bluuebunny/crossref_metadata_2025_split huggingface dataset:
NCOG-48. A PROSPECTIVE LONGITUDINAL NEUROCOGNITIVE OUTCOME STUDY IN PATIENTS TREATED WITH CAR-T-CELL THERAPY AT 6 MONTHS
Authors: Zarrella Giuliana , Lavoie Mitchell , Gardner Melissa , Johnson Patrick , El-Jawahri Areej , Parsons Michael 
Published: November 2022

Abstract

INTRODUCTION
Chimeric Antigen Receptor T-cell (CAR-T) therapy carries risk of significant neurocognitive function (NCF) toxicities. Longer term NCF outcomes have yet to be reported. The goal of the current study was to assess NCF prospectively in patients undergoing CAR-T.

METHODS
Adult patients undergoing CAR-T participated in NCF testing with a cognitive clinical trial battery (CTB) at baseline and 6 months after treatment. Group change on each test and on the composite score (CTBC) was examined with paired t-tests and individual change, defined as +/-1 SD on CTBC, was also reported.

RESULTS
Forty patients (Mage=62.45, 63% male, 97% Non-Hispanic or Latino) completed NCF testing at baseline, and 28 patients completed NCF measures 6 months post-CAR-T (20 complete CTBC, 8 partial CTB, completed virtually). At baseline, 13/40 patients (33%) had significant impairment in NCF (CTBC Z-score &lt; -1.5), and 2/20 (10%) were impaired at follow-up. In the 20 individuals with pre- and 6-month post-CAR-T CTBC scores, there was no significant change (t(19)=-0.926; p=0.366). Examination of each individual test score also showed no changes (immediate memory (t(26)=-0.084; p=0.934), delayed memory (t(26)=-0.207; p=0.837), memory recognition (t (26)=-0.062; p=0.951) executive function (t(18)=-0.447, p=0.660), and verbal fluency (t(27)=-0.035, p=0.972)). Individual analyses of CTBC at follow-up found the number of patients with meaningful decline=1 (5%), improvement=2 (10%), and no change=17 (85%) on CTBC.

CONCLUSION
Although CAR-T can be associated with acute change in NCF, this prospective longitudinal study showed stable cognitive performance 6 months after treatment. To our knowledge, this is the longest prospective longitudinal study of NCF in CAR-T survivors. This study is limited in that some subjects completed NCF testing virtually at follow-up, limiting the sample size for unconfounded comparison of performance. Future work will examine longer term outcomes and subjective cognitive function in CAR-T survivors.
EXTH-05. TOWARD 100% CLINICAL EFFICACY FOR TUMOR-TREATING FIELDS
Authors: Carlson Kristen , Tuszynski Jack 
Published: November 2022

Abstract
In vitro and in animal models of various tumor cell types, empirical data suggest tumor-treating fields (TTFields) can attain 100% efficacy, with two pre-conditions: 1) Delivering sufficient electric field strength to the target tumor cells, and 2) Changing the direction of the imposed electric field such that intra-cellular structures at any angle with respect to the field see the required efficacious field strength. Requirement #2 reflects empirical findings as well as prevailing theories of TTFields’ mechanism of action, which center on mitosis disruption via energy imparted to polarizable intracellular structures aligned with the field. We tried various trial curve-fits to TTFields empirical dose-response curves. Quadratic formulae yield a close fit, resembling well-known radiotherapy linear-quadratic (LQ) curves and suggesting a connection between the mechanisms of the two treatment modalities: F98 (rat glioma): -16.3271x2 - 0.664019x+100 (R2=0.9995); MDA-MB-231 (human breast cancer): -9.64922x2 + 2.96348x + 100 (R2=0.9999); H1299 (human non-small cell lung carcinoma): -12.0515x2 - 1.58272x + 100 (R2=0.9993); B16 (mouse melanoma): -83.8066x2 + 47.4537x + 100 (R2=0.9954). We extrapolate these fits to predict the approximate required field strength seen at the target cells for 100% efficacy: F98: 2.45 V/cm; MDA-MB-231: 3.4 V/cm; H1299: 2.8 V/cm; B16: 1.4 V/cm. Alternatively, the LQ fits may not reflect the extrapolated high amplitude range for which data is lacking. Under two assumptions, 1) intracellular structures are randomly oriented in vivo, and 2) only two changes of TTFields direction are used, as is the current clinical practice, then extrapolating the dose-response curves predicts that infinite field strength is required for 100% efficacy, since some intracellular structures must be oriented at 90 degrees to the imposed field and the cosine of 90 degrees is zero. Adding a third TTFields direction, not necessarily orthogonal to the plane of the other two directions, can solve this problem.
EXTH-14. INHIBITION OF THE ANGIOTENSIN II TYPE 2 RECEPTOR AT2R IS A NOVEL THERAPEUTIC STRATEGY FOR GLIOBLASTOMA
Authors: Perryman Richard , Renziehausen Alexander , Shaye Hamidreza , Kostagianni Androniki , Tsiailanis Antonis , Thorne Tom , Chatziathanasiadou Maria , Sivolapenko Gregory , El Mubarak Mohamed Ahmed , Han Gye Won , Zarzycka Barbara , Katritch Vsevolod , Lebon Guillaume , Nigro Cristiana Lo , Lattanzio Laura , Morse Sophie , Choi James , O’Neill Kevin , Kanaki Zoe , Klinakis Apostolos , Crook Tim , Cherezov Vadim , Tzakos Andreas , Syed Nelofer 
Published: November 2022

Abstract
Glioblastoma (GBM) is a primary malignant brain tumor with poor clinical outcomes. Standard of care consists of surgical debulking followed by radiation and temozolomide, but the tumor invariably recurs, and median survival is only ~18 months. Repurposing drugs used for the treatment of other diseases is a promising avenue to identify novel treatments for this highly aggressive form of cancer. One such class of compounds is angiotensin II (AngII) receptor blockers, commonly used to control blood pressure. We show that ~80% of primary human GBM express the angiotensin II type 2 receptor (AT2R). In the presence of AngII, inhibition of AT2R using either PD123319 or EMA401 significantly inhibits GBM proliferation. This effect was lost in GBM cells with CRISPR/Cas9 mediated knockdown of AT2R. EMA401 inhibited invasion, angiogenesis, reduced GBM spheroid growth and induced apoptosis through caspase 3/7 activation. Furthermore, EMA401 induced changes in a number of growth regulatory pathways including apoptosis, DNA replication and focal adhesion. The crystal structure of AT2R bound to EMA401 revealed the receptor to be in an active-like conformation with helix-VIII blocking G protein or β-arrestin recruitment. We demonstrate that the architecture and interaction of EMA401 with AT2R differs drastically from complexes of AT2R with other compounds. Conjugation of EMA401 to angiopep-2 enhanced its blood brain barrier passage and reduced tumor volume in an orthotopic xenograft model of GBM. Targeting AT2R is a novel therapeutic strategy to treat GBM that should be explored in patients.
EXTH-27. TRANSLATABLE CCL3 THERAPY TO PROMOTE DC VACCINE MIGRATION AND EFFICACY AGAINST GLIOMA
Authors: Hotchkiss Kelly , Halabi Dahlia , Batich Kristen , Cook Sarah , Norberg Pam , Archer Gary , Sampson John 
Published: November 2022

Abstract

INTRODUCTION
Prior evidence from our studies have identified chemokine ligand 3 (CCL3) as a key modulator to increase DC vaccine migration to vaccine draining lymph nodes (VDLNs) which is associated with improved long-term survival clinically.

METHODS
The effect of CCL3 treatment on DC vaccine migration ex vivo and in vivo (n=5), antigen-specific T cell responses (n=5), and efficacy against orthotopic GL261-OVA and SMA560 tumors (n=10) was studied in C57Bl/6 and VMdK mice. CCL3 treatment of mouse and human DC vaccines ex vivo was also tested in transwell assays. DCs were electroporated with OVA-mRNA or pulsed with ODC1 neoantigen peptide. DC migration and T cell responses were quantified by flow cytometry. Median overall survival (mOS) was measure in days (d) post-intracranial implantation.

RESULTS
Ex-vivo treatment of DC vaccines with 20ng/mL CCL3 (18 and 1hr pre-injection) increased transwell (mouse and human) migration and to VDLN. In vivo systemic CCL3 treatment also resulted in a dose-dependent increase in migration of DC vaccine to VDLN (10µg, 20µg, 50µg). CCL3 added to DC vaccination generated more tumor antigen-specific CD8+IFNγ+ T cells at 7-days. CCL3 with tumor antigen-DC treatment also resulted in significantly greater survival compared to OVA-DC alone (GL261-OVA: mOS DCvac: 19.5d, CCL3+DCvac 37d, p=0.0174; SMA560: mOS: DCvac: 25d, CCL3+DCvac: 48d, p=0.002).

CONCLUSIONS
These data combined with previous success of our DC vaccine clinical trials reflect the potency of CCL3 to enhance DC vaccine-specific migration, immune responses, and survival. CCL3 is a novel and safe adjuvant to overcome prior limitations in DC vaccine therapy and may be translatable to increase heterogeneous tumor antigen presentation following vaccine-targeted tumor killing. CCL3 used as a drug could increase vaccine migration without potential systemic toxicity in patients with glioblastoma.
EXTH-33. PRIMING OF SYNNOTCH CAR T CELLS VIA CNS-SPECIFIC ANTIGEN ALLOWS SPATIAL AND TEMPORAL REGULATION OF CAR EXPRESSION, EFFECTIVE HOMING AND PERSISTENCE OF T CELLS IN THE CNS
Authors: Watchmaker Payal , Simic Milos , Diebold David , Pineo-Cavanaugh Psalm , Deucker Jason , Yu Wei , Lim Wendell , Okada Hideho 
Published: November 2022

Abstract
One of the key challenges in the development of CAR-T therapy is the absence of target antigens that are tumor-specific and have homogenous expression. To safely target glioblastoma-associated antigens (GAAs) in the tumor without attacking normal tissue expressing the same GAAs outside of the brain, we adapted a novel synthetic Notch (synNotch) receptor system and established a “prime and kill” sequential two-receptor CAR circuit. We used glioblastoma- (GBM) specific neoantigen EGFRvIII as a priming signal for synNotch receptor and have reported robust antitumor response in the mice bearing intracerebral PDX tumor with heterogenous EGFRvIII expression. However, less than 20% of adult GBM cases express EGFRvIII. Furthermore, EGFRvIII expression can diminish over time even after its detection in the primary GBM, and the EGFRvIII-synNotch primed CAR T cells may deplete EGFRvIII-expressing GBM cells via their cytotoxic effects, thereby losing the priming signal. To overcome these inherent challenges of the EGFRvIII-priming strategy, we used CNS tissue-specific antigens as priming signal to drive localized expression of the CAR against EphA2 and IL-13Rα2 and bypassed the need for tumor-specific antigen. We have found BCAN (also known as Brevican) as the most promising priming antigen among several CNS-specific cell surface proteins that we evaluated. When mice bearing intracerebral GBM6 PDX received a single IV infusion of T cells engineered with the α-BCANsynNotch- &gt; α-EphA2/IL-13Rα2 CAR (B-SYNC) circuit, all mice (10/10) demonstrated complete regression of the tumor. Furthermore, these B-SYNC T cells were significantly more efficacious than constitutively expressed EphA2/IL-13Rα2 CAR T cells, associated with superior persistence and less exhausted phenotype. Thus, the B-SYNC approach represents a conceptual novelty of CNS tissue-specific CAR activation. This also enhances the translational significance of synNotch-CAR T cells by widely extending the eligibility to EGFRvIII-negative glioma patients. We will develop and conduct a phase I study to evaluate our hypothesis.
EXTH-37. TARGETING THE IDH1R132H MUTATION IN GLIOMAS BY CRISPR-CAS PRECISION BASE EDITING
Authors: Weber Remi , Vasella Flavio , Klimko Artsiom , Silginer Manuela , Lamfers Martine L M , Regli Luca , Schwank Gerald , Weller Michael 
Published: November 2022

Abstract

Gliomas are the most frequent malignant primary brain tumors and continue to lack curative therapies. To aid the development of novel therapeutic approaches, a better understanding of glioma-specific molecular patterns is essential. We therefore investigate the role of the canonical point mutation in the isocitrate dehydrogenase 1 gene (IDH1R132H). Its early occurrence in oncogenesis and ubiquitous expression suggests a causative driver function; however, current literature is inconclusive on the impact of IDH1R132H, requiring innovative approaches to further elucidate the functional consequences and therapeutic potential of IDH1R132H.

METHODS
Clustered, regularly interspaced, short palindromic repeat (CRISPR)-Cas precision base editing systems enable the alteration of a specific base pair without suffering from off-target editing associated with previous, double strand brake-inducing systems and thus making them an ideal tool to revert the point mutation in IDH1R132H gliomas.

RESULTS
By selecting a CRISPR-Cas precision base editing system, the IDH1R132H site was edited with editing efficiencies of up to 50%. Primary patient derived cell lines and organoids were corrected in their IDH1R132H locus. Phenotypical changes, such as a change in IDH1R132H protein levels, 2-hydroxyglutarate concentration as well as proliferation rates were observed upon the reversal of the point mutation. Furthermore, the precision base editing system was packaged into a dual-AAV-vector split intein system and showed successful in vitro gene editing. In conclusion, this precise genetic intervention provides a methodology to create accurate patient derived models to analyze the impact of IDH1R132H on glioma biology and provides a framework for in vivo gene therapy.
EXTH-38. NEOADJUVANT PD1 BLOCKADE ALTERS THE TUMOR IMMUNE MICROENVIRONMENT AFTER SURGERY IN A PRECLINICAL MODEL OF RECURRENT GLIOBLASTOMA
Authors: Hoang-Minh Lan , Klippel Kelena , Doonan Bently , Von Roemeling Christina , Trivedi Vrunda , Yang Changlin , Sriharan Akshayaa , Francis Connor , Shin David , Karachi Aida , Galochkina Zhanna , Sarkisian Matthew 
Published: November 2022

Abstract

SIGNIFICANCE
Promising clinical trials for glioblastoma are evaluating the efficacy of neoadjuvant immunotherapy in the context of recurrent tumor surgery.

OBJECTIVE
We investigated the effects of neoadjuvant PD1 blockade on the glioma tumor microenvironment after surgery in a clinically relevant murine model of recurrent tumor.

RESULTS
Using a mouse resection model of KR158 glioblastoma that we established, we show that neoadjuvant PD1 inhibition and surgery enhance mouse survival and enhance the recruitment of CD8+ and CD4+ T cells at recurrent tumor sites following bulk tumor resection when compared with surgery followed by adjuvant immunotherapy. Transcriptome and spatial genomic analyses reveal alterations in immune exhaustion and activation pathway signaling genes after neoadjuvant anti-PD1 treatment when compared with adjuvant anti-PD1-treatment or surgery alone.

CONCLUSIONS
These studies provide insights into the effects of neoadjuvant PD1 blockade on the tumor microenvironment after surgery and uncover additional treatment targets that could be used in combination with this neoadjuvant therapy.
EXTH-39. BIOMARKER DRIVEN TARGETING OF RECURRENT IDH MUTANT GLIOMA WITH ABEMACICLIB
Authors: Nasser Ali , Melamed Lisa , Nagashima Hiroaki , Wakimoto Hiroaki , Cahill Daniel , Miller Julie 
Published: November 2022

Abstract
Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressive, and lead to untimely death. The aggressive change in clinical outcome is driven by insensitivity to conventional methods of treatment, necessitating an improved therapeutic strategy at this stage of the disease. Greater than 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, leading to the loss of the endogenous CDK4/6 inhibitor p16 and aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors which have been approved for use in a variety of other cancer types. We examined the sensitivity of a panel of patient-derived IDH mutant gliomas with either endogenous CDKN2A loss or CRISPR-mediated gene deletion to treatment with CDK4/6 inhibitors. We observed a correlation between CDKN2A loss and enhanced cytotoxicity following abemaciclib treatment in these glioma models. We have characterized the cell cycle profile following abemaciclib treatment by flow cytometry and western blotting in both sensitive and resistant lines. Further, abemaciclib treatment resulted in significant slowing of tumor growth rate in a subcutaneous patient-derived IDH mutant glioma model. Survival studies in an intracranial model are ongoing. These preclinical results provide foundational data to support a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.
EXTH-45. TARGETING GLIOBLASTOMA BY NOVEL INTEGRIN-SPECIFIC CAR T CELLS
Authors: Villars Danielle , Haensch Lena , Silginer Manuela , Weiss Tobias , Weller Michael , Roth Patrick 
Published: November 2022

Abstract

RATIONALE
Innovative treatment strategies are urgently needed to improve the prognosis of glioblastoma patients. Chimeric antigen receptor (CAR) T cell therapy has shown great success in hematological malignancies. However, it remains to be shown that CAR T cells are also active against solid tumors. αv integrins are overexpressed in gliomas and have already been used as therapeutic targets for small molecule inhibitors and antibodies. While these approaches were well tolerated, they did not exert meaningful clinical activity in glioblastoma patients. We aimed at exploiting the presence of αv integrins as targets for anti-glioma CAR T cell therapy.

METHODS
CAR T cells targeting specific integrin heterodimers (αvβ3, αvβ5 or αvβ8) were generated and their anti-glioma activity was determined in co-culture assays with different glioma cells. The efficacy of CAR T cells to control tumor growth in vivo was assessed in clinically relevant orthotopic mouse glioma models.

RESULTS
All newly generated integrin-targeting CAR T cells exerted strong anti-tumor activity in vitro. The highest lytic activity against glioma cells was observed for αvβ5 and αvβ8 integrin-specific CAR T cells. CAR T cells generated from patient-derived immune cells displayed strong lytic activity when tested against autologous tumors cells. Glioma cells with a CRISPR/Cas9-mediated knockout of the target antigen were resistant to CAR T cell-mediated cytotoxicity demonstrating their specificity. The in vivo activity of integrin-specific CAR T cells was tested in 2 orthotopic glioma models. Intratumoral treatment of glioma-bearing mice with αvβ5 or αvβ8 CAR T cells significantly prolonged their survival and cured a substantial fraction of these animals.

CONCLUSION
αvβ5- and αvβ8-specific CAR T cells exert strong and target-specific anti-glioma activity in vitro and prolong the survival of glioma-bearing mice. These data form the basis for a clinical evaluation of integrin-specific CAR T cells against glioblastoma.
EXTH-50. IDENTIFYING TRIM11 AS A POTENTIAL THERAPEUTIC TARGET FOR MALIGNANT GLIOMAS
Authors: Di Kaijun , Abrams Daniela , Yadav Pratik , Das Bhaskar , Bota Daniela 
Published: November 2022

Abstract
TRIM11 (tripartite motif-containing protein 11) belongs to the TRIM/RBCC (the RING B-box coiled-coil) family of E3 ubiquitin ligases. Members of this family have been implicated in development, neurodegenerative diseases, cellular response to viral infection and cancer. Glioblastoma (GBM) is an aggressive infiltrative brain tumor with poor prognosis. Our previous work demonstrated that TRIM11 is over-expressed in high-grade gliomas and promotes proliferation, invasion, migration and tumor growth, suggesting TRIM11 is a target for malignant glioma treatment. Here we reported the effect of TRIM11 on GBM progression in vivo using immunocompromised mice intracranially implanted with GBM xenografts over-expressing TRIM11. The control group mice survived longer than the mice bearing TRIM11 over-expressing xenografts (P&lt; 0.5), suggesting TRIM11 enhances tumor progression in vivo. The oncogenic effect of TRIM11 may be related to its influence on apoptosis pathway as a robust induction of poly (ADP-ribose) polymerase (PARP) was observed in TRIM11 over-expressing GBM cells. PARP could repair DNA damage caused by UV light, radiation, and certain anticancer drugs, etc. Blocking PARP may prevent cancer cells from repairing their damaged DNA, causing them to die. Temozolomide (TMZ) is a standard-of-care chemotherapeutic agent for GBM through alkylating/methylating DNA, leading to DNA damage and death of tumor cells. TRIM11 over-expressing GBM cells were found more resistant to TMZ and showed a higher survival rate compared to parental cells, indicating that TRIM11 might be a therapeutic target for GBM. Based on homology modeling we designed and synthesized small library of TRIM11 inhibitors, and identified one compound (BT# 592) significantly inhibited the growth of GBM cells in a dose-dependent manner, implicating that TRIM11 inhibitors may serve as novel agents for malignant glioma treatment. We are in the process to develop more active compounds using SAR studies to identify hit-to-lead compounds as potential therapeutics for GBM.
EXTH-52. HARNESSING A B CELL THERAPY TO PROMOTE ANTI-GLIOBLASTOMA HUMORAL RESPONSE
Authors: Castro Brandyn , Fischietti Mariafausta , Zolp Andrew , Zhao Junfei , Hou David , Nguyen Linh , Wan Hanxiao , Zhang Peng , Han Yu , Lopez-Rosas Aurora , Platanias Leonidas , Stupp Roger , Miska Jason , Lesniak Maciej , Lee-Chang Catalina 
Published: November 2022

Abstract
Glioblastoma (GBM) continues to retain its dismal prognosis despite numerous new therapeutic modalities to target various aspects of the tumor. There is a need to identify new, and even personalized, targetable GBM specific antigens. Our B-cell-based vaccine (BVax) is generated by isolating immune experienced B cells, identified by 4-1BBL, from murine secondary lymphoid organs or patient blood. We have shown this subset of B cells to have anti-tumoral potential in GBM. These cells are strengthened with BAFF, CD40, and IFNg stimulation to form BVax and then activated in vitro to form plasmablasts. Immunoprecipitation-mass spectrometry is performed using BVax-derived antibodies and tumor lysate from the paired patient specimen. We have identified unique antigens bound by BVax-derived antibodies. Given the significant therapeutic benefit we have seen using BVax-derived antibodies in preclinical murine models, we hypothesize that targeting these unique antigens would have significant therapeutic benefit in GBM patients. We focused on antigens that showed a survival benefit with lower expression using CGGA database analysis. We then confirm the presence and prevalence of the antigens within tumor cells in the patient’s tissue using immunohistochemistry, identifying some antigens in up to 15% of tumor cells. Using our brain tumor bank repository, we screened other GBM patient’s tissue for the presence of these markers to determine the broader applicability of targeting each antigen. We have identified proteins key in extracellular matrix formation which promote tumor growth and progression in cancer, including the ability to induce epithelial-mesenchymal transition. Simultaneously we have developed a computational algorithm to predict which antigens BVax-derived antibodies will bind using single cell RNA sequencing data from GBM patient-derived tumor and BVax, which may have broader applicability to a larger number of patients. Both techniques serve as exciting platforms to identify new therapeutic targets in GBM.