSIONS

These findings show that genetically modified γδT cells can be manufactured to clinical scale under GMP compliance in an automated bioreactor and cryopreserved to produce multiple doses of functionally-competent γδT cells. Patient accrual will initiate in 2019.
ATIM-29. IDENTIFYING IMMUNOLOGICAL BARRIERS TO IMMUNOTHERAPY IN PATIENTS WITH GLIOBLASTOMA MULTIFORME
Authors: Gustafson Michael , Parney Ian , Dietz Allan
Published: November 2019

Recent successes in cancer immunotherapy have provided new avenues for the treatment of glioblastoma multiforme (GBM). Several immunotherapeutic approaches are now being utilized to treat patients with GBM including checkpoint inhibition, autologous/CAR-T cell therapy, and cancer vaccines. Preliminary data suggests that the majority of patients have sub-optimal clinical responses to these therapies. The impaired anti-tumor immune responses observed in these patients are likely a consequence of immune system dysfunction contributed to by a variety of factors that include diminished antigen presentation/detection, leukopenia, alterations in cytokine levels and cellular mediators. We have previously demonstrated that patients with GBM exhibit profound immune suppression resulting from both tumor and treatment related effects via a comprehensive quantitation of peripheral blood leukocytes by flow cytometry. We hypothesize that the depth and breadth of immunosuppression will significantly affect responses to immunotherapy. Prominent phenotypic abnormalities observed in GBM patients include elevated levels of CD14+HLA-DRlo/neg monocytes and reduced absolute CD4 T cell counts. We will present data how these and other phenotypes may potentially influence responses to patients treated with dendritic cell vaccines. Our goal is to understand the role of these cells in the context of immunosuppression not only to facilitate the development of targeted immunotherapies to circumvent their effects, but also to potentially utilize them as biomarkers for understanding diverse responses to immunotherapies.
ATIM-30. COMBATING RECURRENT GLIOBLASTOMA WITH MDNA55, AN INTERLEUKIN-4 RECEPTOR TARGETED IMMUNOTHERAPY, THROUGH MRI-GUIDED CONVECTIVE DELIVERY
Authors: Sampson John , Singh Achrol Achal , Aghi Manish , Bankiewicz Krystof , Brem Steven , Brenner Andrew , Butowski Nicholas , Chandhasin Chandtip , Chowdhary Sajeel , Coello Melissa , Floyd John R , Kesari Santosh , Merchant Fahar , Merchant Nina , Randazzo Dina , Vogelbaum Michael , Vrionis Frank , Zabek Miroslaw , Bexon Martin
Published: November 2019

MDNA55, an IL4R-directed toxin, is being studied in a Phase 2b trial in recurrent GBM (rGBM) patients at first or second relapse. MDNA55 is co-infused with Gadolinium-based contrast agent and delivered as a single intratumoral infusion using Convection Enhanced Delivery (CED). Primary endpoint is median Overall Survival (mOS) and secondary endpoint is objective response rate (ORR) assessed by mRANO-based criteria incorporating advanced imaging modalities. Enrollment is complete (n=46). Current safety data show similar profile to previous MDNA55 trials with no systemic toxicities or drug related deaths. Current mOS in subjects treated with low doses of MDNA55 (median 63µg; n=21) is 11.8 months. When stratified by IL4R expression, a biomarker for more aggressive GBM, IL4R+ve subjects (mOS 15.2 months; n=8) show a survival advantage of 7 months compared to IL4R-ve subjects (mOS 8.1 months; n=10). Updated survival and response outcomes including subjects receiving the high dose (median 180µg; n=25) and stratification by IL4R expression will be reported. Review of serial imaging within 90 days following MDNA55 treatment demonstrated tumor shrinkage or stabilization from baseline in 19/42 evaluable subjects (disease control rate of 45%). To account for initial pseudo-progression in some subjects, tumor response was also assessed from nadir: 83% (35/42) showed disease control. Multi-parametric MRI biomarkers including relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) measurements demonstrated distinct imaging phenotypes among different disease states (pseudo-progression vs true-progression, pseudo-response vs true-response) and improved response staging. This trial is advancing neurosurgical methods for CED, potential of IL4R expression as a biomarker to select GBM patients most likely to benefit from MDNA55 treatment, and optimal use of multi-parametric MRI as an adjunct to clinical decision making. The improved survival and disease control seen after only a single infusion of MDNA55, especially in IL4R+ve subjects, may provide promising clinical benefit for rGBM patients.
ATIM-44. A PHASE I FIRST-IN-HUMAN TRIAL OF TWO ADENOVIRAL VECTORS EXPRESSING HSV1-TK AND FLT3L FOR TREATING NEWLY DIAGNOSED RESECTABLE MALIGNANT GLIOMA: THERAPEUTIC REPROGRAMMING OF THE BRAIN IMMUNE SYSTEM
Authors: Lowenstein Pedro , A Orringer Daniel , Sagher Oren , Heth Jason , Hervey-Jumper Shawn , Gerald Mammoser Aaron , Junck Larry , Leung Denise , Umemura Yoshie , Steven Lawrence Theodore , Miran Kim Michelle , Richard Wahl Daniel , McKeever Paul , Ines Camelo-Piragua Sandra , Lieberman Andrew , Venneti Sriram , Comba Andrea , Altshuler David , M Muraszko Karin , Castro Maria
Published: November 2019

This is an interim report on a first in human Phase I dose escalation trial of the combination of two adenoviral vectors expressing HSV1-TK or Flt3L for the treatment of newly diagnosed, resectable malignant gliomas. Lack of dendritic cells from the brain precludes anti-glioma immune responses. We combined tumor cytotoxicity (Ad-HSV1TK) with recruitment of dendritic cells to gliomas (Ad-Flt3L) to induce anti-glioma immunity. In experimental models this treatment induces powerful cytotoxic CD8 and CD4 T-dependent anti-glioma immunity, immunological memory, and the capacity to recognize neo-antigens. The trial was approved through a FDA-IND, and all institutional cttees. Treatment was administered intraoperatively following complete glioma resection in newly diagnosed tumors. The trial consisted of vector dose escalation, starting at 1x10^9 v.p., and increasing to 1x10^11 v.p. of each vector, through 6 cohorts of 3 patients each. Two cycles of 14 days of valacyclovir were administered to activate HSV1-TK cytotoxicity. Cycle 1 starts on Day 1–3 post surgery for 14 days, and Cycle 2 on Week 8–12. Standard radiation, i.e., 60 Gy in 2 Gy fractions over 6 weeks, with concurrent temozolomide, was followed by cyclic temozolomide. Examination of tumor samples at primary resection and first recurrence show an increase in the infiltration of inflammatory cells. The experimental treatment was well tolerated. An MTD was not reached. There were approx. 248 AEs, and 26 SAEs; these were not linked to treatment. As secondary outcome, median survival of contemporary controls was 604 days, and median survival of trial patients was 742 days. Our results show for the first time that reprogramming of the host’s brain immune system to recognize gliomas reveals a new approach for the treatment of highly malignant brain tumors. Clinical trial information: NCT01811992.
ATIM-45. LONG TERM FOLLOW-UP OF A PHASE I/II STUDY TESTING THE TOXICITIES AND EFFICACY OF PEMBROLIZUMAB IN COMBINATION WITH MRI-GUIDED LASER INTERSTITIAL THERMAL THERAPY (LITT) IN RECURRENT MALIGNANT GLIOMAS
Authors: Campian Jian , Ghiaseddin Ashley , Rahman Maryam , Huang Jiayi , Ansstas George , Kim Albert , Leuthardt Eric , Tran David
Published: November 2019

BACKGROUND

LITT was recently demonstrated to induce temporary blood-brain barrier disruption, possibly allowing bilateral trafficking of tumor neoantigens and immune cells to induce glioma-specific immune activation - a phenomenon akin to in situ tumor vaccination. We hypothesize that combining LITT with immune checkpoint inhibition will create a synergistic therapy for recurrent GBM.

METHODS

The phase 1 study is a standard 3x3 design with a maximum of 18 patients with bevacizumab-naïve recurrent WHO grade 3–4 glioma. The primary endpoint is safety and toxicity of LITT plus pembrolizumab at 100, 150, or 200mg IV q3weeks. Phase 2 includes 40 patients with bevacizumab-naïve recurrent GBM, equally randomized to either pembrolizumab alone or LITT plus pembrolizumab, with progression-free survival as the primary endpoint. Serial immunophenotyping will be performed to evaluate potential positive synergy between LITT and pembrolizumab.

RESULTS

Phase 1 accrual was completed with 9 patients (3 at each pembrolizumab dose level). Two had recurrent anaplastic astrocytoma and 7 recurrent GBM. There was no dose-limiting toxicity with pembrolizumab 200mg IV q3weeks. The median number of doses given per patient was 9 (range 2 to 47). Severe adverse events possibly related to the study treatment included a grade 3 rash and diarrhea in 1 patient (11%) and grade 3 pneumonitis and hypotension in another patient (11%). No grade 3/4 intracranial edema deemed related to study treatment was observed. To date, four (44%) of these patients are still alive without tumor progression. Two (22%) GBM patients have not progressed for 29 and 33 months, respectively. Two (22%) anaplastic astrocytoma patient have not progressed for 23 and 24 months, respectively.

CONCLUSIONS

LITT plus pemprolizumab 200mg IV q3weeks is well tolerated in patients with recurrent high-grade glioma. Prolonged stable diseases were observed in almost half of patients treated. Phase 2 study is ongoing and will be updated.
ACTR-03. FINAL RESULTS OF A PHASE II STUDY OF HYPOFRACTIONATED RADIOTHERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN PATIENTS OVER 70 YEARS OLD WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Yusuf Mehran , Gaskins Jeremy , Woo Shiao , Burton Eric
Published: November 2019

BACKGROUND

We sought to determine the efficacy and tolerability of hypofractionated radiotherapy (HFRT), 34Gy given over two weeks with concurrent and adjuvant temozolomide, in patients over 70 years old with newly diagnosed GBM.

METHODS

Patients ≥ 70 years of age with newly diagnosed GBM received HFRT to a dose of 34 Gy in 10 fractions over 2 weeks, delivered with concurrent and adjuvant TMZ. Quality of life (QOL) data using the validated functional assessment of cancer therapy-brain (FACT-BR) questionnaire was collected. Kaplan-Meier methods and log-rank tests were used for survival analyses. A random intercepts growth model with baseline and linear effect in time terms was used to assess QOL with relation to protocol treatment.

RESULTS

Eleven patients were enrolled from 12/1/2015 to 2/5/2018. Median age and KPS of the cohort was 74 years (range 70 -81) and 80 (range 60–100). Eight patients have died. Median follow-up of the cohort was 13.8 months (range 3 – 26 months). The median progression free survival (PFS) was 6.0 months (CI 4.7 months -not achieved (NA) and the median overall survival (OS) was 24.5 months (CI 10.2 months –NA). MGMT methylation status was significantly associated with both PFS (p =0.02) and OS (p =0.02). All patients completed HFRT with no patients developing ≥ grade 3 adverse treatment events. QOL did not significantly worsen over time with therapy (p =0.75).

CONCLUSIONS

This completed phase II trial suggest a HFRT schedule of 34Gy delivered over 2 weeks with concomitant and adjuvant TMZ is well tolerated in elderly GBM patients without compromising clinical outcomes. This result compares favorably to the longer HFRT regimen of 40Gy over 3 weeks. ClinicalTrials.gov identifier: NCT01985087
ACTR-06. CLINICAL TRIAL OF VAL-083 IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM: HALF-WAY REPORT
Authors: Chen Zhong-ping , Guo Chengcheng , Yang Qun-ying , Li Jia-wei , Wu Shao-xiong , Bacha Jeffrey , Johnson Gregory , Langlands John , Kwan Claire , Kanekal Sarath , Schwartz Richard , Lopez Lorena , Brown Dennis
Published: November 2019

Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT gene, which confers a limited response to standard of care treatment with temozolomide (TMZ) resulting in a lower survival. VAL-083 is a novel bi-functional DNA targeting agent that induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated repair of the O6 guanine alkylator TMZ. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. The study has 2 stages: Stage 1 is a dose-escalation and induction format to confirm the recommended dose of VAL-083 when administered concurrently with radiation therapy (RT) based on safety and tolerability. The subjects received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment. Stage 2 comprises an expansion phase to enroll up to 30 patients. The dose escalation stage is complete and 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. As of 17 May, 2019, 18 patients have been enrolled. Fifteen patients have completed their prospectively planned MRI scans and had their initial assessment for tumor progression. Of these 15 patients, seven were assessed as a complete response (CR), and eight patients as having stable disease (SD). Of the remaining three patients, one died prior to their post-cycle 3 MRI and two have not been on study long enough to reach their planned post-cycle 3 MRI. As of the data cutoff, 14 of the 18 patients were still alive. Consistent with our prior experience, myelosuppression was the most common adverse event. Three dose-limiting toxicities have been reported - one at the 40 mg/m2/day and two at the 30 mg/m2/day dose. Further enrollment, safety & study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.
ACTR-07. LONG-TERM OUTCOMES FROM INTERGROUP NCCTG 86-72-51 (ALLIANCE): FINAL REPORT OF A PHASE III PROSPECTIVE RANDOMIZED TRIAL OF HIGH DOSE VERSUS LOW DOSE RADIATION IN ADULT SUPRATENTORIAL LOW-GRADE GLIOMA
Authors: Breen William , Keith Anderson S , Carrero Xiomara , Brown Paul , Ballman Karla , O’Neill Brian , Curran Walter , Abrams Ross , Laack Nadia , Levitt Ralph , Galanis Evanthia , Buckner Jan , Shaw Edward
Published: November 2019

PURPOSE

To provide a final update on oncologic and cognitive outcomes of high dose versus low dose radiation for low-grade glioma.

METHODS

Between 1986 and 1994, 203 patients with supratentorial low grade glioma were randomized to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Histologic subtype was oligodendroglioma (71%) or astrocytoma (29%). Primary outcome was overall survival (OS). Cognitive status was followed using Folstein Mini-Mental State Examination (MMSE).

RESULTS

For the entire cohort of 203 patients, median OS was 8.4 years (95% CI: 7.2 – 10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3 – 6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve OS (15-yr OS: 22.4% vs. 24.9%, log rank p=0.978) or PFS (15-yr PFS: 15.2% vs. 9.5%, p=0.7142). OS was significantly better for patients with pre-operative tumor diameter < 5 cm (15-yr OS: 39.4% vs. 15.2%, p< 0.001), baseline MMSE > 27 (15-yr OS: 27.3% vs. 9.8%, p=0.001), and for patients who underwent gross total resection (GTR) (15-yr OS: 39.3% GTR vs. 16.4% subtotal resection vs. 24.5% biopsy only, p=0.0119). PFS was improved for patients with oligodendroglioma versus astrocytoma (15-yr PFS: 13.8% vs. 8.6%, p=0.0221). PFS was also improved for patients with pre-operative tumor diameter < 5 cm, patients who had GTR, and patients with baseline MMSE > 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years.

CONCLUSIONS

Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Minimal late decline in cognitive function after radiation was seen by MMSE. SUPPORT: U10CA180821,U10CA180882. https://acknowledgments.alliancefound.org
ACTR-11. SECOND INTERIM AND 1ST MOLECULAR ANALYSIS OF THE EORTC RANDOMIZED PHASE III INTERGROUP CATNON TRIAL ON CONCURRENT AND ADJUVANT TEMOZOLOMIDE IN ANAPLASTIC GLIOMA WITHOUT 1p/19q CODELETION
Authors: van den Bent Martin , Erridge Sara , Vogelbaum Michael , Nowak Anna , Sanson Marc , Brandes Alba , Wick Wolfgang , Clement Paul , Baurain Jean-Francais , Mason Warren , Wheeler Helen , Weller Michael , aldape ken , Wesseling Pieter , Kros Johan , Tesileanu Mircea , Golfinopoulos Vassilis , Gorlia Thierry , Baumert Brigitta , French Pim
Published: November 2019

BACKGROUND

The 1st interim analysis of the CATNON trial showed benefit from adjuvant (adj) temozolomide (TMZ) on overall survival (OS) but remained inconclusive about concurrent (conc) TMZ. A 2nd interim analysis was planned after 356 events.

METHODS

The 2x2 factorial design phase III CATNON trial randomized 751 patients with newly diagnosed non-codeleted anaplastic glioma to either 59.4 Gy radiotherapy (RT) alone; the same RT with concTMZ; the same RT and 12 cycles of adjTMZ or the same RT with both concTMZ and adjTMZ (doi: 10.1016/S0140-6736(17)31442–3). MGMT promoter methylation (MGMTmeth) status was re-assessed with the Infinium Methylation EPIC Beadchip. Isocitrate dehydrogenase 1 and 2 (IDH) mutation (mt) status was assessed with a glioma targeted next generation sequencing panel. At the time of molecular analysis, a 3rd database lock was done.

RESULTS

At the 2nd IDMC (median follow-up 56 months, 356 events observed) the hazard ratio (HR) for OS adjusted for stratification factors after concTMZ was 0.968 (99.1% CI 0.73, 1.28. An IDHmt was found in 368 of 528 assessed cases (70%). After median follow-up of 67 months and with 367 events observed median OS was 19 mo (95% CI 16.3, 22.3) in IDHwt tumors and 116 mo (95% CI 82.0, 116.6) in IDHmt tumors. IDHmt was predictive of benefit from adjTMZ (IDHmt HR: 0.46, 95% CI 0.32, 0.67; IDHwt: HR 1.03, 95% CI 0.73, 1.44; interaction test p = 0.002) and from concTMZ (HR(IDHmt HR: 0.63, 95% CI 0.43, 0.91; IDHwt: HR 1.16, 95% CI 0.83, 1.63; interaction test p = 0.017). MGMTmeth was found in 401 of 478 assessed cases (69%), interaction tests for concTMZ and adjTMZ did not reach statistical significance.

CONCLUSIONS

In IDHmt tumors adjuvant and concurrent temozolomide improves survival, no effect was observed in IDHwt tumors. Further follow-up and molecular analyses are required for mature analyses.
ACTR-15. PHASE 1 TRIAL OF A KETOGENIC DIET IN PATIENTS RECEIVING STANDARD-OF-CARE TREATMENT FOR RECENTLY DIAGNOSED GLIOBLASTOMA
Authors: Gresham Gillian , Amaral Lauren , Lockshon Laura , Levin Dana , Rudnick Jeremy , Provisor Arlene , Shiao Stephen , Bhowmick Neil , Irwin Scott , Freedland Stephen , Hu Jethro
Published: November 2019

BACKGROUND

There is abundant interest in the potential therapeutic and supportive role of a ketogenic diet (KD) in patients with glioblastoma (GBM). The KD is a high fat/low carbohydrate metabolic therapy that modulates several of the bioenergetic and biosynthetic pathways that are dysregulated in GBM. To date, studies of the KD in cancer patients have been limited in scope. This study will provide preliminary evidence on the safety and feasibility of a 16-week ketogenic diet in patients with GBM.

METHODS

This is an open-label single-arm feasibility trial being conducted at Cedars-Sinai Medical Center. We will recruit 20 recently diagnosed GBM patients who are receiving standard-of-care (SOC) treatment. Patients may enroll within 3 months of diagnosis, thus allowing patients who have already begun SOC chemoradiation the opportunity to participate. Excluded are patients with a KPS < 70, BMI < 22, or on high doses of steroids. Consenting patients will maintain a 16-week ketogenic diet (KD) supervised and monitored by study dietitians (RD). The primary outcome of safety will be assessed by monitoring weight, BMI, and adverse events. Secondary outcomes are: 1) Adherence to the KD, as assessed by BID blood glucose and ketone levels; 2) Time to progression and overall survival from date of KD initiation 3) Mean change in overall QOL, as measured using the QLQ30 and QLQ-BN20 questionnaires; and 4) Mean change in cognitive scores at 16 weeks from baseline. Exploratory outcomes include metabolic, inflammatory, and immune biomarkers; gut microbiota analysis; large oncosome analysis; and daily activity assessed with a wearable activity monitor. This novel trial incorporates multiple digital devices and mobile applications into the study design. Accrual is ongoing with 10 patients currently enrolled (NCT03451799).