tbuckley/cabot-search huggingface dataset:
P12.14.A PROFILING THE PERIPHERAL IMMUNE RESPONSE FOLLOWING NEUROSURGICAL RESECTION OF GLIOBLASTOMA
Authors: A B Patterson, A M Zeitlberger, O Bozinov, B Ludewig, N B Pikor, M C Neidert
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND To enhance the efficacy of immunotherapy against glioblastoma, we aim to develop a strategy for the ex-vivo expansion of tumor antigen-specific T cells, followed by an adaptive T cell transfer directly into the tumor cavity. This pilot project, investigating the peripheral immune response, will address the potential release of tumor antigens into the periphery during surgery by examining if there is an increase in the number of antigen-specific T cells following the resection. MATERIAL AND METHODS Patients are enrolled in the study before surgery and peripheral blood mononuclear cells (PBMCs) are isolated from venous blood collected as a baseline time point. A tissue lysate is created from bulk tumor tissue during surgery as the source of antigens for later cell stimulation experiments. A single cell suspension made from tumor tissue will provide two populations of cells: “normal” and “tumor-enriched” to validate the use of lysate-derived antigens. Patients are requested to return to the clinic 2, 4, and 12 weeks after surgery where PBMCs are isolated and viably frozen until all time points are collected. The tumor lysate, cells, and PBMCs are co-incubated and the expression profiles of PBMCs are examined via flow cytometry using a high-dimensional 30 marker panel. FACS-sorted antigen-specific T cells will further be profiled via single cell 5’ sequencing (10x Chromium V3) and functionally tested using autologous patient-derived organoid killing assays. RESULTS Preliminary data using longitudinal blood sampling shows that autologous lysate elicits activation of CD8+ T cells in patient PBMCs, especially 2 weeks after surgery, according to several classical T cell activation markers. Co-incubation conditions have been examined to determine the kinetics of CD137 expression, with 12 hours of incubation revealing the highest expression of CD137 over 48 hours. Concentrations of tumor lysate have also been compared between 100ng/mL and 3µg/mL. Interestingly, lower protein concentrations have shown higher activation of T cells. Lysate protein concentrations, cell ratios, and co-incubation times are tested in patient samples to ensure that the highest expression of CD137+ T cells is captured and analyzed. CONCLUSION The completion of this study will determine the best clinical time point for T cell collection of patient PBMCs for antigen-specific T cell expansion and subsequent administration of the immunotherapy directly into the tumor cavity.
P12.20.B [18F]FDG PET/CT BRAIN SCAN IN THE EVALUATION OF NEUROTOXICITY IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA TREATED WITH CAR-T
Authors: S Asadurova, C Lorenzo, M Simó, H Ariño, A Vilaseca, A Zabalza, G Iacoboni, C Carpio, P Barba
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurotoxicity is one of the serious and life-threatening complications of CAR-T treatment in patients with diffuse large B-cell lymphoma. Our objective is to identify the findings in brain PET/CT, their evolution over time, and their clinical correlation. We also aim to compare the sensitivity of PET/CT with magnetic resonance imaging (MRI). MATERIAL AND METHODS This prospective study includes 33 patients with diffuse large B-cell lymphoma treated with CAR-T therapy. Whole-body and brain [18F]FDG PET/CT scans were performed pre-treatment and 30 days post-therapy. In cases of suspected immune effector cell-associated neurotoxicity syndrome (ICANS), urgent structural imaging (CT or MRI) and [18F]FDG PET/CT brain scans were conducted, among other tests. RESULTS The mean age was 62±12 years, with a male-to-female ratio of 19:14. 70% of patients (23/33) developed grade 1, 2, or 3 cytokine release syndrome (CRS). 27% (9/33), all with prior CRS, showed symptoms of ICANS (3/9 G1, 3/9 G2 and 3/9 G3 ICANS). The most common symptoms were tremor, disorientation, and bradypsychia, starting on average on the 7th day post-infusion (range 1 to 10). Urgent [18F]FDG PET/CT brain scans were performed on 7 of the 9 ICANS patients, showing diffuse cortical hypometabolism compatible with encephalopathy in 5 (5/7) and no significant findings in 2/7. At the 30-day post-treatment evaluation, complete normalization was observed in 2/5 patients, improvement with persistent mild global cortical hypometabolism in 2/5, and one patient (1/5) died before the 30 days (with G3 ICANS and severe cortical and subcortical hypometabolism on PET imaging). Urgent brain MRI was performed on the 7 patients with ICANS and urgent [18F]FDG PET brain scans, and it was normal in 5/7 and pathological in 2/7 (both with grade 3 ICANS). CONCLUSION [18F]FDG PET/CT brain scan is useful for the diagnosis and follow-up of patients with CAR-T related neurotoxicity (ICANS) and shows greater sensitivity than MRI. Future studies should determine the relationship between acute phase PET findings and long-term prognosis.
P17.06.B CSF DRAINAGE IN LEPTOMENINGEAL DISEASE: SURGICAL AND SURVIVAL OUTCOMES IN VENTRICULO-PERITONEAL SHUNT VS. RICKHAM RESERVOIR PATIENTS
Authors: O T Alhalabi, L Klein, C Büsken, A Mellal, D Wasilewski, C Buszello, G Cossu, I Y Eyüpoglu, A W Unterberg, P Vajkoczy, M Messerer, M Misch, S M Krieg, T A Juratli, A Younsi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Leptomeningeal disease (LMD) usually represents a terminal condition that can cause symptomatic hydrocephalus. With improved survival rates under systemic therapy, the role of cerebrospinal fluid (CSF) drainage via ventriculo-peritoneal shunt (VPS) or Rickham reservoir placement for symptom control is gaining more relevance. This study aimed to describe surgical and survival outcomes of hydrocephalic LMD patients after surgical drainage in a contemporary cohort. MATERIAL AND METHODS A multi-center retrospective analysis of adult patients with VPS or Rickham reservoir placement for CSF drainage in the presence of LMD with malresorptive hydrocephalus between 2017 and 2022 was performed. Patients with occlusive hydrocephalus were excluded. Clinical, surgical and survival data were collected and compared. RESULTS A total of 119 patients with a median age of 53 (42-77) years (40 males, 79 females) were included. Of those, 64 underwent VPS (54%) and 55 (46%) Rickham reservoir placement. The most common underlying oncological conditions were breast cancer (n=67, 56%) and non-small cell lung cancer (n=25, 21%). The median time between primary tumor and LM diagnosis was 23 months (0 to 180 months) and 44 patients (37%) had end-stage disease at primary tumor diagnosis. Moreover, 79 (66%) patients showed solid intraparenchymal cranial metastases, for which only 20 patients (17%) had received surgical resection. Most patients (n=95, 80%) presented with symptoms of intracranial hypertension, which were relieved in 79% (n=51/64) after surgery. Compared to VPS placement, Rickham reservoirs were associated with lower complication (11% vs. 30%, p=0.01) and revision (9% vs. 23%, p=0.049) rates. Median overall survival from surgery was 90 (23 -148) days, and longer in VPS patients (107 days) compared to Rickham patients (83 days). However, this difference did not reach statistical significance (p=0.512). CONCLUSION While surgical CSF drainage in patients with LM disease relieves symptoms of intracranial hypertension in many cases, median survival remains expectedly low. Compared to Rickham reservoir placement, VPS bears higher rates of complications and revisions without a clear survival benefit. Nevertheless, decision-making regarding surgical CSF drainage and more importantly VPS or Rickham reservoir placement in LMD patients retains an individual and palliative nature.
P17.04.B CIRCULATING TUMOR CELL NUMBERS IN CSF HAVE ADDED PROGNOSTIC VALUE IN PATIENTS WITH LEPTOMENINGEAL METASTASES
Authors: E van Kessel, N Woerdman, D Pluim, B Milojkovic, D van den Broek, D Brandsma
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Approximately 10% of patients with solid tumors develop leptomeningeal metastases (LM). Median survival rates are low in patients with LM but can vary significantly and are dependent on various patient-, tumor-, and treatment-related factors. Advanced techniques for circulating tumor cell enumeration in cerebrospinal fluid (CSF) can help in diagnosing patients with LM, but they may also have value in prognostication. Our aim was to investigate whether circulating tumor cells (CTCs) in CSF are of added value in survival prediction in LM patients. MATERIAL AND METHODS We performed a single-center retrospective study in a cohort of patients with LM from an epithelial tumor, diagnosed at the Netherlands Cancer Institute - Antoni van Leeuwenhoek, a tertiary comprehensive cancer center. CTCs in CSF were enumerated by an Epithelial Cell Adhesion Molecule (EpCAM - based immunoflow cytometry method) at the diagnosis of LM. The added prognostic value of CTCs in CSF on top of known clinical prognostic factors for LM, was assessed. We compared Cox proportional hazards regression models with and without CTCs by means of loglikelihood ratio tests (LRT) and discriminative performance measures. RESULTS We included 103 eligible patients who were diagnosed with either possible (n=10), probable (n=7), or definitive LM (n=86) according to EANO-ESMO guidelines, with a median survival of 129 days. All patients with possible LM at diagnosis, were found to actually have LM during clinical and radiological follow-up. CTCs in CSF were of significant added prognostic value upon the following known predictors of LM; gender, age, WHO performance score, brain metastases, primary tumor type, targetable driver mutation, systemic progression at diagnosis of LM and switch of systemic therapy. This was indicated by a loglikelihood ratio test with a p-value of ≤ 0.01 and an Area Under the Curve (AUC) of 0.723 (with CTC) versus 0.710 (without CTC). Sensitivity analyses in subgroups with only patients with definitive or probable LM showed similar results. Additionally, the median amount of CTCs differed significantly between the following survival groups: &amp;lt; 6 weeks: 103.9 CTCs/ml; 6 weeks to 6 months: 41.3 CTCs/ml; &amp;gt; 6 months: 5.8 CTCs/ml, with ANOVA p-value =0.031. CONCLUSION Our findings indicate that the number of CTCs in CSF, as measured by EpCAM immunoflow cytometry, is of additional prognostic value to other well-known predictors of survival in LM. The number of CTCs in CSF should be taken in account when assessing the prognosis of patients with LM of solid tumors.
P17.07.A DIRECT COMPARISON OF LUNG-GPA AND LABBM PROGNOSTIC SCORES FOR PATIENTS WITH LUNG CANCER BRAIN METASTASES
Authors: O Furman, S Keret, D Limon, B Waissengrin, A Bittan, D T Blumenthal, F Bokstein, I Wolf, L Zach
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Brain metastases (BM) are the most common malignant CNS tumors in adults, associated with decreased survival and severe impairment to quality of life. The majority of BM originate from lung cancer (40-50%), where availability of new drug therapies calls for personalized risk-benefit calculations. While several prognostic tools were developed to support therapeutic decision-making in the specific context of BM detection, our experience in the clinic suggests none is currently used routinely. MATERIAL AND METHODS We compared the predictive capabilities of two different prognostic scores on a retrospective cohort of 90 lung cancer patients treated for BM at the Tel Aviv Sourasky Medical Center. Both scores were computed for each patient. Lung-GPA score is based on age, Karnofsy performance status (KPS), number of BM, number of extra-cranial metastases and molecular features when relevant (for NSCLC patients, EGFR/ALK mutations, PD-L1 expression). LabBM score is based on levels of hemoglobin, albumin, CRP, LDH and platelets in blood tests taken at BM diagnosis. RESULTS Median age at diagnosis was 67.1 (range 36-88), 43 patients were female, mean number of BM was four (range 1-10), 79 patients had NSCLC, of which 15 (18.9%) had confirmed EGFR/ALK mutations, and 11 had SCLC. Median survival was 6.8 mo (range 0.5mo-103mo). Survival rates at 3mo, 6mo, and 12mo were 73%, 51%, and 40%, respectively. Both scores were significantly predictive of OS at these times, and direct comparison between them using ROC analysis revealed no differences in predictive ability for survival at 3mo (0.7 for LabBM and 0.67 for Lung-GPA); at 6mo (0.7 for LabBM and 0.74 for Lung-GPA) and at 12mo (0.61 for LabBM and 0.71 for Lung-GPA). CONCLUSION In a real-world cohort of patients with lung cancer BM we find that Lung-GPA score and LabBM score both show a similar prognostic ability. Future studies should examine whether predictive scores could improve by use of patient data currently not captured by either score, such as treatment response or neuroimaging-based features.
P12.19.A UNVEILING SYNERGISTIC STRATEGIES: CRISPR-GUIDED OPTIMIZATION OF L19-TNF IMMUNOCYTOKINE THERAPY IN GLIOBLASTOMA
Authors: I Sakic, E Uijttewaal, R De Luca, E Puca, M Weller, D Neri, U Elling, T Weiss
Journal: Neuro-Oncology (2024)

Abstract 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.
P17.03.A CASE REPORT: CLEAR CELL CARCINOMA KIDNEY CANCER WITH BRAIN METASTASIS TREATED WITH KETOGENIC METABOLIC THERAPY
Authors: M Zapata, A Acevedo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Kidney cell carcinoma corresponds to the 14th cause of incidence in cancer in the world. Mortality is about 12.8 ASR in USA and 3.8 in Colombia. Metastatic disease corresponds to 14% of the patients, having worse prognosis compared to those patients with local or locally advanced disease. We want to share our experience of a patient with brain metastatic disease in clear cell carcinoma of the kidney, treated with TKI, IO and ketogenic metabolic therapy (KMT) with outstanding results. Case summary: 65-year-old female, first diagnosed in 2011 with a clear cell carcinoma stage III, due to pT3aNxM0 at diagnosis, managed with radical nephrectomy. After this patient was 3 years free of disease, she developed in 2014 a meta-chronic papillary thyroid carcinoma stage III, due to T1N1M0, managed with total thyroidectomy plus nodal dissection, and adjuvant iodine therapy with 100 mci. In 2019 the patient presented a pulmonary new lesion, with confirmation of clear cell carcinoma, and was treated with pazopanib due to poor tolerance to sunitinib. In September 2022 the patient presented four lesions in both cerebral hemispheres, mainly involving the right frontal lobe as well as the mesial region of both temporal lobes. Neurosurgery performed a biopsy, confirming clear cell carcinoma. The patient received IMRT holoencephalic over 5 daily sessions. We started treatment with nivolumab in September 2022. After receiving 5 cycles of IO, the patient consulted due to new onset of convulsion, documenting edema of the main lesion, and neurologic worsening. After evaluating the case, we started anticonvulsive treatment and a short period of steroid, with recovery of her function. We used this treatment for around 10 days, and continued immunotherapy and anti-convulsant therapy. In January 2023, we started KMT, at a relation 3:1, measuring ketones and neurologic status constantly. After confirmation of ketones in urine or blood, we started adjustment of therapy to improve compliance. In July 2023, the patient didn’t require assistance to medical appointments, was capable of being free of anticonvulsive therapy, and her cognitive functions were all preserved. In January 2024, the patient remained with partial response, and dietary supplementation (ketovie) was stopped. CONCLUSION This case supports the use of KMT in clear cell renal carcinoma scenarios, in which it can be associated with a synergistic effect to ITK and/or immunotherapy, as well as radiotherapy modalities, improving progression-free survival and functional improvement without increasing toxicity.
P12.17.B SHAPING THE IMMUNE LANDSCAPE - ROLE OF NEO(ADJUVANT) CHECKPOINT INHIBITION IN RECURRENT GLIOBLASTOMA
Authors: H Krenzlin, A Dauth, F Corr, E Wagner, H Ubbens, C Sommer, B Alessandri, F Ringel, N Keric
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND In recurrent glioblastoma treatment options are limited. Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. Although ineffective as adjuvant monotherapy in glioblastoma, Pembrolizumab, an anti-PD-1 monoclonal antibody, might be valuable during a neo-adjuvant window of opportunity and in addition to alkylating chemotherapy in patients with recurrent glioblastoma. METHODS In this study, 10 patients with recurrent IDH wild-type glioblastoma (CNS WHO grade 4) scheduled for surgical debulking were treated with Pembrolizumab prior to resection. CPI was continued together with Lomustine/CCNU after surgery. Patients with resection and adjuvant CCNU alone served as controls. Eligibility criteria included Eastern Conference Cooperative Oncology Group (ECOG) Score ≤2, first line therapy with at chemo-radiotherapy, unequivocal evidence of tumor progression. Patients received pembrolizumab 200 mg intravenous infusions 14 ± 5 days prior to- and every three weeks after re-surgery additionally to CCNU (up to six-week cycles). NCI-CTCAE 5.0 was used to evaluate adverse events. To examine CPI induced changes, transcriptome sequencing (RNAseq), T-cell receptor sequencing in tumor samples and detection of inflammatory cytokines (Il-1a, Il-1b, Il-6, Il-8, TNF-a, IFN-y, MCAF, GM-CSF) in blood using ELISA and qPCR, was performed. RESULTS Median age was 58.7 years (43-74 years) in controls and 54.9 years (33-68 years) in those with neo(adjuvant) CPI. Female:male ratio was 4:1. Complete resection was achieved in 70.0%, gross total resection in 10.0%, partial resection in 10.0% and biopsy in 10.0%. A total of 10 neoadjuvant and 24 adjuvant cycles of CPI were given. PFS (12.9±3.6 months; p=0.001) and OS (32.4±6.5 months; p=0.028) was improved in patients with neoadjuvant CPI compared to controls. Fever associated with CPI occurred in 2 patients. No severe adverse occurred. Neo(adjuvant) CPI led to increased IFN-y serum levels (p=0.0057). Using NGS analysis, improved OS was associated with higher number of tumor infiltrating NK cells (p = 0.0264), M1 macrophages (p = 0.029) and TCR clonality (p = 0.0002). NK cell infiltration was higher in patients treated with neoadjuvant CPI (p=0.001). However, no longitudinal transcriptome changes occurred between primary and relapse regarding the immune contexture, TCR diversity (p=0.69) or clonality (p=0.85). CONCLUSION Neoadjuvant checkpoint inhibition is well tolerated and associated with distinct changes to tumor transcriptome and immune milieu leading to prolonged overall survival. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may represent a more efficient approach to the salvage treatment of this uniformly lethal tumor.