bluuebunny/crossref_metadata_2025 huggingface dataset:
P12.04.A CAR-ENGINEERED PRIMARY NK CELLS SHOW PROMISING EFFECTS AS TARGETED THERAPY AGAINST EGFR-POSITIVE GLIOBLASTOMA
Authors: Roller B , Reindl L , Strassheimer F , Ziegener L , Elleringmann P , Kiefer A , Röder J , Steinbach J , Wels W , Ullrich E , Burger M
Published: October 2024

BACKGROUND

Glioblastoma (GB) is the most frequent primary brain tumor with a dismal prognosis despite multimodal treatment regimens. Effector cells such as T cells or natural killer cells (NK) carrying tumor-specific chimeric antigen receptors (CAR) hold promise for the development of more effective treatment strategies. CAR-engineered derivatives of the human NK cell line NK-92 targeting EGFR or EGFRvIII showed potent antitumor activity against glioblastoma cell lines in vitro and in vivo. Nevertheless, NK-92 does have limitations when compared to primary NK cells, such as the required irradiation prior to application in humans.

MATERIAL AND METHODS

To overcome this restriction, we evaluated the suitability of peripheral blood derived human primary NK cells (pNK) as carriers for a CAR targeting the common GB antigen epidermal growth factor receptor (EGFR) and the tumor-specific EGFR variant EGFRvIII. pNK cells from healthy donors were transduced with a lentiviral vector encoding the cetuximab-derived 225.28.z CAR (CAR-pNK), which recognizes an epitope common to both receptors. Specific tumor cell lysis by the CAR-pNK cells was then investigated in FACS-based cytotoxicity assays with GB cells expressing EGFR, EGFRvIII, or both target antigens. In addition, we tested in vivo CAR-pNK cell therapy in the subcutanous and intracranial LNT-229/EGFRvIII glioblastoma xenograft models.

RESULTS

When compared to non-transduced pNK cells, CAR-pNK cells achieved enhanced lysis of LNT-229 GB cells expressing EGFR and EGFRvIII. Likewise, markedly increased cytotoxicity of CAR-pNK was observed against the murine EGFR transduced GB cell line GL261 and the human cell lines SKMG-3 and BS153 with intrinsic EGFR gene amplification or expression of EGFRvIII, respectively. Furthermore, we observed delayed tumor growth following a single intravenous injection of CAR-pNK cells in the subcutaneous LNT-229/EGFRvIII glioblastoma xenograft model.

CONCLUSION

In summary, these results demonstrate promising efficacy of primary CAR-NK cells targeting EGFR and EGFRvIII both in vitro and in vivo. Ongoing work is currently evaluating CAR-pNK cell therapy in the orthotopic LNT-229 glioblastoma xenograft mouse model and an in vitro organoid model, which may provide the rationale for early clinical testing.
P12.05.B COMBINED ANTI-ANGIOGENIC TREATMENT TO INCREASE INTRATUMORAL PERSISTENCE OF CAR T CELLS IN LUNG CANCER BRAIN METASTASES
Authors: Blobner J , Eberle C , Dengler L , Herold J J , Xu T , Mueller K J , Teske N , Karschnia P , Ishikawa-Ankerhold H , Subklewe M , Thon N , Tonn J , von Baumgarten L
Published: October 2024

BACKGROUND

Metastatic lung cancer shows a devastating prognosis. Immunotherapeutic approaches including CAR T-cells show promise in hematologic malignancies. However, the presence of immunosuppressive factors within the tumor microenvironment and physical barriers like elevated interstitial pressure due to dysfunctional tumor vessels are one of the main obstacles especially in solid tumors. Therefore, we investigate potential synergistic effects of a combined anti-angiogenic treatment and CAR T cells.

METHODS

Here, we set up an immunocompetent syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy (TPLSM). This model allows in-vivo characterization of fluorescent tumor cells and CAR T-cells on a single cell level over time. Intraparenchymal injection of red fluorescent EpCAM-transduced Lewis Lung carcinoma cells (EpCAM/tdtLL/2 cells) followed by injection of EpCAM-directed or undirected CAR T-cells into the adjacent brain tissue was performed. Additionally, aVEGF-A combined with aVEGF-R2 and the respective isotype control were injected intraperitoneally.

RESULTS

Compared to undirected CAR T-cells, mice receiving EpCAM-directed CAR T-cells showed higher intratumoral CAR T-cell densities after intraparenchymal injection. This finding was accompanied with reduced tumor growth and eventually translates into a survival benefit. However, intratumoral CAR T-cell numbers diminish over time indicating insufficient persistence inside of the tumor microenvironment. Additional anti-VEGF-A/VEGF-R2 treatment results in reduced tumor growth after EpCAM/GFPCAR T cell and GFPT cell treatment, respectively. Interestingly, in vivo imaging reveals higher intratumoral CAR T cell numbers after anti-angiogenic treatment compared to isotype controls pointing towards enhanced CAR T cell persistence resulting in a survival benefit.

CONCLUSION

Collectively, our findings indicate that locally injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Additional anti-angiogenic treatment provides a mechanism to enhance intratumoral CAR T cell persistence and reduce tumor growth.
P12.15.B PROGNOSTIC VALUE OF CD8+ T-CELLS INFILTRATION IN GLIOMA PATIENTS TREATED WITH IMMUNOTHERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Cai X , Westerman B , Wang D , Garcia Vallejo J
Published: October 2024

BACKGROUND

Glioblastoma (GBM) is the most aggressive subtype of glioma with a five-year survival of 7·2 %. Immunotherapy has become a promising approach in the treatment of it. However, no improved prognosis was reached yet in phase III immunotherapy trials of glioma. Highly intertumoral heterogeneity was one of the reasons for this outcome. Hence, identifying patients who will respond to immunotherapy has become a core task in the research of GBM. In non-CNS malignancy, CD8+ tumor infiltrating lymphocytes (TILs) within tumor has been associated with response to immunotherapy and prognosis. However, no consensus was reached regarding the value of CD8+ TILs in predicting glioma patients’ response to immunotherapy. In this meta-analysis, we investigated the prognostic predictive value of infiltrating CD8+ TIL in glioma patients treated with immunotherapy.

MATERIAL AND METHODS

PubMed and Web of Science were searched from 1st of January 2000 up to 15th of May 2023. Quality assessment was performed using ROBINS-I and JBI critical appraisal check list. Subgroup analyses were conducted according to clinical indicators. The protocol of the meta-analysis was registered on PROSPERO (CRD42023425790).

RESULTS

A total of 8550 records were identified after the duplicates were removed, with 272 records remained for full text screening. Nine records with 187 GBM participants were included in the meta-analysis. Most of them are from Phase I or Phase II clinical trials. The immunotherapies utilized in these studies included peptide vaccination, oncolytic viral vectors therapy, DC vaccination, immune checkpoint inhibitors, and CAR-NK. Overall, no statistically significant effect of CD8+TIL infiltration was observed on overall survival (OS), progress-free survival (PFS), and survival time after immunotherapy. The subgroup analysis on peptide vaccination showed that patients with high CD8+TIL infiltration tended to have a lower OS (HR = 6·57; 95% CI: 1·12, 38·58; P = 0·037). In the subgroup analyses on male (HR = 12·34; 95% CI: 1·09, 139·18; P = 0·042) and recurrence (HR = 0·08; 95% CI: 0·01, 0·79; P = 0·030), CD8+TIL infiltration showed important effect on PFS.

CONCLUSION

In general, CD8+ TIL infiltration has no prognostic predictive value in GBM patients treated with immunotherapy. However, there is predictive value for OS in the subpopulation of peptide vaccination treated GBM patients.
P12.19.A UNVEILING SYNERGISTIC STRATEGIES: CRISPR-GUIDED OPTIMIZATION OF L19-TNF IMMUNOCYTOKINE THERAPY IN GLIOBLASTOMA
Authors: Sakic I , Uijttewaal E , De Luca R , Puca E , Weller M , Neri D , Elling U , Weiss T
Published: October 2024

BACKGROUND

Glioblastoma poses a formidable challenge due to its intricate intra- and intertumoral heterogeneities and the immunosuppressive milieu it creates. Despite advances, the standard of care remains largely ineffective, underscoring the urgent need for innovative treatment strategies. Tumor-targeted cytokine-based therapies, particularly L19-TNF, represent a promising cancer immunotherapy approach, that is currently being studied in clinical trials for patients with newly diagnosed or recurrent glioblastoma in Europe. Particularly combination therapies based on L19TNF, such as the combination with lomustine, have shown promising activity in preclinical models. However, the most promising combinatorial treatment strategy remains to be determined. To address this, we employed a cutting-edge in vivo CRISPR screening approach to identify synergistic partners and druggable targets that could enhance the efficacy of L19TNF cancer immunotherapy.

MATERIAL AND METHODS

The primary limitation in glioblastoma treatment is the identification of effective drugs. Here, we systematically explored tumor growth dependencies and dominant signaling pathways in an orthotopic murine glioma model in the complex setting of an intact host immune system under immunotherapeutic pressure, using in vivoCRISPR screening. We used a novel CRISPR strategy based on an innovative sgRNA cassette switch-system with unique molecular identifiers (UMIs) for controlled induction of the perturbations in vivo. This accounts for cell-to-cell heterogeneities by allowing single-cell lineage tracing and a timed sgRNA activation by Cre-recombinase activation to reduce off-target effects and overcome the bottleneck created by the orthotopic tumor cell implantation.

RESULTS

Through genome-wide and selective CRISPR screens, we uncovered several novel druggable targets, some previously unexplored in glioblastoma and others which demonstrated efficacy in other tumor entities. Additionally, our investigation provided insights into the mode of action of L19-TNF, while at the same time suggesting possible combination opportunities. Importantly, our study identified four highly promising synergistic drugs currently undergoing preclinical evaluation in glioblastoma mouse models. These findings offer tangible avenues for enhancing the therapeutic efficacy of L19-TNF immunotherapy.

CONCLUSION

Our research represents a significant step forward in the quest for innovative treatment strategies in glioblastoma. The CRISPR screening under immunotherapeutic selection has revealed a spectrum of synergistic partners and paved the way for a rational design of combinatory treatment approaches to maximize therapeutic efficacy, laying the groundwork for future clinical translation.
P13.04.A CRANIOPHARYNGIOMA TREATMENT: PROTONS VS. PHOTONS - A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Silva Y P , Sharma E , Łajczak P , Jabbar R , Majeed M W , Ahmed A R , Petry I N S , Chawla D , Chatterjee A , Fagundes W
Published: October 2024

BACKGROUND

Craniopharyngiomas are complex tumors that can present significant challenges for neurosurgeons, sometimes necessitating a range of treatment modalities, including radiotherapy.

MATERIAL AND METHODS

Through a systematic review and meta-analysis, this study evaluates the effectiveness and safety of proton beam therapy compared to traditional photon therapy for craniopharyngioma treatment. We searched major databases (Pubmed, Cochrane, and Scopus) for studies comparing proton and photon therapy for craniopharyngioma. Studies published up until April 2024 were included. We assessed event-free survival and endocrine dysfunction. The risk of bias in each study was evaluated. Pooled estimates of odds ratios using random-effects models were calculated for each outcome for patients undergoing proton versus photon therapies.

RESULTS

This systematic review analyzed data from three non-randomized studies, encompassing 375 patients who received subtotal resection followed by radiation therapy for residual tumors. Patients were divided into two groups: photon therapy (n=147, 39.2%) and proton therapy (n=228, 60.8%). With a median follow-up of 5.0 to 6.4 years, the meta-analysis revealed no significant difference in event-free survival (log OR=-0.28, 95%CI=-1.49-0.93, p=0.65) or endocrine dysfunction (log OR=0.12, 95%CI=-0.36-0.60, p=0.62) between the proton and photon therapy groups. Heterogeneity among studies was low to moderate (I²=50.59% for event-free survival, I²=0.00% for endocrine dysfunction).

CONCLUSION

This review suggests proton therapy offers comparable event-free survival and endocrine dysfunction to photon therapy for craniopharyngioma, which is especially relevant considering the substantial cost differential between these treatment options. However, further research with a greater sample size is warranted to confirm this survival outcome and explore long-term toxicity differences.
P13.07.A INTEGRATION OF WHITE MATTER TRACTS IN STEREOTACTIC BRAIN RADIOTHERAPY TREATMENT PLANNING WITH A FULLY AUTOMATED ATLAS-BASED PIPELINE
Authors: Bockel S , EL AICHI M , SUN R , Benzazon N , DE KERMENGUY F , VERES C , DEUTSCH E , Robert C
Published: October 2024

BACKGROUND

Magnetic Resonance Diffusion Tensor Imaging (DTI), has enhanced our understanding of white matter (WM) anatomy and facilitated the creation of anatomo-functional atlases of WM tracts (WMT). Concurrently, systemic treatments and stereotactic brain radiotherapy (SBRT) have significantly improved outcomes for brain metastasis (BM) patients, with growing concern in decreasing neurocognitive side effects. Nevertheless, WM structural connectivity has not yet been integrated into SBRT treatment planning. We present an automated, and universally accessible method that enables visualization of WM tracts on individual pre-SBRT imaging and planning dose maps through an atlas-based approach.

MATERIAL AND METHODS

After basic image preprocessing steps, pre-SBRT brain CTs used for RT planning were coregistered using affine then non-linear transformation to the ICBM 2009a nonlinear asymmetric space, using the Advanced Normalizations Tools for Python (ANTSPy) ecosystem. This space accommodates a probabilistic atlas of WMT, derived from a sample of 1065 subjects. The composition of the affine transformation matrix and the non-linear deformation field was applied to the initial dose map to warp it to the ICBM space. The pipeline was implemented first on a retrospective cohort of 108 BM (< 2 cm) patients treated with single fraction SBRT. The anatomical accuracy of the registration was evaluated by computing DICE metric from cortical auto segmentations. Then, to evaluate the consistency of warped dose maps, clinically relevant dose statistics for the planning target volume (PTV) and organs-at-risk (OAR) were compared between the initial and transformed dose maps. Eight patients treated with single fraction SBRT were prospectively enrolled and beneficiated from a pre-SBRT DTI tractography (TractSeg DTI tool used for WMT reconstruction). Mean and maximum doses (Dmean and Dmax) on 14 main WMT as defined by the two methods (DTI / atlas-based strategies) were compared to validate the pipeline.

RESULTS

When applying the final registration to our retrospective cohort, mean DICE index on brain cortex was 0.89 (range: 0.62-0.92). The mean absolute dose differences did not exceed 0.03Gy for PTV Dmean and 0.1Gy for PTV Dmax when comparing dose statistics from the initial dose map to the warped one. For the OARs, differences were of the order of a cGy for brainstem, brain-PTV, chiasm and optic nerves Dmean and Dmax. On the prospective cohort, the mean absolute differences on Dmax and Dmean delivered to 14 main WMTs were 1.43Gy (standard deviation: 1.06, range: 0.05-4.2Gy) and 0.18Gy (standard deviation: 0.11, range: 0.02-0.47Gy).

CONCLUSION

This method is the first fully automated pipeline for WMT visualization on pre-SBRT images without performing DTI. This technique has the potential to improve SBRT treatment by enabling WM sparing dosimetry and reducing neurocognitive side effects.
P13.08.A INTRAOPERATIVE OR POSTOPERATIVE STEREOTACTIC RADIOTHERAPY FOR BRAIN METASTASES: TIME TO SYSTEMIC TREATMENT ONSET AND OTHER PATIENT-RELEVANT OUTCOMES
Authors: Dejonckheere C , Layer J , Hamed M , Schneider M , Vatter H , Herrlinger U , Grimmer M , Kugel F , Garbe S , Giordano F , Sarria G R
Published: October 2024

BACKGROUND

Intraoperative radiotherapy (IORT) has become a viable treatment option for resectable brain metastases (BMs). As data on local control and radiation necrosis rates are maturing, we focus on meaningful secondary endpoints such as time to next treatment (TTNT), duration of postoperative corticosteroid treatment, and in-hospital time.

MATERIAL AND METHODS

Patients prospectively recruited within an IORT study registry between November 2020 and June 2023 were compared with consecutive patients receiving adjuvant stereotactic radiotherapy (SRT) of the resection cavity within the same time frame. TTNT was defined as the number of days between BM resection and start of the next extracranial oncological therapy (systemic treatment, surgery, or radiotherapy) for each of the groups.

RESULTS

Of 95 BM patients screened, IORT was feasible in 84 cases (88%) and ultimately performed in 64 (67%). The control collective consisted of 53 SRT patients. There were no relevant differences in clinical baseline features. Mean TTNT (range) was 36 (9 - 94) days for IORT patients versus 52 (11 - 126) days for SRT patients (p = 0.01). Mean duration of postoperative corticosteroid treatment was similar (8 days; p = 0.83), as was mean postoperative in-hospital time (11 versus 12 days; p = 0.97). Mean total in-hospital time for BM treatment (in- and out-patient days) was 11 days for IORT versus 19 days for SRT patients (p < 0.001).

CONCLUSION

IORT for BMs results in faster completion of interdisciplinary treatment when compared to adjuvant SRT, without increasing corticosteroid intake or prolonging in-hospital times. A randomised phase III trial will determine the clinical effects of shorter TTNT.
P13.12.B POST-PROGRESSION SURVIVAL FOLLOWING FOCAL RE-IRRADIATION WITH 20 GY IN 5 FRACTIONS IN PROGRESSIVE CNS WHO GRADE 3 ASTROCYTOMA AND GLIOBLASTOMA - A MONOCENTRIC RETROSPECTIVE ANALYSIS
Authors: Hoffmann E , Linnenschmidt M , Behling F , Renovanz M , Bombach P , Bender B , Schittenhelm J , Bodensohn R , Tabatabai G , Eckert F , Paulsen F , Niyazi K
Published: October 2024

BACKGROUND

Despite multimodal treatment (resection, radiation therapy, alkylating chemotherapy and/or tumor-treating fields), the treatment of progressive CNS WHO Grade 3 astrocytoma and glioblastoma remains challenging. Re-irradiation (Re-RT) might be considered in the course of the disease. Optimal fractionation/dose prescription schedules are still under investigation, underlining a gap in clinical data in this regard. Here, we retrospectively analyzed post-progression survival (PPS) and progression-free survival (PFS) in a single center cohort.

MATERIAL AND METHODS

Patients receiving Re-RT with 20 Gy in 5 fractions (4 Gy per fraction; corresponding to 35 Gy in an equivalent dose normalized to 2 Gy (EQD2)) upon progression of recurrent astrocytoma glioblastoma or grade 3 astrocytoma (12/2020-12/2022) were included. Planning target volume for Re-RT was gross tumor volume = (T1 with contrast) + 5 mm. Clinical endpoints included PPS, PFS since start of Re-RT, therapy in case of further progression, bevacizumab therapy, MGMT promotor methylation (MGMT meth), and IDH status.

RESULTS

To date, 40 patients were analyzed (27 male); median age 62.25 a, range 31-83 a; 34 GBM IDHwt, 6 other), 15 of who showed MGMT meth (24 w/o MGMT meth, 1 not determined). Primary therapy was 60 Gy with concomitant temozolomide (TMZ), TMZ + lomustine, or study medication in 30, 54.0 Gy + adjuvant TMZ in 3, and 40.05 Gy + TMZ in 7 patients. Patients received heterogenous systemic therapies and 0-3 treatment lines prior to Re-RT (median 1 prior treatment modality). Re-RT was considered in localized non-resectable progression. Median time between first line therapy and first progression was 10.8 months and between first line therapy and Re-RT 16.7 months, respectively. Seven patients received an integrated boost of up to 30 Gy. Median PFS was 2.6 months (range <1-10.4 months); with 7,6 months PPS (range <1 - 22.4 months). 19 patients (47.5%) received bevacizumab during further course of the disease. Following Re-RT, 16 patients (40%) received further tumor-directed therapy.

CONCLUSION

This is a heterogenous single-center cohort. PFS after Re-RT was 2.6 months, and PPS was 7.6 months, respectively, published data reporting 6-12 months PPS after re-irradiation (EQD2 ranging between 48-60 Gy) despite a comparatively low and conservative cumulative dose of 20 Gy (35 Gy EQD2). Treatment time was only 5 days. Thus, re-irradiation with 4 Gy x 5 could be an option in a palliative setting and could be included in interdisciplinary treatment discussions for progressive CNS WHO grade 3 astrocytoma and glioblastoma.
P13.15.A SULFASALAZINE AS RADIOSENSITIZER IN COMBINATION WITH STEREOTACTIC RADIOSURGERY FOR RECURRENT GLIOBLASTOMA - A PHASE 1 DOSE-ESCALATION
Authors: Skeie B , Bragstad S M , Sarowar S , Goplen D K P , Heggdal J I , Enger P
Published: October 2024

BACKGROUND

Glioblastoma (GBM) is an aggressive, radioresistant type of cancer with a dismal prognosis. Preclinically, Sulfasalazine (SAS) has shown radiosensitizing properties by blocking intratumoral production of glutathione (GSH). We conducted a phase 1 clinical trial to investigate safety and therapeutic potential of SAS in combination with Gamma Knife Radiosurgery (GKRS) for recurrent GBM (rGBM).

MATERIAL AND METHODS

Patients were pretreated with SAS 3 days prior to GKRS to deplete the tumor of GSH utilizing a 3 + 3 dose escalation design (1.5, 3.0, 4.5 or 6.0 g SAS/day. Endpoints were safety, quality of life (FACT-Br), changes in GSH-levels (GSH-MR spectroscopy), metabolism (11-C-MET-PET) and best radiographic response (RANO criteria). Freedom from local tumor progression (FFTP), progression-free survival (PFS) and overall survival (OS) were compared to contemporary controls.

RESULTS

Twelve patients were included. No dose limiting toxicity was observed. FACT-Br remained stable for 6 months (p= 0.056). SAS led to significant but variable reduction in intratumoral GSH levels. Six (67%) of 9 patients with PET at follow-up had reduced signal indicative of effect. Complete control was achieved for 3 (27.2%), partial response for 6 (54.5 %), stable disease for 1 (9.1 %) and immediate tumor progression in 1 (9.1 %) of the treated lesions. Median FFTP and PFS were 12.1 (95% CI 1.2 - 7.1) and 4.1 months (95% CI 1.2 - 7.1) compared to 1.6 (95% CI 1.4 - 1.8) and 1.6 (0.9 - 2.3) for controls, p < 0.001 and p = 0.006, respectively. OS was longer for patients responding with compete vs. partial/stable response or progressing disease, 26.0 vs. 10.0 and 7.0 months, respectively, p = 0.017.

CONCLUSION

SAS combined with GKRS was well tolerated with preliminary evidence of anti-tumor response.
P13.16.B TARGETING RBM19 TO ENHANCE RADIOTHERAPY IN GLIOBLASTOMA
Authors: Gong Z , Li D , Cao K , Liu T , Wan Z , Wang H , Gao F , Xu T , Yang Y , Chen Y
Published: October 2024

BACKGROUND

Glioblastoma (GBM) treatment faces challenges due to radioresistance. This study focuses on RNA binding motif protein 19 (RBM19), a protein implicated in crucial cellular functions yet underexplored in enhancing radiosensitivity. Our research aims to elucidate the potential of RBM19 in improving radiotherapy outcomes for glioblastoma patients.

MATERIAL AND METHODS

RBM19 expression in GBM patients and normal brain tissue was analyzed using GEO datasets. The expression of RBM19 and its correlation with patient survival were assessed using clinical and follow-up data from TCGA. In vitro, we manipulated RBM19 expression in U87 and U251 glioblastoma cell lines. The radiosensitivity of cancer cells was determined through colony formation assay, apoptosis, and CCK-8 assay. The comet assay and γH2AX assay were used at different time points to detect the kinetics of DNA damage and repair. Western blot assay was applied to explore the functions of RBM19 on DNA damage response after ionizing radiation, further highlighting its role in DNA damage repair pathway. Co-immunoprecipitation was conducted to study the interaction between RBM19 and CHK1 protein. Xenografts were performed to investigate the in vivo effects of RBM19 on tumor growth.

RESULTS

Differential gene analysis identified RBM19 as consistently upregulated in GBM across multiple GEO datasets. TCGA data analysis revealed a negative correlation between RBM19 expression and overall and disease-free survival in post-radiotherapy GBM patients. In vitro, alterations in RBM19 expression influenced glioblastoma cell viability post-irradiation, knockdown reduced viability and enhanced radiosensitivity, while overexpression had the opposite effect. Comet assays demonstrated that RBM19 modification affects the extent of DNA damage post-irradiation, with knockdown exacerbating DNA damage. Immunofluorescence for γ-H2AX foci confirmed increased DNA damage in RBM19-knockdown cells. Furthermore, RBM19 knockdown significantly increased apoptosis post-irradiation. Western blot analysis showed that RBM19 influences key proteins in the DNA damage repair pathway, potentially affecting therapeutic resistance in glioblastoma cells. Co-immunoprecipitation found interactions between RBM19 and Checkpoint kinase 1 (CHK1) and ataxia telangiectasia and Rad3-related (ATR), again shedding light on its role in DNA damage repair pathways. In vivo experiments demonstrated that RBM19 knockdown extended survival and reduced tumor volume in irradiated glioblastoma-bearing mice. More DNA damage was observed in RBM19 knockdown xenografts.

CONCLUSION

RBM19 may serve as a new molecular target for radiosensitization in glioblastoma. This study provides a new direction for research and a potential therapeutic approach for the radiosensitization of clinical glioblastoma treatments.
P14.02.B A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL OF FOCUSED-ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER DISRUPTION PLUS SYSTEMIC PEMBROLIZUMAB FOR PATIENTS WITH NSCLC BRAIN METASTASES (LIMITLESS)
Authors: Ahluwalia M S , Ozair A , Sahni K S , Sanai N , Sahgal A , McDermott M W , Nwaogu K , Dye L , Woodworth G F , Lipsman N
Published: October 2024

BACKGROUND

The efficacy of systemic therapies for brain metastases (BM) is hindered by the blood-brain barrier (BBB), whose disruption is associated with improved systemic drug delivery. Low-intensity focused ultrasound (LIFU), combined with IV microbubble oscillators, leads to non-invasive disruption of BBB. This can potentially enhance intracranial drug delivery of systemically administered immune checkpoint inhibitors like pembrolizumab. Given that non-small lung cancer (NSCLC) remains the most common etiology behind BM, this randomized controlled trial (RCT) aims to evaluate the safety and efficacy of LIFU-mediated BBB disruption combined with systemic pembrolizumab for NSCLC BM.

MATERIAL AND METHODS

LIMITLESS is an ongoing, prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in a 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting measurable disease criteria as per RANO-BM. Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). Patients undergo pre-treatment brain MRI, followed by IV administration of microbubbles for enhanced sonication effects. MR-guided BBB disruption is then performed using a transcranial 220 kHz LIFU device with real-time acoustic feedback-based power control for maintaining effective microbubble activation. Pembrolizumab is infused immediately after the sonication, and a repeat MRI is done 24-48 hours later to assessment to treatment effects. The primary study outcome is the overall objective response rate (ORR) at 6 months as assessed using RANO-BM criteria. Using a Bayesian design for power analysis, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for a total sample size of N = 96, 64 participants in LIFU and 32 in the control arm, for 80% power using a two-sided chi-square test with an alpha of 0.05. For the upper-bound estimate, ORR of 45% in the LIFU arm and 30% in the control arm, the study needs N = 369 participants: 246 in LIFU arm and 123 in control arm. The secondary outcomes are best objective response rate and median time-to-response per treatment arm. Exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life.

RESULTS

Patient enrollment commenced in 2022 and is ongoing.

CONCLUSION

Findings from this trial will be critical to overcoming the historic challenges presented by the BBB to efficacious CNS drug delivery (ClinicalTrials.Gov Registration: NCT05317858).
P14.04.A A PROSPECTIVE STUDY OF TUMOR-TREATING FIELDS COMBINED WITH SYSTEMIC THERAPY IN RECURRENT GLIOBLASTOMA
Authors: Guo C , Yang Q , He Z , Duan H , Lu J , Ke C , Xie H , Chen Z , Liu R , Zhang X , Mou Y
Published: October 2024

BACKGROUND

Tumor-treating Fields (TTFields) monotherapy was approved for recurrent glioblastoma. However, TTFields combined with systemic therapy has not been well studied in China. This study aims to explore the efficacy and safety of such combination therapy for recurrent GBM.

MATERIAL AND METHODS

This study is a prospective, single-arm, open-label clinical trial (NCT04689087) planning to enroll 40 recurrent supratentorial GBM patients and use TTFields combined with physician chose systemic therapy. Kaplan-Meier survival curve was used to estimate PFS, OS and survival rate. The primary endpoint was 6-months OS rate (OS6). Secondary endpoints were PFS, PFS6 and safety. OS and PFS were computed from the day of initiating TTFields.

RESULTS

Fourty recurrent supratentorial GBM patients was enrolled from July 2020 to May 2023. The average age was 51 and median KPS score was 80. Sixty-eight percent (27/40) of them underwent total resection surgery and 5% (2/40) only experienced biopsy as their newly diagnosed GBM surgery. Eighty-eight percent (35/40) of patients started TTFields when they were first diagnosed as recurrence, while 12.5% (5/40) patients started TTFields at their second-time recurrence or latter. Median time from diagnosis of recurrence to initiating TTFields was 27 days. Median duration time of TTFields was 8.7 months and average compliance of TTFields was 87% (20.9 hours/day). As for molecular biomarkers, 50% (20/40) patients were MGMT protein positive and 32.5% (13/40) were TERT mutant. Chemotherapy was included in the systemic therapy in 80% (32/40) patients, antiangiogenic therapy in 60% (24/40) patients, BRAF inhibitor therapy in one patient and immune checkpoint inhibitor therapy in one patient. At data cut-off date of March 20, 2024, the median follow-up period was 20.8 months. The primary endpoint OS6 was 87.2%, the median OS was 20.2 months (95%CI 11.9-NR). Median PFS was 8.5months (95%CI 6.2-NR). PFS6 was 67.5% while the historical reference of physician’s best choice of active chemotherapy from EF-11 study showed a PFS6 of 15%. Scalp adverse events were the most common AE. Seventy-eight (31/40) of patients experienced grade 1 or 2 scalp adverse events which can be relieved by topical corticosteroids.

CONCLUSION

TTFields combined with systemic therapy showed favorable efficacy and safety in Chinese recurrent GBM patients.
P14.18.A POSTERIOR CRANIAL FOSSA RECONSTRUCTION TECHNIQUE TO REDUCE POSTOPERATIVE PSEUDOMENINGOCELE IN PEDIATRIC PATIENTS OF POSTERIOR FOSSA TUMOR SURGERY WITH SUBOCCIPITAL MIDLINE APPROACH
Authors: Tang M , Chen Y
Published: October 2024

BACKGROUND

Pediatric patients undergoing tumor resection through a suboccipital midline approach carry a high risk of pseudomeningocele and cerebrospinal fluid (CSF) leakage. We describe our experience of eliminating the dead space introduced by the original surgical incision compared to traditional methods to reduce this risk.

MATERIAL AND METHODS

The data of children who underwent tumor resection with a suboccipital midline approach were retrospectively analyzed. The patients were divided into a traditional group and an improved group according to whether the new technique proposed in this study was used. Complications such as pseudomeningocele, meningitis, and hydrocephalus during hospitalization and follow-up were retrospectively analyzed. Univariate and multivariate logistic regression analyses were used to explore the relationship between the use of new technology and postoperative complications. All patients were followed up regularly for 2 weeks, 1 month, and 3 months after surgery.

RESULTS

Our retrospective study identified 111 eligible pediatric patients who underwent tumor resection with a suboccipital midline approach and showed that postoperative complications were lower in the improved group than in the traditional group (39.1% vs 55.4%). This difference is particularly marked in the case of PMC (10.9% vs 27.7%, OR 0.26, p = 0.027). The use of new technology was a protective factor for postoperative PMC, while the use of new technology did not significantly lower the occurrence rate of meningitis and postoperative hydrocephalus. The pathological type of tumor may be related to the occurrence of postoperative PMC, but there was no significant statistical difference (p=0.083).

CONCLUSION

Compared with traditional surgery, eliminating the dead space caused by the primary surgical incision is a simple and feasible technique, which can reduce the incidence of pseudomeningocele.
P16.07.A STUDYING NEUROBLASTOMA TUMOR MICROENVIRONMENT THROUGH A NOVEL PRE-CLINICAL MODEL
Authors: Buxbaum C , Deo A , Manobla B , Levin S , Ash S , Shaked Y
Published: October 2024

BACKGROUND

Neuroblastoma is a pediatric cancer that develops from neural crest cells. It has a dramatically variable course, ranging from very aggressive disease to benign differentiation and even spontaneous regression. In neuroblastoma, a crucial prognostic marker is the distinct cutoff at 18 months of age. Thus, children older than 18 months have a significantly worse prognosis than younger children. This age cutoff was studied thoroughly, but no explanatory mechanism has been found. All current pre-clinical research encompasses models in adult subjects while the development of tumors is greatly impacted by its microenvironment, which varies between young and adult individuals, thus creating disparate biological conditions. Therefore, the development of age-relevant neuroblastoma models is of great interest, especially when age is a major prognostic factor.

MATERIAL AND METHODS

C57BL/6 mice aged 12-days (young) and 8-weeks (adults) were used to reflect the different age groups, where 12-day-old mice correspond to children younger than 18-month. Mice were orthotopically implanted into the adrenal gland with 0.5 million 9464D-luciferase tagged murine neuroblastoma cells. Tumor growth assessment was performed once a week using micro-ultrasound to estimate tumor volume. At the endpoint, tumors were harvested and prepared for histopathological and immune characterization using flow and mass cytometry.

RESULTS

Tumors exhibited divergent growth patterns when comparing young and adult mice. In the initial week following implantation, tumors in young mice showed inhibited growth in contrast to those in adult mice (0.65mm3 vs. 5.44mm3 p=0.005). Following this initial phase, tumors in young mice started to grow rapidly, eventually leading to an equal final tumor load in both groups. The tumor characteristics were notably different between the groups. For example, the tumor immune cell infiltration exhibited a significantly increased number of B cells (3.598 vs. 10.01 p=0.01), CD4 cells (31.2 vs. 41.24 p=0.32) in young mice. Conversely, adults exhibited a higher number of G-MDS’c (32.2 vs. 13.856 p=0.005).

CONCLUSION

Our study reveals a delayed development of neuroblastoma in young mice during the early post-implantation phase. This observation mimics the natural biological behavior of this disease and potentially emulates the spontaneous regression seen in children under 18 months-old. In our investigation of the tumor microenvironment, we analyzed immune cell populations, revealing notable differences between the age groups. Further and updated findings are forthcoming. This study proposes a new approach for neuroblastoma research and potentially for all preclinical studies of pediatric cancer.
P16.12.A PROPERLY TIMED AND EFFECTIVE HYDROCEPHALUS INTERVENTION ENHANCES EFFICACY IN PINEAL TUMOR MANAGEMENT
Authors: Nyalali A M , Li F , Zhang K , Leonard A
Published: October 2024

BACKGROUND

Pineal region tumors continue to pose challenges in their management because of their histological heterogeneity, complex anatomical location, age of presentation, and presentation with obstructive hydrocephalus. Hydrocephalus creates a paradox of management whereby both medical and surgical approaches, their timing, and outcomes are interdependent with that of hydrocephalus. We aimed to determine the more effective intervention approaches for the interdependent management of pineal tumors and the associated hydrocephalus.

MATERIAL AND METHODS

We conducted a retrospective cohort study involving 154 patients diagnosed with pineal region tumors between January 2015 and January 2021 with a minimum follow-up of one year.

RESULTS

About seventy percent (111) of patients with pineal tumors had obstructive hydrocephalus that accounted mostly for the presenting clinical symptoms (76.9 %, p=0.0001). 102 patients were intervened for hydrocephalus with about half (54) also undergoing tumor resection meanwhile the other half received chemotherapy and or radiotherapy as definitive treatments for pineal tumors. Hydrocephalus intervention was performed as primary intervention by external ventricular drainage (15), endoscopic third ventriculostomy (32), ventriculoperitoneal shunt (34), and direct tumor resection (21). Tumor resection as a secondary intervention was performed in 33 patients. Within one year, 14% of patients treated for hydrocephalus had persistent or recurrent hydrocephalus which largely occurred in patients who also had tumor removal (p=0.0001). There was a significant difference among hydrocephalus intervention approaches regarding mean surgical interventions under general anesthesia (p=0.006) and hydrocephalus-related invasive procedures such as subdural lumber puncture and drainage (p=0.016). Among the 154 patients with pineal tumors, 122 (79.2%) required intervention whereby 60 patients (49.2%) underwent tumor resection with or without adjuvant chemoradiotherapy while 62 received definitive chemotherapy and or radiotherapy. Interestingly, the extent of tumor resection was negatively affected by the interval between hydrocephalus intervention and tumor resection (p=0.009).

CONCLUSION

Ventriculoperitoneal shunting, endoscopic third ventriculostomy, and direct tumor resection remain the mainstay intervention options for pineal tumor-associated hydrocephalus. Although direct tumor removal has dual therapeutic potential by resolving hydrocephalus and tumor removal, the procedure itself increases the risk of hydrocephalus persistence or recurrence thus calling for diligently effective planning for hydrocephalus intervention parallel to the medical or surgical alternatives.
P17.02.B BMSCOPE: A SCOPING REVIEW TO CHART THE EVOLVING CLINICAL STUDY LANDSCAPE IN BRAIN AND LEPTOMENINGEAL METASTASIS
Authors: Heywood R , Cheng V , Zakaria R , Burger R , Zucker K , Kannan S , Putra M , Fitzpatrick A , Doherty G , Sanghera P , Jenkinson M , Palmieri C
Published: October 2024

BACKGROUND

Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarises BM/LM clinical studies published globally between 2010 and 2023.

MATERIAL AND METHODS

Eleven electronic databases were searched on 21 June 2021, with an updated search on 21 February 2023. Clinical studies were included if they involved the investigation of a therapeutic intervention in patients with BM and/or LM, and a reported patient outcome. Study-level data was extracted by study authors, including study type, date of publication, country of data collection, number of BM/LM patients in study, primary tumour type and type of therapeutic intervention

RESULTS

48222 studies were identified from the electronic search and 4921 unique studies were eligible for analysis, with increasing numbers of studies (and international collaborations) through the study period. 627 of these publications were clinical trials. Over the study period there was a shift towards later stage clinical trials, predominantly trials of systemic therapy that included BM/LM patients. Despite this, only 29.2% reported intracranial-specific outcomes.

CONCLUSION

In this comprehensive analysis of the BM/LM literature, we chart the evolving landscape of studies involving this previously clinically excluded population. Given the increasing clinical research activity, particularly late-stage systemic therapy trials, it is imperative that consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardised reporting of intracranial-specific endpoints will facilitate evaluation of intracranial efficacy
P17.08.B EFFICACY AND SAFETY OF POSTOPERATIVE HYPOFRACTIONATED RADIOTHERAPY FOR RESECTED BRAIN METASTASES: INSIGHTS FROM A SINGLE-CENTRE EXPERIENCE
Authors: Lucas Calduch A , Macià Garau M , García Expósito N , Plans Ahicart G , Rosselló Gómez A , Fernández Coello A , Vidal Sarro N , Modolell Farré I , Sancho Kolster I , Majós Torró C , Pons Escoda A , Simó Parra M , Velasco Fargas R , Ruíz Domínguez M , Alonso Becerra M , Cifre Serra P , Bruna Escuer J
Published: October 2024

BACKGROUND

The addition of radiotherapy (RT) improves local control after surgical resection of brain metastases (BM). The classical whole brain RT has been replaced by different types of focal irradiation. Hypofractionated stereotactic radiotherapy (HFSRT) is an effective option, but the procedure implies several uncertainties related to the volumes contouring, that may generate the risk of local control fail and/or the development of radionecrosis (RN) of the cavity wall.

MATERIAL AND METHODS

We have retrospectively reviewed the outcome of patients with surgically resected BM that have been adjuvantly treated with HSRT in our centre, during the period from 2015 to August 2023.

RESULTS

83 patients have been identified. Median age was 58 (34-79). Males comprised 54% and 46% were females. Lung cancer was the most frequent primary tumour (51%), followed by breast (17%) and melanoma (15%). BM diagnose was synchronous to the primary in 36% of patients. The targeted BM was single in 87% of cases, and its median maximum diameter was 36 mm (13-75). Surgery was complete in 82% of cases. Clinical conditions before RT were favourable in 87% of patients (Karnofsky index ≥70) and DS-GPA (diagnosis-specific graded prognostic assessment) was ≥3 in 47%. Different ways of contouring the planning target volume (PTV) were identified, being the addition of 2 mm to the cavity the most frequent (44%). The median PTV was 29,9 cm3 (1,17-138,8). Regarding radiotherapy scheme, 27 Gy in 3 fractions were prescribed in 36% of patients; however, 30 Gy in 5 or 6 fractions were also frequently used (32%). Tolerance was excellent, except for one patient with Grade 3 seizures. The median interval between surgery and HFSRT was 56 days (r 45-69). After a median follow-up of 19 months, local control in surgical bed was obtained in 92,7% and 89,2% of cases at 1 and 2 years respectively. RN was observed in 15,6% of cases, with only 2,4% of grade 3. Cranial and extracranial progressions were seen in roughly half of patients (53% and 53,7% respectively). Specifically, leptomeningeal spread was seen in 26,5% of patients. Overall survival was 54% at 2 years.

CONCLUSION

HFSRT appears as a highly effective option to ensure local control after surgery in BM. Despite the uncertainties related to contouring and the high number of large cavities, the use of fractionated schemes allows a low incidence of serious RN.
P17.10.A GENOMIC PROFILING OF CEREBROSPINAL FLUID CTDNA TO CHARACTERIZE MOLECULAR FEATURES AND MONITOR INTRACRANIAL RESPONSES OF OSIMERTINIB-RESISTANT NON-SMALL CELL LUNG CANCER PATIENTS WITH LEPTOMENINGEAL METASTASES
Authors: Li X , Hua Y , Xin Y , An J , Ding X , Wei F
Published: October 2024

BACKGROUND

Leptomeningeal metastasis (LM) indicates an unfavorable prognosis in non-small cell lung cancer (NSCLC). Due to the blood-brain barrier, plasma is not an ideal medium to evaluate osimertinib resistance mechanisms in patients with LM. This study aimed to use cerebrospinal fluid (CSF) as a source of ctDNA for characterizing molecular features and monitoring intracranial responses from patients with leptomeningeal metastases who progressed on osimertinib.

MATERIAL AND METHODS

From Jan 2020 to Nov 2022, 65 patients with advanced NSCLC, including 30 osimertinib-treated patients, 7other TKI-treated patients, and 28 treatment-naïve patients, in Beijing Tiantan Hospital were enrolled in this study. CSF obtained via lumbar puncture was used for targeted sequencing and cytologic analysis. In parallel, paired plasma from 37 patients was also subjected to targeted sequencing.

RESULTS

Among 65 patients, the overall positive rate of CSF ctDNA was 77% (50/65), 94% (32/34) in patients with LM, and 58% (18/31) in patients with brain parenchymal metastases (p=0.0008). EGFR alterations were present in the CSF of 96% of patients who progressed on osimertinib, including L858R (64%), copy number gain (29%), exon 19 deletion (18%), T790M (11%), L861Q (7%), G719X (7%) and L747X (7%). EGFR-independent intracranial resistance mechanisms identified in CSF included activation in phosphatidylinositol 3-kinase (PI3K) pathways, RAS-mitogen-activated protein kinase (MAPK), cell-cycle gene alterations, MET amplification, oncogenic fusions. The VAF identified by CSF ctDNA was also higher than that of plasma ctDNA (15.5% versus 4.6%, P<0.001). In patients with LM, 75% of alterations were detected exclusively in CSF ctDNA and 13% in plasma ctDNA. The higher proportion of CSF ctDNA private mutations observed in patients with LM compared to those with PM. Serial surveillance of CSF ctDNA in 6 cases of LM patients treated with osimertinib found that the VAF of CSF ctDNA showed a highly consistent trend with the tumor cell fraction of cytology.

CONCLUSION

For EGFR-mutated NSCLC patients with LM, liquid biopsy of CSF is more sensitive than plasma to characterize osimertinib-resistant mechanisms and guide follow-up treatment. Serial surveillance of CSF ctDNA dynamics may reflect the intracranial tumor responses, which still needs to be validated in a large sample size.This study was supported by Beijing Municipal Education Commission-Beijing Natural Science Foundation Union Program(KZ202010025046), Beijing Natural Science Foundation (NO. 7242007) and Beijing Xisike Clinical Oncology Research Foundation(Y-2021AST/zd-0127).