bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-29. LAG-3 COMPENSATES TIM-3 DOWN-REGULATION IN A HUMAN GLIOBLASTOMA MODEL
Authors: Ogando-Rivas Elizabeth , Castillo-Caro Paul , Jones Noah , Dechkovskaia Anjelika , Yang Changlin , Mitchell Duane
Published: December 2020

INTRODUCTION

There are a few alternatives treatments beside the standard care for glioblastomas, one of them is adoptive cell therapy; our group has shown promising preliminary results with a dendritic cell-based vaccine that has being tested in first-in-human clinical trials. Checkpoint inhibitors have also shown promising results in the cancer arena, but not for brain tumors.

OBJECTIVE

We have assessed whether combination of checkpoint inhibition and transferred cellular therapy may enhance anti-tumor killing of adoptive T-cell therapies to improve survival in GBM patients.

METHODS

PBMCs were isolated from CMV+ donors, in order to generate dendritic cells and pulsed them with CMVpp65-mRNA. DCs were co-culture with T-cells for 15-days. Five groups were made (Tim3 at 300 ug/ml, PD1, Tim3, PD1+Tim3 at 10 ug/ml and PD1+Tim3 at 3 ug/ml) and their respective isotype-control groups. IL2 was added at 100UI/ml every 3 days as well as the blockade. Phenotyping was performed on Day0 and Day15th. Restimulation was made with pp65-pepmixes and UPGL a glioblastoma cell-line created by our group. Supernatant from overnight restimulation was analyzed for 10-cytokines.

RESULTS

PD1/Tim3 condition (3ug/ml), Lag3 expression was increased in central memory T-cells (mean 19.13% vs 30.98% p=0.02). On EM T-cells, Lag3 expression increased (57.98% vs 75.83%; p=0.03); for control vs 10ug/ml from combination checkpoint treatment group. On EMRA T-cells, the results were similar, Lag3 was upregulated in response of low-doses of double checkpoint inhibitor combination (8% vs 21% p=0.002). At increased doses (Tim3 at 300ug/ml), secretion of IFN-□ was reduced in T-cells treated with Tim3 vs relevant control. Secretion of IL-12 in treated T-cells with PD1/Tim3 was significantly increased. IL-1□ secretion was significantly lower in the PD1/Tim3 (10ug/ml) treatment-group compared with control-group (p < 0.004).

CONCLUSIONS

We have identified a potential activation component and dependent pathway between Tim3 and Lag3, once Tim3 and PD1 are blockade.
IMMU-30. DISSECTING THE DYNAMIC RESPONSES OF GLIOBLASTOMA TO CAR T CELL THERAPY USING PATIENT-DERIVED TUMOR ORGANOIDS AND SINGLE-CELL MULTI-OMICS ANALYSES
Authors: Zhang Daniel , Salinas Ryan , O’Rourke Donald , Ming Guo-Li , Song Hongjun
Published: December 2020

Immunotherapy, including chimeric antigen receptor (CAR) T cell therapy, has yielded major advancements for a number of hard-to-treat cancers; however, its transformative potential has yet to be realized in glioblastoma (GBM). Clinical studies of EGFRvIII targeted CAR T cell therapy have indicated that tumor heterogeneity, immune microenvironment, and adaptive responses to treatment may play important roles in limiting overall efficacy. We sought to examine comprehensively the dynamic molecular landscape of CAR T cell therapy in GBM using patient-derived GBM organoids (GBOs), a newly established laboratory model of inter- and intra- tumoral heterogeneity. Especially advantageous in these studies, GBOs preserve the intrinsic composition of somatic mutations, transcriptomic states, and non-neoplastic cells that contribute to the tumor microenvironment. Complementing the complexity of this biological system, we constructed an integrated single-cell multi-omics platform to interrogate gene expression, cell surface protein expression, somatic variants, and TCR sequences all from the same cell. Co-culture of GBOs and EGFRvIII targeted CAR T cells led to rapid T cell activation with concomitant upregulation of cytokine response gene programs in both antigen-positive and antigen-negative tumor cells. The adaptive tumor response also included expression of immune checkpoint receptor (ICR) ligands, such as PD-L1. At later time points, T cells transitioned into a dysfunctional or exhausted state, as characterized by increased cell surface expression of inhibitory receptors, such as PD-1, and decreased markers of effector activity despite the presence of antigen. Interestingly, CAR T cell therapy not only led to changes in immune-related pathways and tumor microenvironment, but it also induced shifts in tumor cell states with the depletion of an oligodendrocyte precursor cell-like state and corresponding enrichment in an astrocyte-like state. This finding suggests that EGFRvIII targeted CAR T cell therapy may leverage intrinsic cellular plasticity to induce differentiation-like effects in the surviving tumor cells.
IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA
Authors: Hoang-Minh Lan , Rivera-Rodriguez Angelie , Pohl-Guimarães Fernanda , Currlin Seth , Von Roemeling Christina , Castillo-Caro Paul , Otto Kevin , Rinaldi Carlos , Mitchell Duane
Published: December 2020

SIGNIFICANCE

Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth.

OBJECTIVE

We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels.

METHODS

gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI.

RESULTS

Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels.

CONCLUSIONS

The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.
IMMU-32. NON-METABOLIC IDO ACTIVITY INCREASES COMPLEMENT FACTOR H LEVELS WHICH ENHANCES IMMUNOSUPPRESSION IN HUMAN GLIOBLASTOMA
Authors: Zhai Lijie , Gritsina Galina , Nyugen Brenda , Bell April , Ladomersky Erik , Bollu Lakshmi , Lauing Kristen , Wainwright Derek
Published: December 2020

Indoleamine 2,3 dioxygenase 1 (IDO) is an immunosuppressive factor expressed in ≥90% of patient resected glioblastoma (GBM). Canonically, IDO suppresses the immune response by metabolizing the essential amino acid, tryptophan, into the downstream metabolite, kynurenine. Based on the in vivo finding that the genetic knockout of tumor cell IDO does not change brain tumor tryptophan and kynurenine levels in syngeneic mice, we recently questioned the mechanistic role of IDO in GBM. To determine whether tumor cell tryptophan metabolism is responsible for the pathogenic effects of IDO, we created IDO-deficient murine GBM cells that were reconstituted with either (i) empty expression vector, (ii) a vector expressing wild-type IDO, (iii) or a vector expressing enzyme-inactive IDO. GBM cell IDO expression increased Tregs and decreased survival, but did so independent of tryptophan metabolism. To understand how IDO causes these effects, we performed Clariom D microarray analysis of human GBM cells and discovered that complement factor H (CFH) is significantly increased in GBM cells expressing IDO but decreased by treatment with IDO siRNA. Notably, CFH siRNA decreased CFH- but not IDO-expression in GBM cells. We next found that GBM cell IDO regulates CFH levels independent of tryptophan metabolism. To determine the effects of CFH on tumor outgrowth, we intracranially-engrafted syngeneic mice with IDO-deficient murine GBM cells reconstituted with either empty expression vector or a vector expressing CFH splice variant 2. Tumor CFH significantly decreased survival from GBM bearing mice similar to that of patient-resected GBM with high CFH levels whereby patients present with a faster rate to tumor recurrence. In summary, our study is the first to report an IDO-dependent non-metabolic regulation of CFH in tumor cells and highlights a new immunotherapeutic target in patients with incurable GBM.
IMMU-37. DIRECT REPROGRAMMING OF GLIOBLASTOMA TO ANTIGEN PRESENTING-LIKE CELLS BY MASTER REGULATORS PREDICTED FROM AN ARTIFICIAL INTELLIGENCE PLATFORM
Authors: Jin Dan , Sebastian Mathew , Le Son , Chen Dongjiang , Thomas Nagheme , Deng Changwang , Tran David
Published: December 2020

Glioblastoma (GBM) is the most common and lethal malignant brain cancer in adults. Immunotherapy has emerged as a potentially powerful approach to achieve long-term survival in patients with GBM. Antigen presenting cells (APCs) play a central role in priming cancer-specific immune responses due to their ability to sample and present tumor neoantigens to the immune system. We hypothesis that antigen presenting cells could be induced by transdifferentiated from GBM in-situ so that these locally created APC will find themselves pre-planted in the tumor microenvironment (TME) with full access to tumor neoantigens. Top ten ranked candidate fate determinants for the GBM-DC transdifferentiation were predicted by NETZEN, an integrated deep-learning and gene network-based ranking artificial intelligence (AI) platform for precision medicine. We successfully transdifferentiated the murine GBM cell line GL261 into CD45+ immune cells accompanying morphological changes to less adhering cells by a combination of four factors (PU.1, IRF8, BATF3, ID2). Of these induced CD45 positive cells, a significant fraction also expresses high levels of the myeloid marker CD11b and antigen presenting molecules MHCII and MHCI by flow cytometry, suggesting these induced CD45+ cells are myeloid lineage APCs (iAPC).These iAPC exhibit phagocytic property, tested by incubating pHrodo Red bioparticles conjugated with Zymosan, an antigen found on the surface of fungi. More importantly, these induced iAPC appear to have lost their proliferative capacity characteristic of the parental GBM cells. Total live cell numbers were significantly reduced in 4F-induced culture compared to the EV control. In conclusion, we successfully transdifferentiated mouse GBM cells into APC-like cells based on NETZEN prediction and our work can potentially provide a novel therapeutic approach for developing an in-situ APC vaccine immunotherapy for GBM, and for other cancers.
IMMU-40. IMPROVING OUTCOMES IN OLDER ADULTS WITH GLIOBLASTOMA BY REVERSING AGE-RELATED CHANGES OF THE CENTRAL NERVOUS SYSTEM
Authors: Ladomersky Erik , Zhai Lijie , Bollu Lakshmi , Bell April , Lauing Kristen , Lukas Rimas , Wainwright Derek
Published: December 2020

De novo glioblastoma (GBM) represents ≥ 90% of all GBM diagnoses and has a median age of onset at 65 years old. Because of its preponderance during advanced age, we investigated the mortality rate of older adult C57BL/6 (WT) mice with CT-2A glioma. Strikingly, we discovered a significant decrease of overall survival among animal subjects depleted for both CD4+ and CD8+ T cells as compared to the group treated with IgG control antibodies. This negative effect of lymphopenia only applied to older adults. We next questioned which of the major T cell subsets contribute to this effect and determined that the depletion of CD4+ T cells significantly decreased overall survival as compared to IgG control or CD8+ T cell-depleting antibodies (n=12/group; p< 0.01). We previously found increased immunosuppressive IDO levels in the mouse and human brain during advanced age. Although 78–86 week old WT mice have no survival benefit after triple combination immunotherapy, age-matched IDOKO mice have an impressive increase in median and overall survival – despite both groups being treated with a pharmacologic IDO enzyme inhibitor. Since IDO is potently-induced by proinflammatory cytokines, we hypothesized that a potential mechanism for the increased IDO during advanced age is associated with an accumulation of senescent cells in the brain with a proinflammatory secretory phenotype. To investigate this, 80 week old mice with intracranial GL261 were treated with (i) vehicle with IgG antibodies, (ii) the senolytic drugs dasatanib and quercetin, (iii) whole brain radiation, anti-PD-1 mAb, and IDO enzyme inhibitor, or (iv) the 5 agent combination. Only animal subjects treated with the 5 agent cocktail showed a significant increase in long-term survival in a subset of mice (n=12–15/group; p< 0.01). These results suggest that optimization of senescent cell eradication treatment may be particularly beneficial to older patients with GBM treated with immunotherapy.
IMMU-43. ZIKA VIRUS TO TREAT GLIOMA: TURNING COLD TUMORS HOT
Authors: Mazzoccoli Luciano , Nair Sharmila , Jash Arijita , Govero Jennifer , Hu Tong , Shresta Sujan , Shi Pei-Yong , Rich Jeremy , Diamond Michael , Chheda Milan
Published: December 2020

GBM is a hallmark example of an immunotherapy-resistant tumor. Previously, we discovered that Zika virus (ZIKV) has a natural honing capacity to specifically kill GBM stem cells (GSCs). Using two syngeneic glioma models, GL261 and CT2A, we found that in vivo intratumoral ZIKV treatment reduces tumor size and extends median survival far beyond that expected for its anti-GSC effects; additionally, approximately 50% of mice were long-term survivors. We now report that ZIKV treatment is associated with an increase in tumor-specific CD8+ T cells and activated myeloid cells expressing MHC-II and NOS2. Treatment with CD8-depleting antibody abrogates the survival advantage conferred by ZIKV, demonstrating that CD8+ T cells are required for ZIKV efficacy. Remarkably, ZIKV treatment also confers protection against tumor re-challenge 1.5 years after the original treatment, and this too is dependent on CD8+ T cells. Lastly, in a bilateral tumor implantation model, intratumoral ZIKV treatment of one tumor increases overall survival, suggesting ZIKV is efficacious because it generates a global anti-tumor response. Building on the observation that ZIKV treatment increases CD8+ T cells in the tumor bed, we combined ZIKV with α-PD1 immunotherapy. We found survival was dramatically increased compared to either treatment alone. Finally, to improve safety of potential ZIKV treatment for patients, we generated an immune-sensitized virus. This strain remains efficacious as a single agent and in combination with immunotherapy in vivo. Overall, our results suggest ZIKV treatment addresses two key problems in our current treatment of GBM: it specifically targets highly resistant GSC and initiates a potent anti-tumor immune response against the remaining tumor. Our work reveals the mechanistic basis of ZIKV efficacy and demonstrates the potential for ZIKV as a therapy for GBM.
IMMU-52. IMMUNE EFFECTOR CELL ASSOCIATED NEUROTOXICITY (ICANS) AMONG PEDIATRIC AND AYA PATIENTS: MD ANDERSON CANCER CENTER EXPERIENCE
Authors: Brown Brandon , Mahadeo Kris , Khazal Sajad , Petropoulos Demetrios , Tewari Priti , Slopis John , Tambaro Paolo , Sadighi Zsila
Published: December 2020

INTRODUCTION

Immune effector cell associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) are potentially life-threatening complications associated with immune effector cell (IEC) therapies. We characterize ICANS in pediatric and adult young adolescent (AYA) patients receiving IEC therapy at our institution.

METHODS

We reviewed clinical characteristics and severity (based on ASTCT Consensus Criteria) in pediatric and AYA patients who received IEC products from 2018–2019 at MDACC.

RESULTS

Nine patients, median age 15.5 (range: 3–25) years received chimeric antigen receptor (CART) IEC therapy. Four (44%) developed ICANS within median of 8 (range: 3–27) days of CAR T cell infusion and median 6 (range: 2–7) days after CRS. Primary diagnoses were pre-B cell acute lymphoblastic leukemia (8) and mediastinal large B-cell lymphoma (1). Median CRS and ICANS severity grade was 2 (range 1–4). Symptoms included altered mental status (AMS) (5), seizure (1), aphasia (2), impaired ability to write a standard sentence (4). Neuroimaging did not correlate to ICANS symptoms or severity. EEG was performed in 3 and 1 had background slowing correlating with aphasia. CSF was obtained in two revealing lymphocytosis. All received prophylactic anti-epileptic medication and tocilizumab for concomitant CRS. Three received steroids.

CONCLUSION

ICANS may present in almost half of pediatric patients within one week of receiving CART products associated with CRS. CAR-T trafficking into the CSF may explain pleocytosis in the CSF. Prospective studies may clarify. Impaired ability to write a standard sentence and the Cornell Assessment of Pediatric Delirium (CAPD) may be early indicators of ICANS in pediatric/AYA patients.
INNV-06. SECOND GENERATION BRAF/MEK INHIBITION IN ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA
Authors: Stocksdale Brian , Liao Yaping Joyce , Coffey Gwen , Nagpal Seema
Published: December 2020

BACKGROUND

Up to 65% of anaplastic pleomorphic xanthoastrocytomas (A-PXA) harbor the BRAFV600E oncogene. Trials and case series have demonstrated that BRAF-mutant gliomas, including A-PXAs, can be responsive to the first generation BRAF inhibitors dabrafenib and vemurafenib, with an ORR ranging from 26–43%. The second generation BRAF/MEK inhibitor combination encorafenib/binimetinib improves systemic outcome in melanoma patients, has better tolerability, and may have better intracranial activity compared to first generation drugs.

METHOD

We review the three patients with BRAFV600E A-PXA treated with encorafenib/binimetinib in our practice.

RESULTS

Two patients were diagnosed with A-PXA in 2014 and one in 2013. The presence of BRAFV600E was confirmed by molecular testing. All patients have received prior surgery, chemotherapy, and radiation and were at a recurrence when BRAF/MEK inhibition was initiated. One patient had CR after 2 months on treatment and remains in CR at 1-year. One patient, who is also receiving bevacizumab, has a PR, with continued clinical and imaging improvement at 6 months. Our third patient had a PR at 2 months and remains on therapy, currently 3 months post-initiation. All 3 patients report improvement in symptoms. The patient who has been on treatment for 1 year experienced rapid onset bilateral multifocal sub-retinal fluid collections followed by rapid resolution, without intervention, within days of starting treatment. This patient has also had mild decrease in EF over time. We will present continued follow up.

CONCLUSIONS

Encorafenib/binimetinib appears feasible, with 3 of out 3 patients with BRAFV600E A-PXA demonstrating radiographic response; 2 of these patients have durable responses. We stress the importance of a clear lab, cardiac, ophthalmologic, and dermatologic monitoring regimen as side effects can be rapid and severe. Prospective studies with encorafenib/binimetinib in BRAF-mutant primary CNS tumors are underway, and we eagerly anticipate their RESULTS:
INNV-07. THE ROLE OF BIOPSY IN MOLECULAR DIAGNOSIS OF DIFFUSE INTRINSIC PONTINE GLIOMA PATIENTS
Authors: Epelbaum Julia , Krystal Julie , Atlas Mark , Schneider Steven , Mittler Mark , Rodgers Shaun
Published: December 2020

INTRODUCTION

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and fatal pediatric brain tumor. Due to its difficult anatomic location and infiltrative nature, DIPGs are not surgically resectable and more than 90% of children die within two years of diagnosis. Historically, standard of care has consisted of clinical and radiological diagnosis followed by palliative radiation for symptomatic relief. Although tumor biopsy is not necessary for diagnosis, there is debate as to whether the procedure provides benefits that outweighs its risk. Recent studies have proposed that biopsy-driven molecular characterization of these tumors can inform prognosis and identify potential treatment targets that could lead to clinical breakthroughs.

METHODS

This study was a retrospective chart review of 26 patients treated for a DIPG diagnosis between July 1998 and July 2019 at Cohen Children’s Medical Center. We compared outcomes of biopsied vs. non-biopsied DIPG patients through quantitative data analyzing the number and types of treatment given. We analyzed post-surgical data regarding safety of DIPG biopsies which were performed by optical stereotactic needle biopsy or robot-assisted stereotactic biopsy procedures.

RESULTS

There were no permanent biopsy complications in any patient and biopsy did not delay treatment as average hospital stay was 1.5 days. All biopsies collected sufficient material for next generation sequencing analysis and revealed targetable mutations for available clinical trial therapies. 67% of patients were subsequently enrolled in clinical trials, 75% of which required biopsy results for enrollment. MGMT promoter methylation assay results in all tested DIPG biopsy cases indicated resistance to temozolomide, the most common treatment agent given to non-biopsied patients.

CONCLUSION

Biopsy of DIPG tumors is a safe and accurate procedure that does not delay treatment and identifies molecular targets for individualized therapy. The role of biopsy in DIPG patients allows for molecular characterization of DIPG tumors which informs and increases treatment options.
INNV-08. COMPARATIVE STUDY OF THE CANCER TREATMENT POTENTIAL EFFECT OF TUMOR-TREATING FIELDS AND COLD ATMOSPHERIC PLASMA
Authors: Yao Xiaoliang , Goldstein Isaac , Lin Li , Sherman Jonathan , Keidar Michael
Published: December 2020

INTRODUCTION

Cold Atmospheric Plasma (CAP) is ionized gas close to room temperature that generates reactive oxygen and nitrogen species, an electromagnetic field (EMF) and UV, which are selectively cytotoxic to cancer cells. Tumor Treating Fields (TTFields) is an FDA approved cancer treatment that utilizes “low intensity” and “intermediate frequency” alternating electric fields to produce an inhibitory effect on cancerous cells.

OBJECTIVES

In this study, we directly compared CAP and TTFields treatments using U87 glioblastoma tumor cells. We aimed to assess the relative merits of both technologies as potential approaches for brain cancer treatment.

METHODS

In this in vitro study, the cells were treated with either CAP or TTFields at room temperature. In both cases in order the optimize the treatment parameters, the energy we applied was varied for both methods by changing the power and time of the treatment. The resulting cell viability changes were measured 72 hours after treatment.

RESULTS

The results revealed that increased energy resulted in decreased cell viability of U87 glioblastoma tumor cells with both CAP and TTFields treatment. The rate of U87 glioblastoma tumor cell viability under CAP treatment was 80% of the original viability after using 4.8J of energy, compared with 15,752J of energy with TTFields treatment. Additionally, the CAP displayed significantly greater time-efficiency as compared to TTFields. For instance, the most effective TTFields treatment took 4 hours, while the CAP treatment displayed a comparable effect on tumor cell viability with a treatment time of 30 seconds.

CONCLUSIONS

This preliminary in vitro study indicates that CAP treatment is potentially a more favorable effective method of brain cancer therapy. This data indicates that CAP is significantly more energy-efficient and requires significantly less treatment time than TTFields. Future research looks to compare the 2 treatments in an intracranial mouse xenograft model.
INNV-10. EFFECTS OF TTFIELDS USAGE AND DURATION OF USAGE ON CELLULARITY AND Ki67 DISTRIBUTIONS AT AUTOPSY
Authors: Bobholz Samuel , Lowman Allison , Connelly Jennifer , Cochran Elizabeth , Mueller Wade , McGarry Sean , Brehler Michael , LaViolette Peter
Published: December 2020

This study used autopsy tissue samples taken from patients with glioblastoma who had undergone Tumor-Treating Fields (TTFields) therapy to examine the effects of treatment usage and duration on cellular and mitotic activity distributions. We hypothesized that treatment duration and percent compliance would be associated with a change in cellularity. Three tissue samples were collected from 10 patients with glioblastoma at autopsy. These samples were specifically collected in regions that demonstrated clear contrast enhancement on the patients’ last clinical imaging, in order to capture regions of suspected active tumor. Samples were stained with both hematoxylin and eosin (HE) and Ki67 immuno-histochemistry (IHC) and digitized at 40X resolution using a digital microscope. A color deconvolution algorithm was used to separate stains, which allowed nuclei segmentation. Number of cells and percent of Ki67 positive cells were computed across 100x100 superpixels. Spearman’s correlations were used to examine the association between TTFields usage (measured as a percent) and duration of use (in days) and signatures of active tumor proliferation, measured as median cellularity and proportion of Ki67 positive cells across each patients’ three samples. Trending negative associations with median cellularity were observed for both TTFields usage (R=-0.60, p=0.065) and duration (R=-0.61,p=0.063). The magnitude of the treatment duration effect increased when controlling for time between diagnosis and death, despite a p-value drop due to the lost statistical degree of freedom (R=-0.62, p=0.073). No significant effects were observed for Ki67 positive staining. These results generally suggest a possible effect of TTFields therapy duration, where longer treatments and increased compliance lead to lower tumor proliferation. However, these results should be interpreted with caution, as larger, more statistically powerful studies will be better suited to assess the generalizability of the preliminary trends seen in these RESULTS:
INNV-12. A SINGLE-INSTITUTION RETROSPECTIVE REVIEW OF PATIENTS WITH CNS TUMORS WHO INITIATED A KETOGENIC DIET
Authors: Amaral Lauren , Welborn Amelia , Lockshon Laura , Gresham Gillian , Panhans Cristina , Rudnick Jeremy , Irwin Scott , Freedland Stephen , Hu Jethro
Published: December 2020

BACKGROUND

Many patients with CNS tumors express interest in initiating a ketogenic diet (KD). Following a discussion with the physician regarding the limited clinical evidence of KD for CNS tumors, interested patients were referred for evaluation by an oncology-certified dietitian.

METHODS

We performed a single institution retrospective chart review of patients with CNS tumors on a KD. Demographics, clinical characteristics, and diet information were extracted from patient charts. Descriptive statistics were conducted to summarize patterns of adherence to KD across patient characteristics.

RESULTS

From May 2016 to May 2018, 40 patients expressed interest in KD; 24 initiated it. M:F = 18:6, median age 46 (range 27–62). Diagnoses: 18 glioblastoma, 1 anaplastic astrocytoma, 2 grade 2 astrocytoma, 1 grade 2 oligodendroglioma, 1 spinal grade 2 astrocytoma, 1 chordoma. 18 tumors with methylated MGMT, 8 with mutant IDH1. At diet initiation, median KPS 80 (range 70–100); median BMI 25.6 (20.8–39). Median days on diet = 190 days; interquartile range 126–673 days; range 24–1479 days. Diet composition: 15 patients on 3:1 diet (grams fat: grams protein + carbs), 7 patients on 2:1, 2 patients on 1:1. 14 patients monitored blood ketone levels. 11 patients stopped KD: 5 for restrictiveness of diet (median 158 days, range 60–239); 1 for decreased KPS (673 days); 1 for excessive weight loss (108 days); 2 for disease progression (24 and 217 days); 2 lost to follow-up (109 and 125 days). In this small sample, no statistically significant associations between time on diet and age / gender / BMI / KPS / diet composition. However, trend toward longer adherence to diet in females, age < 50, 2:1 diet.

CONCLUSION

It is feasible for patients with CNS tumors to adopt KD. Results from prospective studies are needed to assess effects on QOL, neurocognition, performance status, and survival.
INNV-14. UTILIZATION OF A PATIENT FAMILY ADVISORY COUNCIL TO ADVANCE PATIENT-CENTERED CARE OF BRAIN TUMOR PATIENTS
Authors: Pawloski Jacob , Scarpace Lisa , Gay Nestelynn , Fadel Hassan , Hunt Rachel , Haider Sameah , Robin Adam , Snyder James , Walbert Tobias , Kalkanis Steven , Lee Ian
Published: December 2020

INTRODUCTION

Developing and advancing patient-centered care within neuro-oncology is an essential element of any tertiary brain tumor center. Patient-centered care of neuro-oncology patients requires a holistic approach that integrates oncologic treatment with social and psychological support.

OBJECTIVE

The aim of this study is to evaluate how a Patient Family Advisory Council can be created within an existing brain tumor center and utilized to improve patient-centered care.

METHODS

Current patients and caregivers were recruited by brain tumor staff to participate in monthly meetings. All participants underwent screening and training by our Patient Education Research Center team. Discussions focused on current and future brain tumor center initiatives, and participants were encouraged to give feedback from the patient perspective. New ideas to improve the patient experience were solicited.

RESULTS

A total of 15 participants (female = 57%) were recruited, including 10 with grade 3 or higher brain tumors. Monthly meetings, in-person or virtual, were held for two years. Utilizing participant feedback, the group updated our 80-page patient handbook that contained a variety of patient-caregiver focused resources. Participants also provided feedback on other brain tumor center initiatives such as development of a magnet featuring key phone numbers, an easily accessible website URL for emergencies, and numerous updates to the external website. Additional discussions involved development of neuro-oncology care pathways as we move to a stand-alone cancer center facility and initiation of OncoSTAT and palliative services in this population.

CONCLUSION

Brain tumor patients require a comprehensive oncologic treatment team as well as a wide variety of support services. A Patient Family Advisory Council is an effective method of advancing patient-centered care and a step toward improving the neuro-oncology patient experience.
INNV-16. CLINICAL APPLICABILITY OF INDIVIDUALIZED DRUG RESPONSE PROFILING UTILIZING EX-VIVO TISSUE-DERIVED 3D CELL CULTURE ASSAYS IN HIGH-GRADE GLIOMA: A SINGLE INSTITUTION CASE SERIES USING 3D-PREDICT RESULTS
Authors: Lipinski Lindsay , Abad Ajay , Mechtler Laszlo , Fabiano Andrew , Smith Ashley , DesRochers Teresa , Gevaert Matthew , Vibat Cecile Rose , Fenstermaker Robert
Published: December 2020

Recurrent high-grade glioma is a challenging disease process, without consensus on effective second-line therapy options. Individualized, patient-specific, biologically-based data is desirable in driving therapeutic decision-making. Patients with recurrent high-grade glioma and planned surgical re-resection at our institution were prospectively enrolled into the 3D-PREDICT study. Tissue was collected at the time of surgery for ex vivo 3D cell culture assays comprising a panel of agents commonly used for high-grade glioma, including chemotherapies and targeted therapies used in other solid cancers. In all cases, therapeutic agent selection was guided by the neuro-oncologist’s clinical judgement, factoring the patient’s age, performance status, comorbidities, toxicities/side effect profile of potential agents, and drug accessibility, plus ex-vivo drug response RESULTS: We present 3 cases in which the selection of agents was influenced by the tissue-derived 3D cell culture results; treatment led to clinical response observed in terms of progression free survival, quality of life, and pharmacologic tolerability. In Case 1, a patient with recurrent anaplastic astrocytoma was treated with a BRAF inhibitor for 12 months with excellent tolerability and no radiographic progression. Case 2 demonstrates the use of combination bevacizumab and irinotecan after disease progression subsequent to standard treatment. This patient had local radiographic control for 7 months, tolerating the regimen well. In Case 3, an individual with recurrent glioblastoma was treated with combination carboplatin and etoposide based on assay response prediction to both agents; treatment has been tolerated well with radiographic stability at 6 months while maintaining good performance status. This case series represents our institutional experience of utilizing patient-specific, ex-vivo tissue-derived cell drug response profiling to guide choice of therapy for recurrent high-grade glioma patients. Using individualized, tumor-specific drug sensitivity data to guide these decisions is representative of the ongoing paradigm shift into the realm of individualized medicine to improve outcomes in cancer patients.
INNV-18. RECURRENT SHH MEDULLOBLASTOMA EXTRANEURAL METASTASES TO THE BONE MARROW WITHOUT CNS INVOLVEMENT
Authors: Clifton Brad , Anderson Mark
Published: December 2020

Medulloblastoma is the most common primary brain tumor in children, but is rare in adults. Because of the scarcity of adult medulloblastoma cases, treatment guidelines in the adult population are not well established, especially regarding surveillance and treatment of recurrent disease. A 47-year-old African American male presented with one month of progressive unsteady gait and dizziness. Imaging revealed a posterior fossa mass and the patient underwent gross total resection. Histology confirmed medulloblastoma and molecular subtyping revealed Sonic Hedgehog (Shh) pathway activation. No metastases were found at the time of diagnosis, and the patient received adjuvant craniospinal radiation therapy. Three years later the patient developed low back pain with severe sciatica affecting his gait and pancytopenia. Imaging revealed diffuse osseous disease without CNS recurrence and bone marrow biopsy confirmed recurrent medulloblastoma. The patient subsequently began reduced chemotherapy consisting of cisplatin and etoposide because of his severe pancytopenia. Due to a lack of response after 4 cycles, the SMO antagonist vismodegib was added. Follow-up imaging revealed improvement/stability of osseous disease, lab work demonstrated resolution of pancytopenia, and repeat bone marrow was without malignancy. Vismodegib was continued as maintenance therapy. Six months after completion of cisplatin/etoposide, follow-up imaging revealed progression of metastatic disease. Shh activated medulloblastomas have demonstrated responses to SMO inhibition. However, these responses are often transient secondary to rapid development of resistance, but may have a role to play in patients who have bone marrow involvement that limits use of cytotoxic therapy or bone marrow transplant. Due to poor survival outcomes associated with bone marrow metastases, aggressive screening for bone marrow metastases at diagnosis and in surveillance should be considered.
INNV-23. LIFESTYLE COACHING IS FEASIBLE AND IMPROVES PILOT OUTCOMES IN FATIGUED BRAIN TUMOUR PATIENTS: THE BT-LIFE (BRAIN TUMOURS, LIFESTYLE INTERVENTIONS, AND FATIGUE EVALUATION) MULTI-CENTRE, PHASE II RCT
Authors: G Rooney Alasdair , Hewins William , Walker Amie , Withington Lisa , Mackinnon Mairi , Robson Sara , Green Aimee , Anderson Garry , Bulbeck Helen , Cochrane Carol , Gillespie David , Hewitt Christopher , Day Julia , Torrens Claire , Emerson Julie , Dunlop Jo , Welsh Michelle , Hopcroft Lisa , Wells Mary , McBain Catherine , Chalmers Anthony , Grant Robin
Published: December 2020

BACKGROUND

Fatigue is common and disabling for brain tumour patients. We studied the feasibility of two innovative lifestyle coaching interventions for high fatigue.

METHODS

Multi-centre phase II feasibility RCT (ISRCTN17883425). Adult primary brain tumour outpatients reporting significant fatigue (Brief Fatigue Inventory [BFI] score 4+), were randomised to one of three arms: Control; Health Coaching (“HC”, comprising eight structured coaching sessions on lifestyle behaviours); or HC plus Activation Coaching (“HC+AC”, adding two structured interviews targeting motivation to change). Outcomes were measured at baseline (T0), after interventions (T1), and at 16 weeks (T2). The primary outcome of feasibility was required for both recruitment (aim: average n= 5 fatigued patients recruited/month) and retention (aim: minimum 60% retention at T2). Secondary pilot outcomes included change in fatigue, depressive symptom, and QOL measures.

RESULTS

Over a nine-month recruitment period, n= 46 fatigued brain tumour patients were recruited (average n=5.1/month) and n= 34 were retained to endpoint (retention at T2= 73%), meeting the primary outcome of feasibility. Surprisingly, fatigue reduced significantly after HC (T1 mean change in BFI score from T0 baseline, relative to the equivalent change in control group: HC= -2.3 points [95%CI -3.4/-0.3]; HC+AC= -2.0 [-2.9/+0.1]; ANOVA p= 0.02) and was reduced in magnitude in both intervention groups at T2 (p= N.S). Both interventions also improved depressive symptoms (T1 mean change in HADS-Depression: HC= -2.0 points [-5.6/-0.1]; HC+AC= -2.9 [-6.5/-1.0]; Kruskal-Wallis p= 0.02). Patient-nominated QOL outcomes improved persistently after HC+AC (T2 mean change in PSYCHLOPS score: HC= -2.4 points [-5.4/+2.8]; HC+AC= -6.1 [-9.2/-0.8]; ANOVA p= 0.01).

CONCLUSION

Innovative coaching interventions, focused on lifestyle factors, are feasible to deliver to fatigued brain tumour patients. Preliminary signals suggest that these non-drug approaches may benefit several mediators of quality of life and warrant further study.
INNV-24. THE EXPERIENCE OF FATIGUED BRAIN TUMOUR PATIENTS RECEIVING INNOVATIVE LIFESTYLE INTERVENTIONS: QUALITATIVE RESULTS FROM THE BT-LIFE RANDOMISED CONTROLLED TRIAL
Authors: Torrens Claire , Emerson Julie , Hewins William , Walker Amie , Withington Lisa , Mackinnon Mairi , Robson Sara , Dunlop Jo , Welsh Michelle , McBain Catherine , Chalmers Anthony , Grant Robin , Rooney Alasdair G , Wells Mary
Published: December 2020

BACKGROUND

Most brain tumour patients report clinically significant fatigue. Here, we aimed to explore patients’ views of the experience, acceptability and usefulness of participating in a trial of novel lifestyle interventions for fatigue.

METHODS

Qualitative sub-study within the ‘BT-LIFE’ multi-centre phase II RCT (submitted separately). Fatigued adult primary brain tumour patients in receipt of one of the trial interventions (‘Health Coaching’: eight coaching sessions targeting lifestyle behaviours; plus or minus ‘Activation Coaching’: two additional interviews targeting motivation to change) took part in a semi-structured interview following completion of the interventions. A realist approach to the ‘framework’ method was used to analyse verbatim transcripts, with inductive and deductive codes assigned to the realist domains of Context-Mechanism-Outcome.

RESULTS

Twenty themes and 53 sub-themes were derived from the data. Patients’ (n= 21) understanding of and engagement with the interventions were influenced by their expectations, attitudes to life, and experience of living with a brain tumour. Behaviour change was supported by goal-setting, monitoring using a weekly diary, the motivational ‘push’ by coaches, and family/ social support where available. Barriers to engagement included technical diary difficulties, time limitations including work and holiday schedules, and interference from life events. Most patients described beneficial changes in health behaviours, self-efficacy, and general health and wellbeing. About half indicated actual improvement in fatigue levels; others reported no direct change but they could now cope better with fatigue. A minority experienced no change or worsening fatigue.

CONCLUSION

Most fatigued brain tumour patients were able to make positive changes after lifestyle coaching, despite physical and cognitive impairments. However, their experiences were varied. Those for whom the interventions were a good ‘fit’ with their pre-existing outlook, lifestyle, and physical and emotional capabilities, appeared to achieve most benefit. These qualitative findings will inform further work addressing the disabling symptom of brain tumour-related fatigue.
NCMP-03. INTRATHECAL TRASTUZUMAB TREATMENT OF HER-2 POSITIVE LEPTOMENINGEAL BREAST CANCER: THE UNIVERSITY OF MICHIGAN EXPERIENCE
Authors: Peters Kelsey , Robell Lindsay , Morikawa Aki , Umemura Yoshie , Sun Yilun , Leung Denise , Mammoser Aaron , Gill Anoop , Junck Larry
Published: December 2020

PURPOSE

Breast cancer is the most common solid tumor to metastasize to the leptomeninges, affecting up to 5% of breast cancer patients. Overall survival for patients with leptomeningeal metastases (LM) is poor, with median survival of 4–6 months following diagnosis. There is limited data available on the efficacy of intrathecal (IT) trastuzumab in the treatment of Her-2 positive LM.

METHODS

A total of 30 patients with Her-2 positive breast cancer with LM treated at the University of Michigan from 2008–2020 were identified retrospectively. Of these, 13 patients were treated with IT trastuzumab beginning in June 2010 and followed through April 2020. Initial dose was 50–80 mg twice weekly for a minimum of 4 weeks, followed by slow taper. The 17 patients with Her-2 positive breast cancer with LM who did not receive IT trastuzumab served as control.

RESULTS

The median age of patients in the treatment group was 42 and 52 in the control group. Whole brain radiation therapy was received by 92% of patients in the treatment group and 76% in the control group. The median overall survival from diagnosis of LM to death was 20 months (interquartile range [IQR] 13–60 months) in the treatment group and 6 months (IQR 2–17 months) in the control group. Survival at 3 years and 5 years was 40% and 13%, respectively for the treatment group and 8% and 0% (no data available at 60 months), for the control group. Hazard ratio for death with IT trastuzumab 0.38 (95% CI 0.16–0.91, p=0.024). IT trastuzumab was overall well-tolerated (one patient developed meningitis, while another had shunt malfunction necessitating removal of the reservoir).

CONCLUSIONS

Patients with HER2+ LM who received IT trastuzumab demonstrated significantly improved OS compared to control with minimal toxicity.
NCMP-04. INCIDENCE AND OUTCOMES OF BRAIN METASTASES IN PATIENTS WITH EXTRA-PULMONARY NEUROENDOCRINE NEOPLASMS
Authors: Abedin Kapacee Zainul , Dawod Mohammed , Allison Jennifer , Frizziero Dr Melissa , Chakrabarty Bipasha , Manoharan Prakash , McBain Catherine , Mansoor Was , Lamarca Angela , Hubner Richard , Valle Juan , McNamara Mairead
Published: December 2020

BACKGROUND

Brain metastases (BMs) incidence in patients with extra-pulmonary neuroendocrine neoplasms (EP-NENs) is unclear, with no available management recommendations. This study aimed to review the clinical presentation, management and survival outcomes of patients with EP-NENs and BMs at a European Centre of Excellence.

METHODS

A retrospective single-centre analysis of consecutive patients with EP-NENs (Aug 2004-Feb 2020) was conducted. Median overall survival (OS)/survival from BMs diagnosis were estimated (Kaplan Meier).

RESULTS

Of 786 patients, 15 (1.9%) had BMs, median age 61y (range 15–77); 8 (53%) male, primary NEN site: unknown 40%; oesophageal 13%; small bowel 13%; pancreas 13%; gastric 7%; cervix 7% and bladder 7%. Most patients with BMs had grade 3 (G3) NENs (11, 73%), 3 (20%) were G2 and 1 (7%)G1. Eight (53%) had poorly-differentiated NENs, 6 well-differentiated and 1 not recorded. Two (13%) patients had synchronous BMs at diagnosis, whilst 13 (87%) developed BMs metachronously. Median time to development of BMs after initial NEN diagnosis: 15.9 months (range 2.5–139.5). Five patients had a solitary BM, 4 had 2–9 lesions and 6 had >10 BMs. The most commonly affected sites were the cerebrum (13, 87%), cerebellum (6, 40%), leptomeninges (2, 13%) and orbit (1, 7%). The most common presenting symptoms were limb weakness, headache, confusion, visual disturbance (each n=3, 20%), seizures (2, 13%), word-finding difficulty (2, 13%) and facial weakness/ptosis (1, 7%). Median OS from initial NEN diagnosis was 23.6-months [95%-CI 15.2–31.3]; median time to death from BMs diagnosis was 3.0-months [95%-CI 0.0–8.3]. Treatment of BMs was surgery (n=3); radiotherapy (n=6); 5 had WBRT, one localised radiotherapy (orbit). Six (40%) had best supportive care.

CONCLUSION

BMs in patients with EP-NENs are rare and predominantly in G3 NENs, with diverse intracranial distribution. Although uncommon, BMs from NENs behave aggressively and greater understanding is needed to improve therapeutic outcomes.
NCMP-05. DECODING THE IMMUNE SYSTEM RESPONSE TO LEPTOMENINGEAL METASTASIS
Authors: Remsik Jan , Tong Xinran , Sener Ugur , Isakov Danille , Chi Yudan , Iacobuzio-Donahue Christine , Pe’er Dana , Schietinger Andrea , Boire Adrienne
Published: December 2020

For decades, the central nervous system was considered to be an immune privileged organ with limited access to systemic immunity. However, the leptomeninges, the cerebrospinal fluid (CSF)-filled anatomical structure that protects the brain and spinal cord, represent a relatively immune-rich environment. Despite the presence of immune cells, complications in the CSF, such as infectious meningitis and a neurological development of cancer known as leptomeningeal metastasis, are difficult to treat and are frequently fatal. We show that immune cells entering the CSF are held in an ‘idle’ state that limits their cytotoxic arsenal and antigen presentation machinery. To understand this underappreciated neuroanatomic niche, we used unique mouse models and rare patient samples to characterize its cellular composition and critical signaling events in health and disease at a single-cell resolution. Revealing the mediators of CSF immune response will allow us to re-evaluate current therapeutic protocols and employ rational combinations with immunotherapies, therefore turning the patient’s own immune system into an active weapon against pathogens and cancer.