bluuebunny/crossref_metadata_2025_split huggingface dataset:
RADT-39. CENTRAL NERVOUS SYSTEM BRIDGING RADIOTHERAPY (CNS-BRT) ACHIEVES RAPID CYTOREDUCTION PRIOR TO CAR T-CELL THERAPY FOR AGGRESSIVE B-CELL LYMPHOMAS
Authors: Cederquist Gustav , Schefflein Javin , Devlin Sean , Shah Gunjan , Shouval Roni , Hubbeling Harper , Tringale Kathryn , Fregonese Beatrice , Hajj Carla , Boardman Alexander , Dahi Parastoo , Lin Richard , Ghione Paola , Salles Gilles , Perales Miguel-Angel , Palomba M Lia , Falchi Lorenzo , Scordo Michael , Grommes Christian , Yahalom Joachim , Imber Brandon 
Published: November 2024

Abstract

BACKGROUND
CAR T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extra-cranial lymphoma to improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that CNS-BRT would achieve similar, significant cytoreduction prior to CART for CNSL.

METHODS
We analyzed CNSL patients with non-Hodgkin B-cell lymphomas who received CNS-BRT prior to commercial CART. Best CNS response post-CART was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or RANO for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was calculated as change in lesion size prior to CART.

RESULTS
Twelve patients received CNS-BRT, with median follow up of 11.8m (IQR: 8.5–21.9). Ten had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All ten CNSL patients had progressive disease at the time of CNS-BRT. RT targets included whole brain (n=3), involved site (partial) brain (n=4), involved site spine (n=4), and orbits (n=1) with median dose 24Gy (range: 15-33). 1/12 patients experienced grade ≥3 cytokine release syndrome (CRS), and 3/12 patients experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS). CNS-BRT achieved a 74.0% (95%CI: 62.0–86.0) mean reduction in lesion size from baseline (p=0.014) at a median of only 12d from BRT completion and pre-CART infusion. Best CNS response included 8 complete responses (CR), 1 partial response (PR), and 1 progressive disease (PD). Three patients experienced CNS relapse outside the BRT field for a 12-month estimated risk of CNS progression post-CART of 20.0% (95%CI: 3–49).

CONCLUSIONS
Early data suggest CNS-BRT achieves rapid cytoreduction and favorable CNS response. The rates of severe CRS/ICANS were similar to comparison series of CNSL patients treated with CART without BRT suggesting an acceptable safety profile. Our data support further study of BRT as a bridging strategy for CNSL-directed CART.
RADT-40. EVALUATION OF SMALLER CLINICAL TARGET VOLUMES AND PATTERNS OF PROGRESSION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA TO INFORM FUTURE DIRECTIONS IN RADIATION TREATMENT PLANNING
Authors: Hill Jordan , Tan Yujue , Tjong Michael , Youssef Gilbert , Aizer Ayal , Tanguturi Shyam , Shi Diana , Haas-Kogan Daphne , Huang Raymond , Wen Patrick , Rahman Rifaquat 
Published: November 2024

Abstract

BACKGROUND
NRG Oncology Group guidelines recommend a clinical target volume (CTV) including generous expansions and incorporation of T2/FLAIR to account for potential tumor infiltration for glioblastoma patients, though smaller CTV expansions may be feasible. We retrospectively reviewed a large cohort of GBM patients to characterize patterns of recurrence and to assess the potential for smaller CTV margins.

METHODS
312 consecutive adult patients with histologically confirmed diagnosis of glioblastoma treated with radiation therapy and temozolomide at a single institution were included in this study. All relevant clinical and pathological data was retrieved from local electronic medical records. MRIs from four timepoints 1) Pre-operative, 2) post-operative, 3) post-radiation and 4) time of progression were reviewed and fused with each other with rigid registration. We created a gross tumor volume including the resection cavity and residual enhancing tumor (GTV-GAD) and a GTV which included the GAD-GTV and pre-radiation T2/FLAIR signal (GTV-FLAIR). Multiple CTV expansions were applied to the GAD-GTV and FLAIR-GTV to evaluate coverage of subsequent progressive disease.

RESULTS
We evaluated 312 patients with a median age of 59.8 (range 20-93), 59% male, 61% KPS ≥ 90, 49% underwent gross total resection (51% subtotal resection/biopsy), 43% methylated and 57% unmethylated. CTV expansions of 2 cm, 1.5 cm, 1 cm, 0.5 cm, and 0 cm from GTV-GAD would have covered the epicenter of recurrent tumor in 90.7%, 88.1%, 84.6%, 77.5%, and 53.5% of cases respectively. CTV expansions from GTV-FLAIR of 2 cm, 1.5 cm, 1 cm, 0.5 cm, and 0 cm would have covered the epicenter of recurrent tumor in 93.5%, 92.6%, 91.3%, 88.1%, and 78.8% of cases respectively. On multivariable analysis, GAD-GTV and FLAIR-GTV volume were not associated with progression-free or overall survival(P&gt;0.05).

CONCLUSION
Based upon our analysis, smaller treatment volumes could represent an opportunity to reduce treatment-related morbidity without compromising clinical outcomes.
RADT-45. INTEGRATION OF FUNCTIONAL MAGNETIC RESONANCE IMAGING INTO STEREOTACTIC RADIOSURGERY PLANNING TO REDUCE SYMPTOMATIC RADIATION NECROSIS
Authors: Gui Chengcheng , Jenabi Mehrnaz , Daly Jillian , Gillick Claire , Bradley Teresha , Sze Emily , Maldonado Ruth , Tiwari Akhil , Stember Joseph , Mankuzhy Nikhil , Yamada Yoshiya , Pike Luke , Pasquini Luca , Peck Kyung , Ballangrud-Popovic Åse , Holodny Andrei , Imber Brandon 
Published: November 2024

Abstract

BACKGROUND
Radiation necrosis (RN) is a common complication of stereotactic radiosurgery (SRS). Functional magnetic resonance imaging (fMRI) localizes eloquent cortical areas for neurosurgical planning but is seldom applied to SRS. We explored the relationship between symptomatic RN and functional neuroanatomy on fMRI. We evaluated the potential benefit of reducing radiation dose to functional areas.

METHODS
From 2011 to 2022, patients with an fMRI within 3 months of SRS for resected or unresected brain metastases (BM) were included. The BM nearest to the primary motor, language, or visual cortices was designated as the index BM. The functional area on fMRI nearest to the index BM was designated as the fOAR. Focally symptomatic RN (FSRN) was defined as radiographic RN alongside new or worsening focal neurologic symptoms consistent with the fOAR. Patients treated with 5-fraction SRS and modern planning techniques after 2013 were included in the dosimetric analysis. Associations between fOAR dose and FSRN were evaluated with logistic regression. SRS replanning was performed to determine if fOAR dose could be reduced without sacrificing target coverage.

RESULTS
Among 94 patients, 82% received SRS postoperatively, and 71% received 5-fraction SRS. fOARs included the primary motor (77%), language (19%), and visual (2%) cortices. Of 20 patients with radiographic RN, 20% were neurologically asymptomatic, 20% had anatomically unrelated neurologic symptoms, and 60% had FSRN. The dosimetric analysis included 39 patients. The fOAR volume receiving a single-fraction equivalent dose ≥14 Gy (V14Gy) was associated with FSRN at 18 months post-SRS (OR=6.8/mL, p=0.05). Replanning reduced fOAR V14Gy in all cases. The mean reduction was 28%.

CONCLUSION
Neurologic symptoms of SRS-induced RN reflect nearby functional neuroanatomy on fMRI. Dose reduction to functional areas while maintaining target coverage is consistently achievable and may mitigate symptomatic RN. Integrated fMRI-based SRS planning may protect neurologic function when treating tumors near eloquent areas.
RADT-47. CLINICAL OUTCOMES AFTER SURGICAL RESECTION OF BRAIN METASTASES IN SMALL CELL LUNG CANCER PATIENTS
Authors: Qureshi Tanya , Zureick Andrew , McCall Neal , Wilhite Tyler , Wilke Christopher , Burns Timothy , Hadjipanayis Costas , Burton Steven , Choi Serah 
Published: November 2024

Abstract
Small cell lung cancer (SCLC) has a high propensity to metastasize to the brain. Radiotherapy is the primary treatment for SCLC brain metastases. Whole brain radiotherapy (WBRT) has been the standard of care, but recent studies show similar overall survival (OS) in patients treated with upfront stereotactic radiosurgery (SRS). Surgery does not typically have a role in SCLC although it can provide relief of neurologic symptoms and pathologic diagnosis. We sought to determine the clinical outcomes of patients who underwent surgical resection of SCLC brain metastases. A retrospective chart review of SCLC patients treated at UPMC from 2010 – 2022 was performed. OS after resection was estimated using the Kaplan-Meier method with log-rank test. 4,213 patients were diagnosed with SCLC, of which 715 patients (17%) had synchronous brain metastases at initial diagnosis. Forty patients underwent resection of SCLC brain metastases, all of whom were symptomatic. The median diameter of the resected brain metastases was 3.8 cm (range 1.7 – 8 cm). Seventy-five percent (n=30) had resection of synchronous brain metastases and 25% (n=10) had resection of metachronous brain metastases. Median OS for the surgical cohort was 13.6 months (interquartile range (IQR), 3.4 – 21.9 months). Patients with metachronous and synchronous brain metastases had median OS of 6.8 months (IQR, 2.8 – 24.6 months) and 14.3 months (IQR, 3.6 – 20.4), respectively. Of patients with synchronous brain metastases (n=30), 53% (n=16) received post-operative WBRT, 40% (n=11) received post-operative SRS and 10% (n=3) died within 7 weeks of surgery. Median OS of patients with synchronous brain metastases treated with WBRT and SRS were 11.9 months (IQR, 3.8 – 21.7) and 19.0 months (IQR, 14.6 – 30.3), respectively, and the difference was not statistically significant (p=0.53). Surgery for SCLC brain metastases is uncommon. Patients who received SRS versus WBRT post-operatively for synchronous brain metastases had no difference in OS.
RADT-49. IMPACT OF SHORT COURSE RADIOTHERAPY IN REDUCING LYMPHOPENIA IN PATIENTS WITH GLIOBLASTOMA (SAGA STUDY)
Authors: Campian Jian , Zhang Chaocai , Porter Alyx , Johnson Derek , Trifiletti Daniel , Peterson Jennifer , Vora Sujay , Sener Ugur , Ruff Mike , Mahajan Anita , Sarkaria Jann N , Brown Paul , Laack Nadia , Kowalchuk Roman O , William G Breen 
Published: November 2024

Abstract

INTRODUCTION
Lymphopenia attributed to postoperative chemoradiotherapy (CRT) can accelerate tumor recurrence and contribute to poor prognosis in GBM. We hypothesize that short course (1-2 weeks) CRT can mitigate lymphopenia compared to standard course and may provide immune benefits for future combination therapy.

METHODS
GBM patients were randomized on a multi-site phase II study comparing short course (35Gy/5Fx or 40Gy/10Fx depending on target volume) (Arm A) versus standard dose fractionation (60Gy/30Fx or 40Gy/15Fx, Arm B). All patients received concurrent and adjuvant temozolomide (TMZ). This unplanned interim analysis evaluates changes of absolute lymphocyte count (ALC), CD4 and CD8 prospectively at 3-timepoints: baseline (prior to CRT), end of CRT, and 1-month post-CRT.

RESULTS
To date, 72 patients enrolled (34 Arm A, 38 Arm B). Median age 66 (35-86), ECOG 0-2. Patients characteristics as followed in Arm A vs. Arm B, respectively: female 47% vs. 42%, MGMT promotor methylated 31% vs. 34%, steroid use 46% vs. 45%, ALC 1310 cells/mm3 (330 –9730) vs. 1480 (750 –7750), CD4 531 cells/mm3 (86 –1368) vs. 662 (318 –1671), and CD8 151 cells/mm3 (56 –940) vs. 272 (68 –875). Lymphocytes data were collected in 49 patients (21 Arm A, 28 Arm B). There were signficantly fewer reductions of ALC, CD4 and CD8 in Arm A. Median ALC changes were 95% and 99% of baseline (Arm A) vs 52% and 61% of baseline (Arm B) at the end of CRT and 1-month post-CRT, respectively (p&lt;0.01). Median CD4 changes 93% and 96% of baseline (Arm A) vs 51% and 49% (Arm B), and median CD8 changes 97% and 98% of baseline (Arm A) vs 57% and 71% (Arm B) at the end of CRT and 1-month post-CRT, respectively (p&lt;0.05).

CONCLUSIONS
This interim analysis suggests that short course RT could reduce treatment-related lymphopenia and immune suppression compared to standard RT, thus could be potentially beneficial to combine with immunotherapy.
RADT-50. CLINICAL OUTCOME OF DAILY 5-FRACTIONATED GAMMA KNIFE RADIOSURGERY FOR LARGE BRAIN METASTASES
Authors: Jun Juhee , Kim Young-Hoon 
Published: November 2024

Abstract

INTRODUCTION
With the introduction of the Gamma Knife Icon, hypo-fractionated Gamma Knife radiosurgery (GKRS) for large brain metastases (LBMs) is beginning to be performed. This study aimed to assess the clinical outcome and risk of the daily 5-fractionated GKRS for LBMs.

METHODS
A total of 100 patients who underwent 5-fractionated GKRS for LBMs (&gt; 14cm3) were enrolled. Forty-six were male patients, and the median age was 60 years. Most common primary cancer sites were lung (41 non-small cell cancers), breast (24), and kidney (14). The median tumor volume was 22cm3 (14 – 69cm3) and marginal dose was 35Gy (50% isodose line) in 5 fractions. Median follow-up duration was 18 months (3 – 72 months).

RESULTS
The last follow-up showed local tumor control in 74 cases. The cumulative 1, 2, and 3-year local tumor control rates were 73, 65, and 60%, respectively. Eighty-six tumors showed best MRI response in a year, and median tumor volume decrease rate was 80% (22 – 100%). Thirty patients experienced dramatically tumor volume decrease (&gt; 95%). Median progression free and overall survival were 7 and 16 months, respectively. Radiation necrosis occurred in 24 patients, of which only 9 had neurological symptoms and treated with steroid and bevacizumab.

CONCLUSIONS
The daily 5-fractionated GKRS for very LBMs showed favorable local tumor control and acceptable radiation necrosis, but questionable survival benefit. In the future, prospective multi-center study is needed.
CTIM-15. LOCOREGIONAL ADMINISTRATION OF B7-H3-CAR T CELLS EXPRESSING 41BB LIGAND FOR PEDIATRIC PATIENTS WITH PRIMARY CNS TUMORS: PRELIMINARY RESULTS FROM A PHASE I STUDY
Authors: Bertrand Kelsey C , Kostecka Anna , Smith Kyle , Han Katie , Chiang Jason , Pinto Soniya , Tlais Dana , Selukar Subodh , Orr Brent , Hanzlik Emily , Langfitt Deanna , Metais Jean-Yves , Lockey Timothy , Willis Catherine , Fazio Frank , Shanmugam Raghu , Tian Liqing , Walhart Tara , Wang Yu , Allmon Patricia , Perry Scott , Schell Sarah , Adams Polly , Ward Meghan B , Meehl Michaela , Akel Salem , Poston Leigh , Bag Asim , Mack Stephen C , Leggas Markos , Klimo Paul , Gajjar Amar , Thomas Paul , Robinson Giles W , Park Julie R , Crawford Jeremy Chase , Gottschalk Stephen , Northcott Paul A , Krenciute Giedre , DeRenzo Christopher 
Published: November 2024

Abstract
Outcomes for pediatric patients with diffuse midline glioma (DMG) and relapsed/refractory CNS malignancies remain poor. Loc3CAR is an ongoing, first-in-human, phase I clinical trial (NCT05835687) evaluating intracranial delivery of B7-H3-CAR T cells expressing 41BB ligand (B7-H3-CAR-T) for patients ≤21 years old with i) relapsed/refractory B7-H3+ CNS tumors (Cohort A), or ii) DMG post-radiation (Cohort B). Treatment included 6 intracerebroventricular B7-H3-CAR-T infusions administered over 7 weeks. Primary and secondary outcomes were safety and disease response, respectively. To date, 84% (21/25) of tumors screened were B7-H3+ (median H-score 200; range 0-300). CAR-T products were successfully manufactured for all patients enrolled on the collection/manufacture phase of the trial (n=11). Eight patients (7 cohort A; 1 cohort B) were treated with a total of 42 infusions on dose level 1 (1x107/3x107 CAR+ T cells/dose). Post-infusion, multiple participants exhibited neurologic findings suggestive of on-tumor CAR-T activation, including seizure, dysphasia, and localized pain. One patient, with a large tumor burden and high B7-H3 expression (H-score = 300), experienced a dose limiting toxicity with unresponsiveness and decorticate posturing approximately 16 hours post-infusion #1. Their clinical status rapidly improved following CSF removal and intravenous dexamethasone. Common adverse events attributable to B7-H3-CAR-T included headache (8/8), fever (7/8), and nausea/vomiting (5/8). Two of 7 (29%) evaluable patients achieved clinical benefit with stable disease at week 8. B7-H3-CAR-T and inflammatory cytokines were detected in the CSF from all patients evaluated. Circulating tumor DNA (ctDNA) was measured using a novel DNA methylation-based sequencing pipeline and detected in the CSF from 6/8 patients. For 2 patients, ctDNA abundance increased post-infusion, followed by clearance, suggesting subclinical antitumor activity. Single cell RNAseq of immune cells in the CSF from 1 patient analyzed to date, demonstrated abundant Tregs post-infusion #4, suggesting B7-H3-CAR-T may induce local anti-inflammatory responses. Overall, intracranially administered B7-H3-CAR-T have an acceptable safety profile and warrant continued exploration for pediatric patients with CNS tumors.
CTIM-21. FIRST-IN-HUMAN PHASE I CLINICAL TRIAL USING 8R-70CAR T CELLS FOR NEWLY DIAGNOSED ADULT GLIOBLASTOMA
Authors: Ghiaseddin Ashley , Tao Haipeng , Deleyrolle Phuong , Rahman Maryam , Rinonos Serendipity Zapanta , Kresak Jesse , Massini Tara , Hiemenz John , robinson Christopher , Hsu Jack , Lin Tuo , Wynne Kristine , King Jennifer , Hodik Marcia , Lybarger John , Manso Eugenio Simon , Wang Anqi , Sekora David , McKibben Kathryn , Dechkovskaia Anjelika , Castillo Paul , Ligon John , Sayour Elias , Deleyrolle Loic , Mitchell Duane , Huang Jianping 
Published: November 2024

Abstract

BACKGROUND
To address the challenges of chimeric antigen receptor (CAR) T cell therapy in GBM, we utilized IL-8 release from tumor cells as a ‘GPS homing signal’ to enhance T-cell trafficking with a novel CD70-specific CAR design (8R-70CAR) that targets GBM. The 8R-70CAR offers several advantages: 1) Improved CAR T-cell trafficking, enhancing antitumor efficacy; 2) Reduced CD70, reshaping the tumor microenvironment (TME) and boosting endogenous immunity; 3) Utilized CD27 as the CAR, a co-stimulatory molecule that enhances T-cell functions; 4) Enabled CAR T cells to act as a sink to neutralize or remove IL-8, a pro-cancer chemokine, from the TME; and 5) Required only 120 ml of whole blood (not leukapheresis) for CAR T cell production. Preclinically, 8R-70CAR significantly enhanced CAR-T cell tumor migration and persistence, leading to complete tumor regression and sustained immune memory in a chemo/radiation/PD-1-blockade-resistant GBM model. These findings led to a phase-I trial (IMPACT trial: FDA-IND#23881, NCT05353530) using 8R-70CAR T cells for CD70 -positive newly diagnosed adult GBM.

METHODS
We aim to recruit 18 adult patients (3 + 3 dose-escalation design) with CD70-positive (&gt;20%) tumors. The CAR T cells will be given intravenously after completing standard-of-care (SOC) therapy. Primary endpoints: Evaluate safety, tolerability, and dose-limiting toxicities (DLTs) to determine the maximum tolerated dose. Secondary endpoints: Assess preliminary efficacy. Immune monitoring and correlative studies will also be conducted.

RESULTS
To date, four patients have been enrolled in the IMPACT trial, with 2 eligible patients participating in treatment at dose level 1 (1x10^6/kg). One patient has completed treatment with 8R-70CAR T cells, experienced no DLTs, and is currently in follow-up. The remaining patient is under SOC therapy before receiving CAR T cell treatment.

CONCLUSIONS
This study aims to address current therapeutic gaps and offers options for implementing a novel CAR design for the development of a more effective therapeutic modality for GBM.
CTIM-23. A PHASE II STUDY OF RETIFANLIMAB (PD-1 INHIBITOR) AND EPACADOSTAT (IDO1 INHIBITOR) IN COMBINATION WITH BEVACIZUMAB AND HYPOFRACTIONATED RADIOTHERAPY FOR RECURRENT GLIOBLASTOMA: NCT03532295
Authors: Butt Abeer , Luo Jingqin , Tao Yu , Butt Omar , Etter Kelsey , Nehring Leslie , Hissim Deanna , McKean Cole , Ansstas George , Kim Albert , Abraham Christopher , Kizilbash Sani , Strowd Roy , Johanns Tanner , Huang Jiayi , Ciorba Matthew , Campian Jian , Chheda Milan 
Published: November 2024

Abstract

INTRODUCTION
Immunotherapy has not improved survival in recurrent GBM (rGBM). Indoleamine 2,3 dioxygenase 1 (IDO1), highly expressed in ~90% of patients with malignant glioma, is a rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn) and enables immune escape.

METHODS
We hypothesized combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies would overcome tumor-related immunosuppression. This was an open-label Phase II study of two regimens: Arm A consisted of retifanlimab (anti-PD1, 500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B added the IDO inhibitor, epacadostat (400mg po BID), initiated prior to HFRT. Key inclusion criteria included dexamethasone ≤ 4 mg/day. The primary endpoint was overall survival (OS) at 9 months (OS-9). 24 evaluable patients were required to detect an OS-9 of 60% with 80% power, compared to 38% in historical controls (bevacizumab alone) by 1-sided 1-sample log rank test at alpha=0.1.

RESULTS
We previously reported Arm A. Here, we present results from Arm B. 25 of the 27 patients enrolled to regimen B were evaluable: median age 58years (23-71); 28% female; 23% MGMT promotor methylated; median KPS 90 (70 - 100); a median of 6 cycles of epacadostat as of May 2024 (1 - 13). 18 of 25 died with a median follow up 9.23 months. Median PFS was 7.52 months (95%CI: 5.52-9.43). Median OS was 9.5 months (95%CI 8.08-11.96). Regimen B met its primary endpoint with OS-9 of 61.07% (95%CI: 38.23-77.65%). There were 5 possible immune-related grade 3+ toxicities to date (2 ALT/AST increase; 3 rash).

CONCLUSIONS
Retifanlimab, epacadostat, HFRT, and bevacizumab in rGBM is well-tolerated, with encouraging OS and PFS at the time of submission. Arm B met its primary endpoint. Further studies are warranted to identify biomarkers to predict long-term responders.