bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-27. GLIOBLASTOMA CELL STATE PLASTICITY AND THERAPEUTIC RESISTANCE IS MEDIATED BY BRD2
Authors: Vadla Raghavendra , Taylor Brett , Miki Shunichiro , Miyake Yohei , Kawauchi Daisuke , Furnari Frank
Published: November 2024

GBM is a highly aggressive primary brain tumor in adults, notable for its heterogeneity, high recurrence rates, and increased resistance to therapy. Multi-omics analyses have consistently identified three distinct transcriptionally defined cell states – proneural (PN), classical (CL), and mesenchymal (MES) – in IDH-wildtype GBM, with high plasticity among these states in response to diverse stimuli. Transition of GBM cells to a MES cell state is particularly associated with high invasiveness, resistance to therapy, and recurrence. However, the underlying mechanisms driving the MES transition remain poorly understood. In this study we identified the PTEN/NF-kB/BRD2 pathway as key driver of the MES transition, with BRD2 acting as a crucial epigenetic modulator for cell state transitions in GBM. We demonstrate that PTEN plays a critical role in regulating the chromatin binding of BRD2, BRD4 and p65/RelA. Additionally, acetylation of RelA at lysine 310 is required for BRD2 localization to the promoters of MES genes, which is essential for their expression. Loss of BRD2 leads to transition of GBM cells from MES to PN cell state and displayed enhanced sensitivity to ionizing radiation (IR). Further, bromo domains (BDs) of BRD2 are important for MES transition, as mutations in these domains resulted in transitioning of GBM cells from MES to other cell states. Furthermore, we show that BD2-specific BET inhibitors displace BRD2 from MES gene promoters, abrogate MES transition, and enhance GBM sensitivity to IR. Using a brain-penetrant BD2 inhibitor, we effectively reduced GBM cell invasion and tumor-associated microglia/macrophage (TAM) abundance in orthotopic xenograft models. These findings establish BRD2 as a key regulator of MES transition and therapeutic resistance in GBM models, paving the way for the use of bromodomain-specific BET inhibitors in targeting MES GBM.
RADT-05. VASCULAR OVERLAP PROVIDES PROTECTION FROM GAMMA-KNIFE-INDUCED RADIATION NECROSIS IN A METASTATIC BRAIN TUMOR COHORT
Authors: Berke Chandler , Knott Maxon , Spatz Jordan , Silva Michael , Khalafallah Adham , Valderrama Alessandro , Diwanji Tejan , Komotar Ricardo , Ivan Michael , Rich Benjamin , Benjamin Carolina
Published: November 2024

INTRODUCTION

Radiation necrosis (RN) is a long-term complication of Gamma-Knife (GK) Radiosurgery, an established treatment for metastatic brain tumors. Few dosimetric parameters have shown to predict RN, including tumor target volume, treatment dose, and V12 Gy (volume of normal brain receiving 12 Gy). Vascularity has yet to be explored as an independent predictor of RN.

OBJECTIVE

To evaluate the role of vascular overlap in GK-induced RN.

METHODS

All metastatic brain tumor patients treated with GK between 2014-2019 were retrospectively screened for post-treatment radiographic RN. Vascular overlap, defined by the MCA-ACA and MCA-PCA border regions, was determined by two blinded neurosurgeons and one radiation oncologist. Multivariate logistic regression analysis was performed to determine factors predictive of RN using variables determined significant by univariate analysis and clinical relevance. Covariates included V12 as a binary variable (≥8 vs. <8 cm3), vascular overlap, supratentorial location, and eloquent location.

RESULTS

6% (20/321) of all metastatic brain tumor patients developed RN and were included for analysis, with the final cohort being 60% (12/20) female with a mean age of 59 years, comprising 77 lesions. V12 (≥8 cm3) showed a significant increase in risk of developing RN [OR = 8.18; (coef, 95% CI: 2.10 (0.49, 3.72), p=0.011)]. Conversely, vascular overlap showed a protective effect against RN [OR = 0.23 (-1.49 (-2.79, -0.19), p=0.024)], with a lower rate of RN in areas of vascular overlap (10%) than non-vascular overlap (26%). Neither supratentorial location [OR = 3.31 (1.20 (-0.76, 3.16), p=0.231)] nor location within eloquent brain [OR = 0.96 (-0.04 (-1.48, 1.39), p=0.95)] showed significance.

CONCLUSION

For the first time, we show that patients with metastatic brain lesions in anatomical regions of vascular overlap treated with GK are less likely to develop RN. Future work should validate these findings with the goal of optimizing radiation dosing to mitigate RN incidence and recurrence rates.
RADT-06. IDENTIFICATION OF NEW RADIATION RESPONSE PREDICTOR GENES FOR GLIOBLASTOMACRUCIAL CONTRIBUTION OF THE LUNATIC FRINGE GENE (LFNG)
Authors: Naim Asmaa , baddou abdallah
Published: November 2024

Glioblastoma (GBM) is adults’ most common aggressive primary intracranial tumor. The current standard of care involves maximal safe surgery followed by radiochemotherapy.

OBJECTIVE

our study was to identify genes that predict response to radiochemotherapy.

MATERIALS AND METHODS

We collected molecular and clinical data, including primary glioma mRNA expression, from two international online databases - TCGA and CCGA. A total of 76 cases were examined, with 41 patients in the TCGA cohort and 35 in the CCGA cohort. The patients were divided into two groups before assessing the data. Group 1 included patients who were alive at the time of the analysis, and Group 2 included patients who had passed away. Then, we performed a single-center Moroccan transcriptomic study involving 28 cases to assess the impact of the individualized gene in our environment.

RESULTS

The following genes, namely SRPX, S100A16, LFNG, CD5, CMBL, and TCTN2, are among the top genes co-overexpressed in TCGA and CGGA patients. We conducted a multivariate COX survival test, taking into account known prognostic clinical parameters, and found that the LFNG gene is the only marker of poor prognosis independent of other clinical markers in TCGA and CGGA patients treated with radiotherapy. Our results indicate that patients who overexpress LFNG have elevated IFNg levels and low granzyme B levels, while the levels of perforin and granzyme A remain unaffected by LFNG variation. Furthermore, our results demonstrate positive correlations between LFNG gene expression and four immune checkpoints (PD1, PDL1, CTLA4, and VISTA), but negative correlations only with TIM3.

CONCLUSION

Our findings suggest that LFNG could serve as a useful biomarker for identifying patients with poor prognosis and that LFNG expression may be associated with specific immune checkpoint expression patterns. These results have important implications for the development of new therapeutic approaches in the treatment of TCGA and CGGA patients.
RADT-14. EARLY OUTCOMES FROM PROTON CRANIOSPINAL IRRADIATION FOR LEPTOMENINGEAL METASTASIS FROM SOLID TUMORS
Authors: Lam Keng , Nasr Lewis , Andersen Clark , Marqueen Kathryn , Li Jing , Wang Chenyang , Majd Nazanin , Aaroe Ashley , Loghin Monica , McGovern Susan , O’Brien Barbara
Published: November 2024

INTRODUCTION

Treatment options for leptomeningeal metastasis (LM) are limited. A phase II study found that proton craniospinal irradiation (pCSI) was well-tolerated and improved survival. We report our experience with pCSI for solid-tumor LM.

METHODS

This is a retrospective review of patients treated with pCSI for solid-tumor LM from December 2020 to January 2024 at our center. Patient characteristics were summarized using descriptive statistics. Median overall survival (OS) and median central nervous system progression-free survival (CNS-PFS) from the first day of pCSI were estimated using Kaplan-Meier survival curves.

RESULTS

We identified 45 patients who completed pCSI. Median age was 54 years (range, 23-79); 73% were female, and 53% lived more than 100 miles from our center. Breast cancer (53%), lung cancer (20%), and melanoma (9%) were the most common primary cancers; 51% of patients had stable systemic disease at LM diagnosis. All had imaging evidence of LM, and 64% were confirmed by cytologic examination of the cerebrospinal fluid. Eighty percent had symptomatic LM, and the median Karnofsky Performance Scale (KPS) at LM diagnosis was 80. The median time from primary cancer diagnosis to LM diagnosis was 23.1 months (range, 0-221.3). Fifty-three percent of patients had active brain metastasis at LM diagnosis. At the first visit following pCSI, median KPS was 70. Seventy-six percent reported new or worsening nausea, 51% headache, and 31% fatigue. Following pCSI, 18% received LM surveillance, 4% intrathecal chemotherapy, 67% systemic therapy, 9% hospice care, and 2% lost to follow-up. Median OS was 13.7 months (95% confidence interval [CI], 11.2 to infinity), and median CNS-PFS was 6.5 months (95% CI, 4.9 to 12.8).

CONCLUSIONS

The outcomes in our cohort are comparable to those recently reported in a phase II trial. Further study is indicated to determine the optimal candidates for pCSI and sequential therapies.
RADT-18. DEDICATED 3D-FSE SEQUENCE-BASED RADIOSURGERY REDUCES DISTANT INTRACRANIAL RELAPSE RATES IN A HISTOLOGY-AGNOSTIC PATIENT COHORT
Authors: Akdemir Eyub Y , Rubens Muni B , Gurdikyan Selin , Abrams Kevin J , Sidani Charif , Press Robert H , Hall Matthew D , Wieczorek D Jay , Lee Cecillia , Tolakanahalli Ranjini , Gutierrez Alonso N , McDermott Michael W , Mehta Minesh P , Kotecha Rupesh
Published: November 2024

INTRODUCTION

Stereotactic radiosurgery (SRS) is a cornerstone in the treatment of brain metastasis (BM), despite a known risk of distant intracranial failure (DIF). Recent imaging advances, specifically, sensitive 3D-FSE sequences, have started to be incorporated into SRS practice; however, comparisons of outcomes to historical imaging approaches are limited. We evaluated the impact of adding 3D-FSE to MPRAGE in BM detection and prolongation of DIF in a histology-agnostic patient group.

METHODS

Outcomes of patients treated with SRS for BM between 01/2019-01/2024 were evaluated. MPRAGE sequences were obtained for all; 3D-FSE sequences were implemented in 02/2020. Median times to DIF were estimated using the Kaplan-Meier method.

RESULTS

215 patients underwent 332 SRS courses for 1456 BM imaged with MPRAGE and 3D-FSE (primary cohort), compared to the control cohort (92 patients, 135 SRS courses, 462 BM). MPRAGE sequences revealed 1636 lesions in 307 patients (462 in 92 control cohort, 1174 in 215 primary cohort). In the primary cohort, an additional 282 lesions were identified with 3D-FSE (24% increase) by neuroradiologists and multidisciplinary review. There was a statistically significant prolongation in the median time to DIF between the cohorts (11.4 vs. 6.8 months, p=0.029), most pronounced in the 1-4 metastases subgroup (14.7 vs. 8.1 months, p=0.008) and in those with a single BM (36.4 vs. 10.9 months, p=0.001). While patients relapsing on immunotherapy or targeted therapy did not significantly benefit from 3D-FSE (7.2 vs. 5.7 months, p=0.280), those who relapsed on chemotherapy or were off systemic therapy at least four weeks prior to SRS (including synchronous metastases) exhibited a trend towards longer time to DIF with 3D-FSE (14.7 vs. 7.9 months, p=0.057).

CONCLUSIONS

3D-FSE added to MPRAGE lengthens time to DIF via improving BM detection, especially for limited BM, and those relapsing on systemic therapy with limited intracranial penetration or no systemic therapy.
RADT-20. POSTOPERATIVE RADIOTHERAPY PROVIDES ADDITIVE PROGRESSION-FREE SURVIVAL BENEFIT IN ATYPICAL MENINGIOMAS REGARDLESS OF EXTENT OF RESECTION
Authors: Tosi Umberto , Simonetto Marialaura , Giantini-Larsen Alexandra , Ramakrishna Rohan , Stieg Philip , Schwartz Theodore
Published: November 2024

WHO Grade II meningiomas represent a minority of all meningiomas. The creation of treatment algorithms has remained challenging, with the need to add postoperative radiotherapy (RT) following satisfactory gross total resection being oftentimes debated. Thus, the goal of this study was to understand which factors, if any, predispose to recurrence of atypical meningiomas following resection. Therefore, we retrospectively review a 90-patient cohort of WHO grade II meningiomas who underwent surgical resection. Patients were clustered based on tumor location, (convexity or non-convexity) and whether they had received postoperative RT. Following extraction of biographic characteristics, the extent of tumor resection and tumor recurrence were measured. A detailed uni- and multivariate analysis was carried out to determine which factors, if any, predisposed to recurrence. The cohort consisted of 90 patients with a WHO Grade II meningiomas. A gross total resection was achieved in 66.7% of patients. Patients who had a gross total resection and received postoperative RT had longer progression-free survival (p = 0.031) than patients with subtotal resections (STR), regardless of radiation status, and patients with a GTR who did not receive radiation. On uni- and multivariate analysis, receiving postoperative RT was the only factor associated with no recurrence of disease (p = 0.023); no association was found for extent of resection (p = 0.63) or location (p = 0.18). In conclusion, the treatment of WHO grade II meningiomas remains challenging. In this study, we showed how the addition of radiotherapy remains beneficial even in cases of gross total resection, regardless of location. We postulate how microscopic disease not observed on MRI may be responsible for these findings.
RADT-21. EFFICACY AND SAFETY OF DONUT-SHAPED CIRCUMFERENTIAL SPINE CYBERKNIFE STEREOTACTIC BODY RADIOTHERAPY FOR METASTATIC SPINE DISEASE
Authors: Park David , Kattaa Ahed , Chang Steven
Published: November 2024

BACKGROUND

Spinal metastases (SM) with epidural spinal cord compression (ESCC) are challenging to manage due to the risk of radiation-induced injury. Traditional approaches often avoid circumferential stereotactic body radiotherapy (SBRT) because of these risks. The efficacy and safety of donut-shaped circumferential SBRT, which envelops the spinal column while sparing the cord, remains underexplored.

OBJECTIVE

This study evaluates the safety and efficacy of donut-shaped circumferential spine CyberKnife SBRT in treating spinal metastases, focusing on preventing radiation-induced myelopathy and achieving local tumor control.

METHOD

We retrospectively analyzed patients treated with donut-shaped circumferential spine SBRT from 2014 to 2023. We evaluated demographics, grade of ESCC (Bilsky), prior treatments, symptoms, treatment parameters, and outcomes. Key measures included SBRT dosimetric data, radiation exposure to the spinal cord or cauda equina, adherence to dose-volume constraints, occurrence of post-SBRT myelopathy, other radiation-induced complications, and local tumor control.

RESULTS

Forty-eight lesions from 43 patients (median age: 65 years; range: 20-78) were analyzed. Only one patient underwent separation surgery for severe ESCC (Bilsky grade 3). The median clinical target volume (CTV) was 63.77 cc (range: 20.31-270.05), and the median margin dose was 24 Gy (range: 18-30). Over a median follow-up of 8 months (range: 1-91), local tumor control rates were 91.1% at 6 months, 87.1% at 1 year, 82.8% at 3 years, and 62.1% at 5 years. Median overall survival was 17 months. Of 20 lesions exceeding dose constraints, only one patient displayed clinical myelopathy symptoms, correlating with local tumor recurrence. There was no radiographic myelopathy or other radiation-induced complications during follow-up.

CONCLUSION

Donut-shaped circumferential spine CyberKnife SBRT provides effective and safe treatment for spinal metastases with or without epidural involvement. It achieves substantial local tumor control and has a minimal incidence of radiation-induced myelopathy, offering a viable non-surgical option for managing this complex condition.
RADT-28. THE ROLE OF CRANIAL RE-IRRADIATION IN EGFR MUTANT LUNG CANCER PATIENTS WITH BRAIN METASTASES
Authors: Luke Raymond , Ashamalla Hani , Beal Kathryn , Knisely Jonathan , Lee Jonathan , Garcia Christine , Mokhtar Bahaa , Panariti Anthony , Formenti Silvia
Published: November 2024

INTRODUCTION

Re-irradiation with stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) may be used for treating recurrent brain metastases. Here, we are reporting on the rate of cranial re-irradiation based on our institutional experience in patients with mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer (mEGFR-NSCLC).

METHODS

This is a retrospective review of patients from three NYP-WCM hospitals with brain metastases treated with radiotherapy and Tyrosine Kinase Inhibitors (TKIs) from December 2012 to May 2023.

RESULTS

Ninety-eight patients (60.5%) out of 162 with brain metastases from mEGFR-NSCLC were treated with radiation. Twenty-seven patients (27.5%) were treated with WBRT. Among 71 patients treated with SRS, 10 (14.1%) patients underwent surgical resection of the dominant brain lesion followed by fractioned SRS (FSRS) to the surgical bed. Sixty-one (85.9%) patients received SRS for intact brain lesions ranging from single fraction 16-20Gy to FSRT with 24Gy –30Gy in 3-5 fractions based on the size and eloquence of the brain site of the brain metastasis. In the SRS group, fifteen (21.1%) patients required at least one more course of cranial irradiation. The mean duration of local intracranial control between the first and the second course of radiation was 19.6 months [range from 2.0- 56.7 months], while from the start of TKI to the first intracranial failure was 11.3 months [0.8m-45.3 months]. In the WBRT group, two patients (7.4%) were treated with another course of WBRT 20Gy in 5 fractions. These two patients started TKI simultaneously with their first course of WBRT; the mean duration of intracranial local control was 12.8 months [range from 11.6-14.1 months]. Both patients suffered significant cognitive declines.

CONCLUSION

In the Tyrosine Kinase Inhibitor era, patients with brain metastases from mEGFR-NSCLC have protracted progression-free survival. Multiple courses of cranial re-irradiation may be needed. Stereotactic radiotherapy should be preferred for the best results in preserving cognitive functions.
RADT-42. DISSEMINATED TUMORAL AMYLOIDOSIS OF THE CRANIAL NERVES IN THE ABSENCE OF SYSTEMIC DISEASE: CASE REPORT
Authors: Rogers Aubrey , Heller Robert
Published: November 2024

Tumoral amyloidosis, characterized by tumor-like deposits without systemic disease, is rare in the central nervous system. Most often located in the periventricular white matter, tumoral amyloidosis typically consist of immunoglobulin light chains (AL). While prior reports describe cases of tumoral amyloidosis isolated to the trigeminal nerve, we report herein a first known case of diffuse cranial nerve involvement. The patient is a 43-year-old man who presented with left trigeminal dysesthesias, which led to self-excoriation and erosion of the left naris. On exam, he had absent sensation in the V1-V3 distributions, left trochlear nerve palsy, and bilateral abducens nerve palsies. Imaging demonstrated significant thickening of the left trigeminal nerve and diffuse cisternal contrast enhancement of the other cranial nerves, including the oculomotor, abducens, facial, and glossopharyngeal nerves. Work-up began with a lumbar puncture that found elevated protein with otherwise benign results, including flow cytometry. He was therefore recommended to undergo open biopsy of the left trigeminal nerve and cavernous sinus. Pathology from this surgery demonstrated congo red- positive AL amyloid deposits. Following this pathologic diagnosis, he subsequently underwent a full workup for systemic amyloidosis including bone marrow biopsy, abdominal fat pad biopsy, and a PET CT scan. Biopsy of a long nodule was negative for amyloidosis. Systemic amyloid testing did not demonstrate non-CNS sites of amyloid deposition. Medical therapy with daratumumab, cyclophosphamide, bortezomib, and dexamethasone was started but then discontinued due to ineffectiveness. He underwent radiation treatment of 4500 cGy to the left cavernous sinus where the tumoral amyloidosis was most severe. He has had no further progression of his disease. Tumoral amyloidosis of the cranial nerves remains a rare and poorly-understood disease. Prior reports have described the disease isolated to the trigeminal nerve. This report raises attention to this diagnosis in cases of rare multi-nerve involvement and suggests that radiation may be a useful first-line treatment.
RADT-43. RADIOSURGERY FOR BRAIN METASTASES FROM GYNECOLOGICAL PRIMARIES: AN INSTITUTIONAL PERSPECTIVE OF 58 METASTATIC LESIONS
Authors: Sreenivasan Sanjeev , Jung Jessica , Calugaru Emel , Schulder Michael , Goenka Anuj
Published: November 2024

Stereotactic radiosurgery (SRS) is being increasingly employed in the treatment of brain metastases. The evidence of radiological response of metastatic lesions from gynecological primary is lacking in literature. To assess the response rate of metastatic lesions to gamma knife SRS over a longitudinal follow-up period, a single centre prospectively maintained database was analysed retrospectively from 2014 to 2024. Lesion volumes were contoured at each follow up scan using Leksell Gammaplan software. Response assessment in neuro-oncology (RANO) criteria was used to assess radiological tumor response rates. Fifteen patients with 58 lesions were included. Average duration of radiological follow-up available was 16.7 months. The primary gynecological source of brain metastases in patients were cervical(n=4), ovarian(n=7), endometrial(n=3) and vulvar (n=1). Single fraction SRS was used for 49 lesions (range 16-20 Gy) and hypofractionated SRS for 9 lesions (8Gy x 3 to 9Gy x3). Average time to complete response was 9.01 months (range 1-25.7). The average follow-up for lesions with partial response was 12.2 months (range 1 -32) As per RANO criteria, complete response was seen in 33(56.9%) lesions and partial response in 25(43.1%). At 6month follow up, complete response was seen in 58.49% (n=31) of the lesions available(n=53) for assessment and partial response in 41.51%(n=22). At 18-months, complete response was seen in 66.67%(n=22) and partial response in 33.33%(n=11). Within pathological subgroups, endometrial (60%,n=3) primary showed higher rate of complete response at 6months than ovarian (52.7%,n=19), vulvar (50%, n=1) and cervical (40%,n=6) subgroups. Brain metastases from ovarian primary source were most encountered and endometrial metastases showed highest response rates to SRS. Six month and 18-month response rates were better than previously reported literature.
CTIM-04. MODULATION OF THE INTRATUMORAL IMMUNE MICROENVIRONMENT BY LOCAL THERAPY WITH NATURAL KILLER CELLS ENGINEERED WITH A HER2-TARGETED CHIMERIC ANTIGEN RECEPTOR IN COMBINATION WITH SYSTEMIC ANTI-PD-1 CHECKPOINT INHIBITION IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Burger Michael , Ehrend Elisabeth , Straßheimer Florian , Cakmak Pinar , Krenzlin Harald , Elleringmann Philipp , Zeiner Pia , Herkt Stefanie , Poschke Isabel , Macas Jadranka , Weber Katharina , Schupp Jonathan , Lun Jennifer , Opitz Corinna , Roller Bastian , Manns Patricia , Klinsing Svenja , Breuer Stella , Hehlgans Stephanie , Lee Seo-Youn , Mildenberger Iris , Ludmirski Gleb , Hermann Julian , Müller Elvira , Schmitz Marc , Mehlitz Marcus , Senft Christian , Harter Patrick , Rieger Michael , Rödel Franz , Czabanka Marcus , Ratliff Miriam , Platten Michael , Herold-Mende Christel , Ringel Florian , Herrmann Eva , Hattingen Elke , Reiss Yvonne , Bunse Lukas , Bonig Halvard , Plate Karl , Forster Marie-Therese , Tonn Torsten , Wels Winfried , Steinbach Joachim
Published: November 2024

Glioblastoma (GB) is characterized by a marked immunosuppressive tumor microenvironment. In the multicenter CAR2BRAIN phase I first-in-human clinical trial, we investigated the modulation of the tumor microenvironment by repetitive local injection of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2 alone and in combination with systemic anti-PD-1 checkpoint inhibitor therapy in patients with recurrent HER2-positive GB. 6 patients were treated with repetitive doses of CAR-NK cells as monotherapy and 12 patients received a combination therapy with the anti-PD-1 checkpoint inhibitor ezabenlimab. In three of those, we were able to implement a biopsy-treat-resect-treat strategy. After initial biopsy, combination treatment was initiated before planned tumor resection, enabling analysis of the transformation of the tumor immune microenvironment by highplex multispectral fluorescent analyses and cytokine quantification. None of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Profound alterations of the immune cell distribution in the cerebrospinal fluid (CSF) and in the tumor were observed. In CSF sampled from the resection cavity, combination immunotherapy induced a local immune response with elevated pro-inflammatory cytokines and cell counts. In post-treatment tissue samples, we observed an increase of CD4+ and CD8+ T cells, and a decrease of regulatory CD4+FoxP3+ T cells. The three patients treated following the biopsy-treat-resect-treat strategy achieved a median progression-free survival (PFS) of 24 weeks, compared to 10 weeks for patients with upfront resection. Local immunotherapy with HER2-targeted CAR-NK cells is feasible and safe both as monotherapy and in combination with the systemic checkpoint inhibitor ezabenlimab and induces local immune reactions in CSF and tumor tissue. Given the signal for possible clinical benefit provided by the increase in PFS in the patients of the biopsy-treat-resect-treat cohort, further trials are warranted.
CTIM-09. INB-200: FULLY ENROLLED PHASE 1 STUDY OF GENE-MODIFIED AUTOLOGOUS GAMMA-DELTA (ΓΔ) T CELLS IN NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM) PATIENTS RECEIVING MAINTENANCE TEMOZOLOMIDE (TMZ)
Authors: Lobbous Mina , Goswami Trishna , Lamb Larry , Rochlin Kate , Pillay Thiru , ter Haak Mariska , Nabors Louis B
Published: November 2024

IN8bio’s DeltEx drug resistant immunotherapy (DRI), comprising TMZ-resistant γδ T cells engineered to express methylguanine-DNA methyltransferase (MGMT), enables γδ T cells to target upregulated NKG2D ligands on tumor cells in real time during alkylating chemotherapy exposure. Updated results from the fully enrolled Phase 1 trial evaluating DRI in adult newly diagnosed GBM subjects with IDH wild type and mutant tumors, adequate organ function and KPS ≥ 70%. Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 107 DRI cells/dose) into the resection cavity with 150 mg/m2 of IV TMZ on Day 1 of each of 6 Stupp maintenance cycles. The primary endpoint is safety and secondary endpoints include survival; immunologic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. A total of 23 subjects were enrolled and 13 dosed (61% male; median age 68 (range: 21-74); 92% IDH-WT, 54% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS), neurotoxicity (ICANS) or treatment related deaths were reported. The most common adverse events were decreased WBC/platelet count, asthenia, fatigue, hydrocephalus, headache, decreased appetite, urinary tract infection, thrombosis and balance disorder with ≥G3 platelet count decreased in 23% and WBC/ neutrophil/ lymphocyte count decreased in 7.7% each. Peripheral TMZ-based lymphodepletion was maintained for up to 1 year evidenced by near or below normal range T, B, and NK subsets. With median follow-up of 10.8 months, 83% of subjects exceeded the median 7 month Progression Free Survival (PFS) of the Stupp regimen alone, had manageable toxicity with a continued encouraging trend in PFS. Subject with IDH mutant tumor remains progression free for > 35 months. Long-term follow-up for durability of PFS and OS continues.
CTIM-10. PHASE 1 TRIAL OF PERSONALIZED NEOANTIGEN VACCINES IN COMBINATION WITH STANDARD CARE TO TREAT GLIOBLASTOMA
Authors: Bozkus Cansu Cimen , Kodysh Julia , Cheng Szu Jung , Cheng Samantha , Rubinsteyn Alex , O’Donnell Tim , Saxena Mansi , Akturk Guray , Meseck Marcia , Yong Raymund , Losic Bojan , Mandeli John , Kim Ryung S , Gnjatic Sacha , Bhardwaj Nina , Hormigo Adilia
Published: November 2024

The tumor microenvironment (TME) of glioblastoma (GBM) is populated by cells that foster immunosuppression. Reversing immunosuppression and promoting tumor surveillance by T cells that recognize the antigens generated by tumor-specific mutations (neoantigens) is critical to eliminating the tumor cells. In a phase 1 clinical trial of newly diagnosed GBM (NCT03223103), patients were treated with personalized neoantigen vaccines (PNV) combined with standard of care (resection, radiotherapy, temozolomide chemotherapy, and TTFields). The neoantigens were identified using the OpenVax computational pipeline. Primary endpoints included safety and feasibility, and the secondary endpoints included PFS, OS, TME analysis, and immunogenicity assays. The study enrolled 12 patients, ages 32-84, between December 2017 - July 2020. With a feasibility endpoint of one successful PNV administration, all patients got at least 6. All developed PNV-related injection site reactions, and flu-like symptoms grade 1-2. Concomitant use with TTFields did not increase toxicity. None of the patients exhibited dose-limiting toxicity within 30 days of receiving the PNV. However, one developed grade 3 SAE, consisting of seizures, neck pain, and progressive neurological deficits, after vaccine 10, culminating in a grade 5 SAE and brain demyelination 10 months later. Assays performed on this subject showed induction of neoantigen-specific responses with PNV. PNV induced CD4+ and CD8+ T cells reactive against multiple vaccine peptide sequences with CD8+ T cell cross-reactivity against one wild-type epitope. Other patients had immunogenicity against the vaccinated peptides. Overall, the 6 months PFS was 100%, with 67% 2-year and 58% 3-year survival. Although the mutation burden is low in GBM, neoantigens were detected in all tumors, and PNV were manufactured for all patients. PNV with synthetic long peptides combined with standard care treatment may help improve outcomes in GBM. Cross-reactivity may potentially be responsible for post-vaccination T-cell demyelination. Further evidence is needed to substantiate a direct effect. Funding: CRI - V Foundation CLIP (#3680)
CTIM-12. A RETROLECTIVE ANALYSIS ON THE SAFETY, EFFICACY AND IMMUNOGENICITY OF 203 GLIOBLASTOMA PATIENTS TREATED WITH PERSONALIZED THERAPEUTIC CANCER VACCINES (PTCV)
Authors: Latzer Pauline , Zelba Henning , Battke Florian , Bartsch Oliver , Reinhardt Annekathrin , Pertuch Eike , Shao Borong , Rabsteyn Armin , Okech Thomas , Golf Alexander , Kyzirakos-Feger Christina , Kayser Simone , Feldhahn Magdalena , Wünsche Julian , Hadaschik Dirk , Götte Dieter , Biskup Saskia
Published: November 2024

BACKGROUND

Glioblastoma multiforme (GBM) is the most common and malignant primary brain tumor. Despite of the current SoC, patients have a poor prognosis with a median OS of about 14-17 months.Method,

RESULTS

We report retrospectively analyzed data from 203 GBM patients (IDH wildtype) who added PTCV derived from patient individual tumor mutations to their treatment regimen in the setting of individual treatment attempts (ITA) in Germany. Data were analyzed re. vaccine induced T cell responses and safety acc. to CTCAE terminology version 5.0. Subsets of patients with and without hypermethylation of the MGMT promoter were further evaluated re. efficacy. Treated patients had a median age of 53 years at diagnosis, started vaccination after a median of 11 months after diagnosis, received a median of 8 immunizations with a median of 20 neoepitope peptides, and had a median follow-up time since first vaccination of 21 months. They usually received SoC (Stupp scheme), often accompanied by additional therapies. In general, the PTCV was well tolerated, and most patients experienced only Grade 1 and 2 AEs. Most frequently injection site reactions were observed (67%). Seven patients developed Grade 3 allergic or anaphylactic reactions after 7 or more vaccinations. For 119 patients T-cell responses against the vaccinated neoepitopes were investigated. Almost all patients developed vaccine induced T-cell responses (97%). 71% of patients showed both CD4+ and CD8+ T-cell responses towards vaccinated peptides. Immune responses usually increased over time peaking within 3-6 months. Median OS of the whole cohort was 26 mo (95% CI 24, 31). Primary GBM patients without recurrence events before the start of vaccination and with or without hypermethylated MGMT promoter status showed a mOS of 41 months (95% CI: 32, NA) or 23 months (95% CI: 20, NA), respectively.

CONCLUSION

The retrospective data analysis from a real-world cohort of GBM patients suggests that PTCV are safe, immunogenic, and may prolong the survival of patients.
CTIM-14. EARLY SAFETY DATA FROM A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY, VERSUS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Bradley Elder J , Hanft Simon , Lee Ian Y , Farrell Christopher , Boockvar John A , Zacharia Brad E , Kim Lyndon , Schulder Michael , Correia Carlos Eduardo Silva , Ramakrishna Rohan , Wong Eric T , Wu Julian , Agarwal Vijay , Amankulor Nduka , Bhatia Ankush , Evans Linton T , Brennan Cameron , Gill Brian J , Sengupta Soma , Quiñones-Hinojosa Alfredo , Giglio Pierre , Wu Kyle , Wu Synphen H , Falo Cristina , Walbert Tobias , Robin Adam , Alnahhas Iyad , Vojnic Morana , Wernicke A Gabriella , Aregawi Dawit , Maurer Robert , Ghatan Saadi , Singer Samuel , Jeyapalan Suriya , Magge Rajiv , Malik Athar N , Patel Nitesh , Chan Amy , Iwamoto Fabio , Hormigo Adilia , Higgins Dominique , Dey Mahua , Moss Nelson S , Sherman Wendy , Neese Leila , Pennock Gregory K , Scott Charles , Perez-Olle Raul , Andrews David W
Published: November 2024

Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.
CTNI-03. DECREASED GROWTH VELOCITY IN A PHASE 1 TRIAL (PNOC014) OF TOVORAFENIB IN PATIENTS WITH RECURRENT OR PROGRESSIVE MAPK-ALTERED TUMORS
Authors: Wright Karen , Kline Cassie , Abdelbaki Mohamed Shebl , Sayour Elias , Crotty Erin , Raabe Eric , Elster Jennifer , Prados Michael , Haas-Kogan Daphne , Mueller Sabine
Published: November 2024

BACKGROUND

The mechanisms by which MAPK-targeted agents affect children in active phases of neurocognitive and physical development are poorly understood and hence, may place them at risk, particularly for uncommon patient toxicities that may require longer monitoring or larger patient cohorts to understand the long-term implications. Decreased growth velocity was identified in our investigator-initiated phase 1 trial (NCT03429803) of tovorafenib in relapsed MAPK-altered tumors.

METHODS

Forty-four patients enrolled from February 2018-October 2021. Toxicity was assessed according to CTCAE version 5 term growth suppression (GS). Patients were also evaluated retrospectively based on age-specific growth velocity norms. Post-pubertal patients (n=14), those with pre-existing growth abnormalities (n=3), and those on drug less than 6 months (n=10) were excluded (total n=27; 61%). Growth velocities for each patient were calculated prior to, on, and after discontinuing treatment as available.

RESULTS

Our safety database included 17 reported events of GS. Sixteen patients experienced grade 3 GS, defined as growth velocity reduction ≥50% ideally measured over a year compared to baseline. One patient experienced grade 2 GS, defined as reduced growth velocity by 30-49% compared to baseline. Separate retrospective analysis using age-specific growth velocity norms further confirmed that all 17 patients (100%) demonstrated decreased growth velocity compared to age-specific norms following start of treatment regardless of dose (3, 5 and 9 patients at 280, 420 and 530 mg/m2/dose, respectively with a mean dose of 507 mg, range: 220-840 mg). Four of 9 patients on 530 mg/m2 were dose reduced for other reasons and hence treated at 420 mg/m2. In 14/15 patients off drug, growth rates recovered at near normal or normal rates within 12 months of discontinuation.

CONCLUSIONS

Patients on tovorafenib experience decreased growth velocity, which is recoverable off drug. Long-term monitoring of growth and further preclinical investigations to mitigate this toxicity and understand its effect are warranted.
CTNI-07. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TRK FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN UPDATED ANALYSIS
Authors: Perreault Sébastien , Spano Jean-Philippine , Nilsson Anna , Deyell Rebecca J , Doz François , Geoerger Birgit , Gumus Mahmut , Lassen Ulrik N , Nysom Karsten , Valero-Arrese Lorena , Idbaih Ahmed , Bernard-Gauthier Vadim , Neu Natascha , Brega Nicoletta , Drilon Alexander , Laetsch Theodore W , van Tilburg Cornelis M
Published: November 2024

BACKGROUND

Larotrectinib is a highly selective TRK inhibitor approved for TRK fusion tumor-agnostic use. We report updated data on larotrectinib-treated patients with TRK fusion primary CNS tumors.

METHODS

Patients enrolled in 2 clinical trials (NCT02637687 [SCOUT], NCT02576431 [NAVIGATE]) were included. Responses were independent review committee (IRC)-assessed (RANO). Patients from SCOUT could stop larotrectinib in the absence of on-treatment progression (wait-and-see). Data cutoff: July 2023.

RESULTS

Fifty-five patients (38 aged <18 years at enrolment) were evaluated, including 16 with non-measurable disease at baseline. Tumor histologic groups included: high-grade glioma (HGG; n=32), low-grade glioma (LGG; n=15), and other (n=8). For all patients (n=55), ORR was 27% (95% CI 16-41): 3 CR, 12 PR, 24 SD (15 for >24 weeks), 12 PD, and 4 not evaluable. For pediatric patients (n=38), ORR was 37% (95% CI 22-54). ORR in patients with measurable disease only was 38% (95% CI 23-55) for all patients (n=39) and 52% (95% CI 32-71) for pediatric patients (n=27). The 24-week disease control rates were 55% (95% CI 41-68) and 74% (95% CI 57-87) for all patients and pediatric patients, respectively. Median time to response, DoR, PFS, and OS were 2, 12 (95% CI 6-not estimable [NE]), 12 (95% CI 7-20), and 38 months (95% CI 23-NE), respectively. Treatment duration ranged from 1 to 64+ months. At data cutoff, 1 pediatric patient with HGG and 4 with LGG entered wait-and-see; median duration of first wait-and-see period was 20 months (range 4-29). One pediatric patient with LGG resumed treatment following disease progression in wait-and-see. Treatment-related adverse events were predominantly Grade 1/2.

CONCLUSION

Larotrectinib demonstrated rapid, durable responses and manageable safety in patients with TRK fusion primary CNS tumors. This supports the adoption of NGS panels containing NTRK gene fusions when testing patients to identify those who might benefit from TRK inhibitor therapy.
CTNI-08. DOSE ADJUSTED TEDDI-R FOR PRIMARY CNS DIFFUSE LARGE B-CELL LYMPHOMA
Authors: Green Richard , Miranda Candy
Published: November 2024

We report our initial experience treating 4 patients with the dose adjusted TEDDI-R protocol as reported by Dunleavy et al in 2015. The median age was 63 years, 2 patients were male, median KPS 60. Two patients were newly diagnosed: one of these had inadequate renal function for methotrexate; and the other had experienced acute methotrexate leukoencephalopathy. Two patients were treated for their first recurrence, having progressed during therapy with the MT-R protocol; one of these received salvage WBRT prior to starting. The protocol consisted of temozolomide 90 mg/sq m IV, cycles 1-6, days 2-5; etoposide 45 mg/sq m/day IV cycles 1-6, Days 2-5; liposomal doxorubicin 40 mg/sq m IV, cycles 1-6, day 2; dexamethasone 10 mg PO bid, cycles 1-6, days 1-5; ibrutinib 560 mg qd starting 3 days before cycle 1, day 1, then 560 mg qd, cycles 1-6, days 1-10; rituximab 375 mg/sq m IV cycles 1-6, days 1-2; and cytarabine 70 mg via Ommaya reservoir, cycles 2-6, days,1 and 5. Aspergillosis prophylaxis with isavuconazonium 372 mg mg PO bid was used. Overall, only 1 patient completed all 6 planned cycles; the median number of cycles completed was 4.5. Both newly diagnosed patients died during therapy; one died after 1 cycle from CMV colitis, and the other after 5 cycles from tumor recurrence, pneumonia, and septic shock. One patient with recurrent disease achieved a complete response and went on to high dose chemotherapy and autologous bone marrow transplantation; the other had a partial response after 4 cycles but died from pulmonary embolism. Median PFS for the newly diagnosed patients was 177 days, and for the recurrent patients, 221 days. Median OS for the cohort was 242 days. These preliminary data suggest that the TEDDI-R protocol was relatively toxic, especially for patients with poor neurological function, but can be an effective salvage therapy after progression on methotrexate-based therapy.
CTNI-18. RESULTS FROM A PHASE 1 STUDY OF SONODYNAMIC THERAPY WITH WHOLE HEMISPHERIC LOW INTENSITY NON-ABLATIVE ULTRASOUND IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA
Authors: Schulder Michael , Johans Tanner , Mechtler Laszlo , Agarwal Vijay
Published: November 2024

We report the first use of a novel device that delivers non-ablative low intensity diffuse ultrasound (LIDU) across the entire hemisphere in combination with the oral sonosensitizing agent 5-ALA for the treatment of recurrent high grade glioma. LIDU in combination with 5-ALA focally targets tumor cells with sonodynamic therapy (SDT), causing selective tumor cell death across the entire hemisphere via 1) direct tumor targeting and 2) stimulation of immunogenic cell death. In this 3x3 clinical trial designed for safety (n=12, NCT05362409), two patients were enrolled after multiple recurrences and seven patients had multifocal or multicentric disease. Treatments were delivered monthly for a minimum of four sessions. A treatment duration of 120 minutes was established after dose escalation and expansion. SDT delivered via a novel device and in conjunction with 5-ALA was well tolerated, with no duration-limiting toxicities or serious related adverse events. Compared to historical data, we observed a significant increase in overall survival (mOS of 14.0+ months, with 7 of 12 patients still alive at the time of this submission and final median OS not yet achieved). A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been planned to commence in 2025 to assess the safety and efficacy of LIDU with sonosensitization in patients with newly diagnosed GBM.
CTNI-21. PIVOTAL, PHASE 2B RENEU TRIAL OF MIRDAMETINIB IN CHILDREN AND ADULTS WITH NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMA (NF1-PN): A SPOTLIGHT ON PATIENTS ACHIEVING DEEP RESPONSE
Authors: Gershon Timothy , Moertel Christopher , McNall-Knapp Rene , Shuhaiber Hans , Weintraub Lauren , Hajjar Fouad , Nickerson Molly , Weber Michael , Lokku Armend , Babovic-Vuksanovic Dusica , Hirbe Angela
Published: November 2024

BACKGROUND

Patients with NF1-PN in the phase 2b ReNeu trial (NCT03962543) of mirdametinib in adults (N=58, ≥18y) and children (N=56, 2-17y) had a deeper median (range) best reduction (adults: -41% [-90% to 13%]; children: -42%, [-91% to 48%]) from baseline in target PN volume than previously published in trials of other agents in NF1-PN.

METHODS

In the 24-cycle (1-cycle=28d) treatment phase, objective response rate (ORR) was the percentage with confirmed objective responses (OR) of ≥20% target PN volume reduction from baseline on consecutive MRIs (by blinded independent central review). This analysis includes patients achieving deep response (>50% best reduction from baseline in target PN volume) regardless of OR and inclusive of patients in the long-term follow-up. Exploratory analysis of baseline characteristics compared patients with deep response and patients with ≤50% volume reduction.

RESULTS

ORR was 41% (24/58) in adults and 52% (29/56) in children treated with mirdametinib. 62% (15/24) of adults and 52% (15/29) of children who achieved OR had deep response. To further characterize deep response, 2 adults and 3 children with deep response without confirmation or in long-term follow-up were included. Of those with a deep response, 35% (6/17) of adults and 72% (13/18) of children were investigator-defined as having progressing PN. Patients achieved deep response regardless of baseline age, sex, target PN volume, tumor location, or progression status. For adults and children, median time to best percent change from baseline in PN volume for patients achieving deep response was 25.4 and 21.8mo; for patients with reductions of ≥20% to ≤50% was 15.3 and 15.2mo; for patients with reductions of <20% was 7.8 and 4.2mo, respectively.

CONCLUSIONS

Patients had a similar likelihood of achieving deep response across assessed baseline characteristics. A trend between deep response and longer treatment duration suggests a benefit of prolonged therapy with mirdametinib.