bluuebunny/crossref_metadata_2025 huggingface dataset:
BIOM-30. DECREASED B CELL AND ALTERED CD4+ T CELL SUBSET RATIO PREDICT FAVORABLE RESPONSE TO RUXOLINITIB IN HIGH-GRADE GLIOMAS
Authors: Rauf Yasmeen , Jia Xuefei , Lathia Justin , Peereboom David , Ahluwalia Manmeet
Published: December 2020

Altered cellular growth and suppression of anti-tumor immune response collectively drive progression and therapeutic resistance of high-grade gliomas (HGGs), suggesting that successful treatments will likely target these key mechanisms. Janus-associated kinase (JAK)-STAT pathway comprises one such therapeutic node, as STAT3 signaling is upregulated in proliferating glioma cells and immunosuppressive cell types. We performed retrospective analysis on 13 HGG patients treated with the JAK1/2 inhibitor ruxolinitib in combination with radiation or radiation plus temozolomide in a Phase I setting (NCT03514069). Disease progression and treatment response was determined based on the Response Assessment in Neuro-Oncology (RANO) criteria. Peripheral blood mononuclear cells (PBMCs) cells were collected from patients prior to treatment, and 2- 4- and 6-week time points to characterize early immunological changes that are indicative of treatment response with flow cytometry. 6 patients responded favorably, define as progression-free survival >6 months. Investigation of myeloid and lymphoid cell populations revealed no differences in dendritic cell, myeloid-derived suppressor cell and CD8+ T cell subset frequencies in blood. Similarly, expression of checkpoint inhibitors PD-1, TIGIT, CTLA-4 and TIM3 were not altered with ruxolinitib treatment. However, there was a ~2-fold reduction in the frequency of peripheral B cells in favorable responders at 4-week time point, whereas the levels remained stable in non-responders (p<0.05). In addition, while 5 out of 7 non-responders had increased CD4+ T cells by 4-weeks, 5 out of 6 responders had stable or reduced CD4+ T cells. This effect was driven by reduction in immunosuppressive regulatory T cells (Tregs) as the relative ratio of immunostimulatory T helper 1 (Th1)-to-Treg ratio was 3-fold higher in responders compared to non-responders. These results support evaluation of B and CD4+ T cells in the peripheral blood as biomarkers to identify HGG patients likely to benefit from such approach.
BIOM-36. THE UNIQUE METABOLOMICS BASED BIOMARKERS OF RESPONSE TO IMMUNOTHERAPY FOR GLIOBLASTOMA
Authors: Dastmalchi Farhad , Karachi Aida , Mehkri Yusuf , Khattri Ram , Merritt Matthew , Kubilis Paul , Mitchell Duane , Rahman Maryam
Published: December 2020

INTRODUCTION

The adaptive immune response requires robust T cell proliferation and activation. These T cell changes are dependent on metabolic program shifts that can be measured using metabolomic analysis. The objective of this project was to identify a metabolomics profile to serve as a biomarker of response to immunotherapy for the treatment of brain tumors.

METHODS

GL261-gp100 tumor-bearing mice were received anti-PD1 or bone marrow-derived dendritic cell (DC) vaccine that was generated ex vivo. Urine samples were collected for Nuclear Magnetic Resonance (NMR) analysis. A more in-depth Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) revealed global metabolic changes induced with immunotherapy.

RESULTS

The metabolic changes were most dramatic at 24 hours post DC vaccination and slowly returned to baseline at 7 days post DC vaccination. The main drivers of the differences included creatine, n-dimethyl glycine, alanine, lactate, glucose, glutamine, leucine, citrate and formate. Anti-PD1 therapy-related metabolic changes were largest around day 20 post therapy and the main drivers of the differences included dimethyl sulfone, succinate, lactate and isobutyrate.

CONCLUSION

Immunotherapy results in systemic metabolic changes that serve as a biomarker treatment effect. These findings have translational relevance in predicting patients who will develop an immune response to immunotherapy and ultimately have better outcomes with treatment.
BIOM-60. BIOMARKER EVALUATION FOR IMIPRIDONE ONC206 REVEALS ClpP, ATF4, MYC, EGFR and HIF1 AS KEY PREDICTORS OF ANTI-CANCER EFFICACY
Authors: Morrow Sara , Garnett Mathew , McDermott Ultan , Benes Cyril , Allen Joshua , Prabhu Varun
Published: December 2020

ONC206 is a DRD2 antagonist and ClpP agonist that is a chemical derivative of ONC201, which is in Phase II clinical trials for H3 K27M-mutant glioma. We have previously reported that dopamine receptor expression correlates with ONC201 and ONC206 efficacy. Here, we evaluated additional predictive biomarkers for both agents in the GDSC panel using RNA-seq expression data. ClpP emerged as a strong predictor of efficacy for ONC206 (IC50: p = 1.83E-4, AUC: 9.92E-13). ClpP activation enhances degradation of its substrates, including electron transport chain members responsible for oxidative phosphorylation (OXPHOS). Imipridones activate the integrated stress response involving ATF4 and cause proteasomal degradation of c-myc, which also reduces OXPHOS. Accordingly, high ATF4 (IC50: p = 4.92E-5, AUC: p=2.84E-9) and elevated c-myc correlated with ONC206 efficacy (IC50: p = 6.42E-6, AUC: 3.31E-12). EGFR expression is inversely correlate with DRD2 expression in glioma and its activation is associated with glycolysis. Low EGFR expression correlated with increased ONC206 efficacy (IC50: p = 4.32E-7, AUC: p = 6.44E-20). Loss of HIF1 shunts cellular metabolism toward OXPHOS. Low HIF1 expression correlated with increased anticancer efficacy for ONC206 (IC50: p = 1.96E-3, AUC: p = 1.56E-11). Expression of each of the five markers was significantly different in cell lines that achieved an IC90 with ONC206 (~10%) versus those that did not. A similar analysis for ONC201 revealed that ClpP, MYC and EGFR are more predictive of efficacy relative to ATF4 and HIF1. Combinatorial biomarker analyses revealed MYC/EGFR as the most significant predictor of IC50 for both agents. ClpP/MYC and ClpP/HIF1 were the most significant predictors of AUC for ONC201 and ONC206, respectively. Ongoing studies are further investigating tumor type enrichment of biomarkers. Prediction of innate imipridone sensitivity using biomarkers identified in this study may guide patient and tumor type selection in clinical trials.
CBIO-06. MKlp2 INHIBITION AS A NOVEL ANTIMITOTIC FOR GLIOBLASTOMA
Authors: Schrock Morgan , Scarberry Luke , Stromberg Benjamin , Torres Adrian , Chakravarti Arnab , Venere Monica , Summers Matthew
Published: December 2020

Despite innovations in therapy and surgery, glioblastoma remains one of the deadliest tumor types with a 5-year survival rate of approximately 5%. There is a desperate need for new therapeutic strategies to block the growth and survival of glioblastoma. To circumvent toxicities associated with traditional antimitotics, there has been a growing interest in developing therapies that impede mitosis-specific microtubule functions, such as the inhibition of kinesins, mitotic motor proteins that travel along microtubules. Our work with motor kinesin-like protein 2 (MKlp2), in combination with reports from published literature, suggest a previously undescribed role for MKlp2 in early mitosis that would make its inhibition effective at impeding glioblastoma cell growth without neurologic side effects. The objective of this study was to further define this novel function of MKlp2 and to determine the efficacy of MKlp2 inhibition in glioblastoma. Our data indicate that MKlp2 inhibition induced a spindle assembly checkpoint-mediated arrest, suggesting that function of MKlp2 is important for recovery progression to anaphase in addition to its well-known function in late mitosis. In addition, MKlp2 inhibition with a small molecule MKlp2 inhibitor significantly decreased short-term and long-term survival of human glioblastoma patient-derived lines. Furthermore, our data indicate that it is loss of this early mitotic function that is responsible for the anti-proliferative effects caused by MKlp2 inhibition. Ongoing work will continue to delineate the mechanism of MKlp2 in early mitosis and determine the effect of small molecule MKlp2 inhibition in vivo, all the while exploring a new therapeutic strategy for glioblastoma
CBIO-16. SUPPRESSION OF HISTONE H3.3 MITOTIC PHOSPHORYLATION DRIVES DEVELOPMENT OF H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS
Authors: Day Charles , Langfald Alyssa , Grigore Florina , Sepaniac Leslie , Stumpff Jason , Vaughan Kevin , Robinson James , Hinchcliffe Edward
Published: December 2020

Pediatric midline gliomas – including DIPG – are lethal brain tumors in children, with poor prognosis and limited treatment options that provide only short-term benefits. The majority have a lysine-to-methionine substitution at residue 27 (H3K27M) in genes expressing histone H3 – predominantly in the H3.3 variant. This causes a global reduction in H3 Lys27 tri-methylation (H3K27Me3), comprehensive epigenetic reprogramming, and is a key driver in gliomagenesis. We show that the H3.3K27M mutation also induces chromosome segregation defects, which in high-grade tumors, results in extensive copy number alterations (CNAs). Ser31 is one of five amino acid substitutions differentiating H3.3 from canonical H3.1. Mitotic phosphorylation of H3.3 Ser31 by Chk1 kinase is restricted to pericentromeric heterochromatin, where it plays a role in chromosome segregation. We show that the K27M mutation affects neighboring Ser31 phosphorylation and pericentromeric heterochromatin organization. We demonstrate that (i) H3.3 K27M protein is defective for Ser31 phosphorylation by Chk1 kinase in vitro; (ii) DIPG cell lines have significantly decreased mitotic Ser31 phosphorylation, and are chromosomally unstable; and (iii) CRISPR-reversion of H3.3K27M to Lys27 restores phospho-Ser31 (and Lys27 tri-methylation) and significantly decreases chromosome instability. Expression of H3.3K27M or non-phosphorylatable H3.3S31A mutants in WT cells results in chromosome missegregation; this is suppressed by co-expression of phospho-mimetic H3.3K27M/S31E. In normal cells, chromosome missegregation stimulates p53-dependent cell cycle arrest in G1 to prevent the proliferation of aneuploid daughters. However, cells expressing H3.3 K27M or S31A failed to arrest following missegregation - despite having WT p53. Finally, in a novel mouse model of glioma, mean survival of mice with tumors induced with H3.3K27M and H3.3S31A was 81 and 68 days: 100% of H3.3S31A mice developed high-grade tumors. H3.3 WT controls developed only low-grade tumors and all survived 100 days. H3.3S31A is WT for Lys27 tri-methylation and thus, loss of Ser31 phosphorylation alone is oncogenic.
CBIO-19. LOW GLOBAL HISTONE H4 ACETYLATION LEVELS REVEAL CANDIDATE QUIESCENT CELL POPULATIONS IN GLIOMA AND DISTINGUISH TUMORS BY GRADE
Authors: Mihalas Anca , Feldman Heather , Patel Anoop , Paddison Patrick
Published: December 2020

Current standard of care therapy for glioblastoma (GBM) includes cytoreduction followed by ablative therapies that target rapidly dividing cell types. However, the presence of quiescent-like/G0 states, therefore, represents a natural reservoir of tumor cells that are resistant to current treatments. Quiescence or G0 phase is a reversible state of “stasis” cells enter in response to developmental or environmental cues. To gain insight into how glioblastoma cells might regulate G0-like states, we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) harboring a G0-reporter to identify genes that when inhibited trap GSCs in G0-like states. Among the top screen hits were members of the Tip60/KAT5 histone acetyltransferase complex, which targets both histones (e.g., H4) and non-histone proteins for acetylation. NuA4 functions as a transcriptional activator, whose activities are coordinated with MYC in certain contexts, and also participates in DNA double-strand break repair by facilitating chromatin opening. However, currently little is known about the roles for NuA4 complex in GBM biology. Through modeling KAT5 function in GSC in vitro cultures and in vivo tumors, we find that KAT5 inhibition causes cells to arrest in a G0-like state with high p27 levels, G1-phase DNA content, low protein synthesis rates, low rRNA rates, lower metabolic rate, suppression of cell cycle gene expression, and low histone H4 acetylation. Interestingly, partial inhibition of KAT5 activity slows highly aggressive tumor growth, while increasing p27hi H4-aclow populations. Remarkably, we that low grade gliomas have significantly higher H4-aclow subpopulations and generally lower H4-ac levels than aggressive grade IV tumors. Taken together, our results suggest that NuA4/KAT5 activity may play a key role in quiescence ingress/egress in glioma and that targeting its activity in high grade tumors may effectively “down grade” them, thus, increase patient survival.
CBIO-24. KINETOCHORE MISREGULATION IN GLIOBLASTOMA AND OTHER CANCERS
Authors: Herman Jake , Zhu Jun , DeLuca Jennifer , Paddison Patrick
Published: December 2020

Aneuploidy is a hallmark of most late stage cancers and contributes to tumor cell evolution, invasiveness, therapy resistance, and recurrence. A major cause of aneuploidy is lagging anaphase chromosomes that have merotelic kinetochore (KT) attachments in mitosis. In this scenario, a KT (i.e., the proteinaceous structure assembled onto centromeres in mitosis) is bound to microtubules (MTs) emanating from both spindle poles, causing chromosome mis-segregation. “Background” chromosome missegregation likely contributes to the initiation of multiple cancers, including glioblastoma (GBM), where chr 7 gain and chr 10 loss are early events. However, we have found that in GBM and transformed cells activation of the RAS signaling pathway significantly increases lagging anaphase chromosomes, and, as a result, aneuploidy and tumor heterogeneity. However, the underlying mechanism of RAS-induced chromosome instability has remained elusive. Here we present one possible cause: MAPK-driven KT stress. The hallmarks of KT stress include chronic KT-MT attachment instability in mitosis, dramatic changes in KT morphology, and increases in merotelic KT attachments and chromosome segregation errors. KT stress is lethal to cancer cells. However, stressed cells survive by relying on BUB1B/BubR1 activity to strengthen KT-MT attachments. We first observed KT stress in GBM patient isolates, where ~60–70% display its hallmarks. We subsequently found that RAS or MEK activity is sufficient to induce KT stress in both CNS and non-CNS derived cell types. We propose that KT stress is caused by aberrant mitotic RAS/MAPK activity, which likely targets one or more KT proteins resulting in KT-MT attachment defects and chromosome instability. In addition, Dr. Jun Zhu’s lab has also created a computational classifier that can identify KT stressed cells and tumors based on the expression of 838 genes associated with KT stress, which can be also used to identify orthogonal therapeutic sensitivities. We will present these findings as well at this meeting.
COVD-03. ASSESSING THE IMPACT OF CORONAVIRUS 19 PANDEMIC ON NEURO-ONCOLOGY AT GUY’S CANCER CENTRE LONDON
Authors: Little Jessica , Al-Salihi Omar , Brazil Lucy , Swampillai Angela
Published: December 2020

BACKGROUND

Immunosuppressive treatment increases COVID-19 risk. Neuro-oncology patients may not qualify for ITU if they deteriorate, but without oncological treatment, prognosis is poor. The pandemic has seen the introduction of new guidelines; including alternative treatment schedules which balance risks of contracting COVID-19, against safely delivering effective cancer treatment. We assess COVID-19 impact on neuro-oncology treatment at Guy’s Cancer Centre, London.

METHODS

Notes of patients seen March-April 2020 were reviewed. Demographic data, tumour grade, treatment and changes due to COVID-19 recorded.

RESULTS

111 patients were identified (69 male: 42 female, median age 51years). 65 were WHO Grade 4, 24 Grade 3, 17 Grade 2, 2 Grade 1, 1 metastatic-neuroblastoma, 1 anaplastic-medulloblastoma and 1 radiological diagnosis of high-grade-glioma. 14% (32) of consultations were in person (16 new, 7 consents, 9 attending for treatment); 86% (198) were telephone. 8 had concurrent chemo-radiotherapy, 22 radiotherapy alone, 64 chemotherapy alone, 15 had active-surveillance and 2 best-supportive-care. To minimise COVID-19 risk, 22.5% (25) had treatment altered: - A 76-year-old had a radiological diagnosis; - 4 had hypofractionated radiotherapy (30Gy in 6#) to minimise hospital visits; - 7 had no chemotherapy (5 were unmethylated /age, 2 patient choice); - 4 switched from PCV to Lomustine; - 11 stopped chemotherapy early; - 50% (36) were given prophylactic GCS-F; - No patients were recruited for trials. 19 reported possible COVID-19 symptoms – 7 had delays and 3 stopped treatment. 4 tested COVID-19 positive (although not all tested). 1 died of COVID-19 (off treatment). Review of March-April 2020 service showed similar new patient referrals compared to the same time in 2019 (16 and 19 respectively).

CONCLUSION

Despite concern about decreasing new referrals during the pandemic, this wasn’t the case for our service. 77.5% of patients had no treatment changes due to COVID-19 and all 22 patients on trial were able to continue treatment throughout this period.
COVD-09. INVESTIGATION AND SUMMARY OF DIAGNOSIS AND TREATMENT OF NEUROLOGICAL TUMORS DURING COVID-19 IN CHINA
Authors: Liang Zhen , Hu Yuanjun , Chen Zhong-ping
Published: December 2020

In order to realize the condition of diagnosis and treatment of neurological tumors in China during COVID-19, CSNO (China Anti-Cancer Association Neuro-Oncology Professional Committee) organized this questionnaire survey. The survey was conducted online from June 3rd to 16th in 2020. A total of 373 replies were received and 370 were confirmed valid questionnaires. The respondents were mainly neurosurgeons, as well as radiotherapists and pathologists in general hospitals and specialized hospitals in 29 provinces and municipalities in China. The survey results are summarized as follows. Firstly, the number of outpatient and inpatient of neurological tumors significantly declined during the epidemic compared with the same period last year in more than 90% of hospitals surveyed, and a few specialized hospitals even stopped treatment due to the outbreak of COVID-19. Compelled by illness was the main reason for most of the patients to go to hospital. As the epidemic prevention and controlling, the normal treatment process for each patient was tedious than that for the same period before, and the costing time also turned longer. Most patients might feel poor medical experience, but they also expressed understanding for the hospital and cooperated with the diagnosis and treatment works. Secondly, during the epidemic period, the participation in academic conferences or MDT decreased significantly for most doctors, and scientific research work even stopped in some hospitals. Online tools have risen as the primary means of communication, not only for academic communication but also for diagnosis and treatment works. More than 90% of doctors believe the style of online communication was a new mode in this special period, with advantages such as convenient and quick. It could be an effective supplement to daily work and would be utilized into work in future.
CSIG-04. ROLE OF c-Met/β1 INTEGRIN COMPLEX IN THE METASTATIC CASCADE
Authors: Sudhir Sweta , Lau Darryl , Wadhwa Harsh , Jain Saket , Chandra Ankush , Nguyen Alan , Spatz Jordan , Shah Sumedh , Cheng Justin , Safaee Michael , Yagnik Garima , Jahangiri Arman , Aghi Manish
Published: December 2020

Metastases cause 90% of human cancer deaths. The metastatic cascade involves 5 steps: local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. While individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a structural complex between receptor tyrosine kinase c-Met and β1 integrin in metastases that form under certain biological and therapeutic inducers, including bevacizumab. Using novel cell culture and in vivo assays, we found that c-Met/β1 complex induction promotes breast cancer intravasation and adhesion to the vessel wall but does not increase extravasation. These effects may be driven by the ability of the c-Met/β1 complex to increase mesenchymal and stem cell characteristics in breast cancer cells. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/β1 complex induction in breast cancer cells. We subsequently used CRISPR to introduce a β1 integrin point mutation that prevented binding to c-Met and led to reduced intravasation, confirming the importance of c-Met/β1 integrin binding for the metastatic cascade. OS2966, a therapeutic B1 integrin blocking antibody, disrupted c-Met/β1 binding as well, and decreased invasion, mesenchymal gene expression, and mesenchymal morphology of breast cancer cells. Bone-seeking breast cancer cells exhibited higher c-Met/β1 complex levels than parental controls and preferentially adhere to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/β1 complex levels than brain metastases. Thus, our research suggests the c-Met/β1 complex drives breast cancer cell intravasation and preferential affinity for bone tissue-specific matrix. Pharmacological targeting of the complex may prevent metastases, particularly osseous metastases.
CSIG-15. INNOVATIVE COMPUTATIONAL PLATFORM ADDRESSES PROSTAGLANDIN E RECEPTOR 3 AS THE MASTER REGULATOR MEDIATING RESISTANCE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA CELLS
Authors: Chen Dongjiang , Le Son , Hutchinson Tarun , Tran David
Published: December 2020

OBJECTIVES

Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. The addition of TTFields resulted in a significant improvement in overall survival. However, most GBM patients eventually develop resistance to TTFields and the mechanism remains unexplored.

METHODS

Multiple GBM cell lines were treated continuously at clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally.

RESULTS

TTFields-induced chromosomal instability is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay, stemness markers such as CD44 and increased tumorigenesis when implanted into mouse brain. Using an innovative computational platform-NETZEN, we methodically dissected this stemness program in resistant cells. 3 networks were found disrupted and all play critical roles in GBM stemness. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked regulator responsible for resistance. PTGER3 is rapidly upregulated both in vitro and in vivo upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Immunofluorescence staining shows PTGER3’s nuclear translocation along with Lamin A/C disruption in response to TTFields. Pharmacological inhibition of PTGER3 using aspirin or PTGER3-specific inhibitors resensitized or prevent cells becoming resistance to TTFields.

CONCLUSIONS

We have identified a novel regulator PTGER3 at the apex that plays a critical role in TTFields resistance. This is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.
CTIM-07. IDENTIFICATION OF A BASELINE BIOMARKER ASSOCIATED WITH TUMOR RESPONSES IN A PHASE I/IIa TRIAL OF A THERAPEUTIC CMV VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM)
Authors: Wen Patrick , Reardon David , Forst Deborah , Lee Eudocia , Iwamoto Fabio , Diaz-Mitoma Francisco , Anderson David , Lassman Andrew
Published: December 2020

Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. We enrolled 10 patients (6 women, 4 men) with KPS at least 70 and first recurrence of GBM to a trial (Phase IIa extension) of gB/pp65 enveloped virus-like particles (eVLPs) with GM-CSF. Intradermal vaccination was administered every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks. Median age was 59 years (range 33–67). Among 8 response-evaluable patients, we observed 1 SD and 1 PR. Among all patients treated on phase I and II (n=26), a normal baseline ratio of CD4/CD8 T cells in peripheral blood predicted response (n=6). Other baseline peripheral blood markers did not correlate with efficacy, including total white blood cell, lymphocyte percentage, and absolute lymphocyte count. During treatment, the peripheral blood of responders demonstrated dynamic losses followed by subsequent reappearance and expansion of CMV-specific CD4+ effector memory T cells. Based on these encouraging results, a new arm is enrolling subjects combining gB/pp65 eVLPs (at the same dose) formulated with adjuvant intramuscular AS01B and results will be presented.
CTIM-08. COMBINATION OF THE IMA950/POLY-ICLC MULTIPEPTIDE VACCINE WITH PEMBROLIZUMAB IN RELAPSING GLIOBLASTOMA PATIENTS
Authors: Dutoit Valérie , Marinari Eliana , Dietrich Pierre-Yves , Migliorini Denis
Published: December 2020

The IMA950 peptide vaccine is composed of 9 HLA-A2-restricted peptides eluted from the surface of GBM samples and of two HLA class II-binding peptides1. It was tested in combination with poly-ICLC in patients with newly diagnosed GBM, demonstrating safety. The vaccine was able to elicit CD4 and CD8 T cell responses in the peripheral blood in the majority of patients, with however an overall low magnitude of T cell responses and suboptimal migration of elicited T cells to the brain, probably limiting clinical efficacy2,3. With the aim to improve homing of vaccine-specific T cell to the tumor, we are conducting a phase II clinical trial in patients with recurrent GBM testing the IMA950/poly-ICLC multipeptide vaccine with or without the anti-PD1 antibody pembrolizumab (NCT03665545). 24 patients will be included (12 patients in each arm) and pre- and post-vaccination tumor sample will be available, allowing assessing effect of the vaccine at the tumor site. The primary objective of this trial is safety of IMA950/poly-ICLC given together with pembrolizumab. Secondary objectives include (i) estimation of 6, 9 and 12-month progression-free survival (PFS), (ii) overall survival, (iii) analysis of patient quality of life and (iv) of the synergy/immunogenicity of IMA950/poly-ICLC and pembrolizumab. Immunomonitoring will include measure of vaccine-induced immune responses, IHC for immune cell markers, RNA/TCR sequencing and methylome analysis, to assess vaccine-induced T cell responses, immune modulation and potential signatures predictive of response. Thus far, 6 patients have been included (3 in each arm). Preliminary results show CD4 and CD8 T cell responses to the vaccine are detected in both groups in the peripheral blood. Analysis at the tumor site and comparison between arms will be performed once all patients have been included. 1. Dutoit, V. et al. Brain (2012); 2. Migliorini, D. et al. Neuro Oncol (2019); 3. Rampling, R. et al. Clin Cancer Res(2016)
CTIM-10. PHASE II STUDY OF PEMBROLIZUMAB PLUS SurVaxM FOR GLIOBLASTOMA AT FIRST RECURRENCE
Authors: Ahluwalia Manmeet , Peereboom David , Rauf Yasmeen , Schilero Cathy , Ciolfi Marci , Ciesielski Michael , Fenstermaker Robert
Published: December 2020

BACKGROUND

Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 2 (PD-L2). Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. It acts in concert with the mitotic spindle apparatus to regulate cell division and localizes to the spindle microtubule organizing center (MTOC) during the G2/M phase of cell cycle progression. Survivin has also been shown to modulate the function of a number of terminal effector cell death proteases (caspases) leading to an inhibition of apoptosis.

METHODS

This is a Phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of 10 patients who have failed prior anti-PD1 therapy. The ongoing study is a phase II clinical study with a 10 patient, toxicity run-in. All patients will receive the study drug combination consisting of SurVaxM and pembrolizumab with no randomization, stratification or dose escalation.

RESULTS

So far ten patients have been enrolled on the study as safety run in. Primary endpoint is Progression free survival at 6 months. Safety and tolerability of Pembrolizumab and SurVaxM, Response rates of Pembrolizumab and SurVaxM determined using RANO criteria are secondary endpoints. Additional secondary endpoints include Overall survival and Progression Free survival Exploratory endpoints include Cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM.

CONCLUSION

This is an ongoing clinical trial.
CTIM-20. PHASE I STUDY OF IBRUTINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Rauf Yasmeen , Peereboom David , Fallah Jaleh , Schilero Cathy , Lackner Pamela , Stevens Glen , Ahluwalia Manmeet
Published: December 2020

BACKGROUND

Glioblastoma is a devastating disease that is notoriously resistant to current therapies, leading to dismal patient outcomes and a median survival of just 14.6 months. A major problem in glioblastoma treatment is the inability to effectively target the cell population that gives rise to recurrence. These cells, known as glioma stem cells (GSCs) or tumor propagating cells are endowed with a large capacity for self-renewal to propagate the tumor. GSCs are resistant to radiation. Ibrutinib is a first-in-class, potent, orally administered, covalently binding Inhibitor of Bruton’s Tyrosine Kinase (BTK). Ibrutinib is a small-molecule tyrosine kinase. It also inhibits BMX. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. Hence a combination of ibrutinib with radiation and or temozolomide in patients with newly diagnosed Glioblastoma is warranted.

METHODS

This is a two arm study. Arm 1 is for patients with unmethylated MGMT Glioblastoma. Every patient gets ibrutinib and 60 Gy radiation over 6 weeks. Patients will undergo a 4-week break and Ibrutinib treatment will then continue until disease progression, intolerable toxicity or death. Arm 2 is for patients with MGMT methylated glioblastoma. Every patient will receive Ibrutinib and 60 Gy radiation and daily Temozolomide at 75 mg/m2 for 6 weeks. Patients will undergo a 4-week break then receive daily ibrutinib and adjuvant Temozolomide. The temozolomide will continue until disease progression, intolerable toxicity or death or maximum of 6 cycles. Ibrutinib treatment will continue until disease progression, intolerable toxicity or death.

RESULTS

The maximum tolerated dose (MTD) of Ibrutinib with radiation (2 Gy x 30) in patients in each arm will be reported. The safety of Ibrutinib with radiation and with radiation and temozolomide will be reported. The Progression free survival and overall survival in each arm will be reported.

CONCLUSION

This is an ongoing clinical trial. Results will be reported once study is complete.
CTIM-21. PEPTIDE VACCINE DIRECTED TO CMV pp65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL
Authors: Thompson Eric , Landi Daniel , Thompson Eric , Lipp Eric , Balajonda Bea , Herndon James , Buckley Evan , Flahiff Charlene , Jaggers Denise , Schroeder Kristin , Randazzo Dina , Desjardins Annick , Johnson Maggie , Peters Katherine , Khasraw Mustafa , Malinzak Michael , Mitchell Duane , Ashley David , Sampson John
Published: December 2020

INTRODUCTION

The cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma.

METHODS

Vaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly.

RESULTS

To date, 17 patients have been enrolled. Diagnoses include medulloblastoma (n=1), glioblastoma (n=9), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=2), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 41% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 0.8, not estimable) and median OS is 6.5 months (95% CI 1.8, not estimable). Interim analysis of immune monitoring bloodwork and perfusion MRI to quantify responses to PEP-CMV has been delayed due to COVID-19. However, adults with GBM who received PEP-CMV (NCT02864368) had significant (p≤0.05) increases in GCSF, GM-CSF, IFN-γ, IL-10, IL-2, IL-8, MIP1-α, and TNF-α levels.

CONCLUSIONS

Preliminary results demonstrate that PEP-CMV is feasible and well-tolerated in heavily pretreated, multiply recurrent patients.
CTIM-26. PATIENT-SPECIFIC DENDRITIC CELL VACCINE (DC-ATA) PULSED WITH ANTIGENS FROM SELF-RENEWING AUTOLOGOUS TUMOR CELLS IN THE TREATMENT OF NEWLY-DIAGNOSED GLIOBLASTOMA: A PHASE II TRIAL
Authors: Bota Daniela , Piccioni David , LaRocca R , Duma Christopher , Kesari Santosh , Carrillo Jose , O’Donnell Robert T , Aiken Robert , Hsu Frank , Kong Xiao-Tang , Hsieh Candace , Langford Chris , Carta Krystal , Wang Adrienne , Langford James , Taylor Thomas , Nistor Gabriel , Dillman Robert
Published: December 2020

GBM standard treatment is associated with poor survival. Adjunctive therapy with patient-specific vaccines may improve outcomes by enhancing anti-GBM immune responses. A multi-institutional phase II clinical trial was designed with a primary objective of 75% survival 15 months after intent-to-treat enrollment. IL-4 and GM-CSF were used to generate dendritic cells (DC) from monocytes. DC were incubated with autologous tumor antigens (ATA) from the lysate of cultured GBM cells to produce each patient-specific DC-ATA vaccine. Each dose was admixed with 500 mcg GM-CSF at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Enrollment has been completed in April 2020 (n=60). Three patients withdrew from the study prior to starting treatment leaving 57 patients for whom data is available. So far 57 patients have received 344 doses; 27 have completed all 8 doses, 11 received fewer than 8 doses at the time they discontinued treatment, 19 are currently in treatment. No patient has discontinued treatment because of toxicity. 9 pt had died and the preliminary 12 months overall survival is 74%. In a preliminary serologic analysis 12 of 16 patients (75%) had an increase in markers associated with Th1/NK, Th2/immunoglobulins, and Th2 hypersensitivity (eotaxins, IgE and IL17F) by week-3; 9 of 15 (60%) had a decrease in angiogenesis factors, growth factors, and tumor markers by week-8. Immunologic data for all 55 patients who received at least two injections will be available November 2020. This patient-specific DC-ATA immunotherapy approach is feasible, is associated with changes in serologic markers, and may be increasing intratumor inflammation that may be associated with on-target toxicity and efficacy. A interim survival analysis will be conducted in mid-October 2020, 15 months after the 28th patient was enrolled; results will be available November 2020 [Clinicaltrials.gov NCT03400917].
CTIM-30. EFFICACY OF PEMBROLIZUMAB IN PATIENTS WITH PITUITARY CARCINOMA: RESULTS FROM A PHASE II STUDY
Authors: Majd Nazanin , Waguespack Steven , Filip Janku , Fu Siqing , Penas-Prado Marta , Xu Mingxuan , Alshawa Anas , Kamiya-Matsuoka Carlos , Raza Shaan , McCutcheon Ian , Aung Naing
Published: December 2020

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region that leads to debilitating symptoms and poor survival. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there is interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated four pituitary carcinoma patients with pembrolizumab as part of a phase II clinical trial (NCT02721732). Here, we present their clinical course and outcomes and correlate responses with available molecular data: hypermutation status, PD-L1 staining, tumor-infiltrating lymphocyte score, microsatellite status and tumor mutational burden. Patients 1 and 2, with heavily pretreated, refractory corticotroph pituitary carcinoma, had partial radiographic (60% and 32% per irRECIST, respectively) and hormonal responses. Patient 1’s response continues 42 months after initiation of pembrolizumab and his baseline tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2’s tumor was not sampled after exposure to temozolomide, but prior somatic mutational testing was negative. Patient 3 (non-functioning corticotroph tumor) had a best response of stable disease for four months. Patient 4 (prolactin-secreting carcinoma) had progressive disease. The latter two patients’ tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. PD-L1 staining was negative in all tumors. TIL score was 2 in Patients 1 and 4, negative in Patient 3 and not available in Patient 2. All patients tolerated the treatment well with mild adverse events. Our study generates the hypothesis that an alkylating agent-induced hypermutator phenotype may be an indicator of response to CPIs in pituitary carcinomas. The role of CPI in treating patients with pituitary carcinoma and mechanisms of hypermutation in this population require further study.
CTIM-33. THE REMIND TRIAL: MULTI-ANTIGEN TARGETED T CELLS FOR PEDIATRIC CNS TUMORS
Authors: Grant Melanie , Fortiz Maria Fernanda , Wang Jennifer (Lu) , Lang Haili , Datar Anushree , Reynolds Emily , Terpilowski Madeline , Lazarski Christopher , Tanna Jay , Pitino Adriana , Zhang Nan , Hoq Fahmida , Hanley Patrick , Kilburn Lindsay , Packer Roger , Rood Brian , Bollard Catherine , Hwang Eugene
Published: December 2020

BACKGROUND

Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity.

METHODS

Patients (n=15) received autologous tumor antigen-associated T cells (TAAT) (up to 4x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response.

RESULTS/DISCUSSION

15/15 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Adverse events were minimal despite multiple pretreatments in Group B. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) respectively. Specificity for 1–3 TAAs was demonstrated in 13/15 TAAT by a-IFN-γ ELISPOT. Plasma cytokine and proteomic analyses are ongoing but have demonstrated dynamic post-infusion immune cytokine and protein responses. Increases in the inflammatory and immune-stimulatory cytokines IL-1b, IL-6, IL-2 and IL-7 were observed post-infusion in most patients evaluated. Infusion-related increases in regulatory cytokines IL-10 and IL-13 were also observed in 4/7 patients. These results are consistent with an infusion-mediated immune response in vivo. Of 9 patients who have been tested thus far, 29/92 plasma proteins showed significant differences between dose levels 1 and 2, including increased IL-7 (p < 0.0004) and CD40L (p < 0.046) and reduced IL-4 (p < 0.0004). T cell receptor sequencing data on in vivo TAAT persistence is pending. In summary, TAAT have thus far been safe and elicit immune responses in vivo. Clinical and immunologic response assessments are ongoing.
CTNI-31. INTERIM RESULTS OF A PHASE I/IIA STUDY TO EVALUATE THE SAFETY AND EFFICACY OF BBB OPENING WITH THE SONOCLOUD-9 IMPLANTABLE ULTRASOUND DEVICE IN RECURRENT GLIOBLASTOMA PATIENTS PRIOR TO IV CARBOPLATIN
Authors: Idbaih Ahmed , Ducray François , Stupp Roger , Baize Nathalie , Chinot Olivier , de Groot John , Guyotat Jacques , Sonabend Adam , Menei Philippe , Dufour Henry , Weinberg Jeffrey , Desseaux Carole , Canney Michael , Schmitt Charlotte , Carpentier Alexandre
Published: December 2020

Low intensity pulsed ultrasound (LIPU), in combination with systemic injection of microbubbles, can be used to transiently disrupt the blood-brain barrier (BBB) and increase brain-drug concentrations. In pre-clinical models, carboplatin can be enhanced by a factor of 5x in the brain using LIPU and increase the survival of GBM-bearing mice. In clinical studies, a single emitter, implantable ultrasound device (SonoCloud-1) was used to disrupt the BBB in 19 rGBM patients prior to carboplatin chemotherapy (NCT02253212). The feasibility of this approach was demonstrated, and safe acoustic parameters were determined. The primary objective of this subsequent Phase 1/2a study (NCT03744026) was to demonstrate the safety of BBB disruption over a larger volume, including the tumor and surrounding peritumoral region using a nine-emitter version of the device (SonoCloud-9). This study was a 3 + 3 design using escalating numbers of activated 1-cm diameter emitters (3, 6, 9). GBM patients at any recurrence, with a maximum tumor size of < 70 mm were included. The SonoCloud-9 device was implanted during tumor debulking/resection surgery and replaced the bone flap. The device was activated every four weeks for 270 seconds, concomitantly with DEFINITY® microbubbles to disrupt the BBB prior to administration of carboplatin. Magnetic resonance imaging was performed to verify safety and the extent of BBB disruption. As of June 2020, the escalation phase of the study (9 patients) was complete, with a median of four monthly cycles of sonication and carboplatin chemotherapy per patient. No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with only a few, transient, and manageable related adverse events. The safety of administration of multiple repeat treatments of BBB opening using nine emitters of the device at an acoustic pressure of 1.03 MPa will be confirmed in an additional 12 patients to be included in the ongoing expansion phase.
CTNI-37. EFFICACY OF ONC201 IN PATIENTS WITH ONC201 FOR RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Arrillaga-Romany Isabel , Kurz Sylvia , Tarapore Rohinton S , Sumrall Ashley , Butowski Nicholas , Harrison Rebecca , de Groot John , Chi Andrew , Shonka Nicole , Umemura Yoshie , Odia Yazmin , Mehta Minesh , Nghiemphu Phioanh , Cloughesy Timothy , Taylor Lynne , Graber Jerome , Kilburn Lindsay , Dixit Karan , Lu Guangrong , Allen Joshua , Batchelor Tracy , Lassman Andrew , Wen Patrick
Published: December 2020

H3 K27M-mutant diffuse midline gliomas (DMG) have a dismal prognosis. We report an integrated analysis for ONC201, a DRD2 antagonist and ClpP agonist, in patients with recurrent H3 K27M DMG administered as monotherapy in 3 clinical studies (NCT03295396, n=20; NCT02525692, n=6; or expanded access, n=4) by independent, central radiology review among 30 patients. At baseline, patients had measurable contrast-enhancing disease by RANO criteria, KPS>60, and were >90 days from prior radiation. Patients with primary lesions that involved the pons or spinal cord or had evidence of leptomeningeal or cerebrospinal fluid dissemination were excluded. ONC201 was orally administered at 625 mg (scaled by body weight for patients < 18 years old) weekly in 29 patients and every 3 weeks in 1 patient. Median age was 31 years (range 8–70; two patients < 18). There were 16 women and 14 men. Tumors were predominantly thalamic (73%), with other locations including the cerebellum (5%), brainstem (non-pontine) (3%), basal ganglia (3%), and midbrain (3%). Median time from prior radiation was 7.5 months. The most frequent drug-related adverse events were low grade nausea (10%) and fatigue (10%). Nine patients (30%) had >50% regression of T1 contrast enhancement and 11 (36.7%) patients had regression of T2/FLAIR. Objective response rate and progression-free survival by RANO criteria, as well overall survival will be reported. Among 8 patients with sustained radiographic regressions, 6 were tapered off dexamethasone and 4 had improvement in KPS. Five patients (16.7%) remain on treatment with a median of 9.5 months (range 7.3–12). In conclusion, single agent ONC201 is well tolerated and clinically active in recurrent H3 K27M DMG patients.