bluuebunny/crossref_metadata_2025 huggingface dataset:
RADT-39. CYBERKNIFE: THE CURRENT STATE OF LINAC AS TREATMENT FOR VESTIBULAR SCHWANNOMAS
Authors: Brown Nolan , Musmar Basel , Nguyen Oanh , Neil Zachery , Kuo Cathleen , Gendreau Julian
Published: November 2023

INTRODUCTION

In the present study, we systematically review the extant literature describing CyberKnife radiosurgery (CKRS) as treatment for vestibular schwannoma (VS). We then perform pooled meta-analysis of long-term tumor control and hearing preservation rates reported across all retrospective observational series describing the efficacy of CKRS.

METHODS

We queried three databases to identify all primary retrospective studies reporting local tumor control and hearing preservation rates following CKRS for treatment of vestibular schwannoma. All studies returned across the three databases were subject to systematic screen according to pre-defined inclusion and exclusion criteria in a multi-step process performed by two investigators.

RESULTS

Following a comprehensive systematic search, a total of 15 studies comprising 2018 vestibular schwannoma patients were included. The proportion of females ranged from 30% to 60.3%, and the mean age of all 2,018 patients was 60.2 years. There were 64 patients who had neurofibromatosis type 2 (NF-2). Additionally, 309 patients had previously undergone surgical resection and/or radiosurgery for VS. In regard to CKRS treatment parameters, the marginal dose ranged from 1.9-25.78 Gy. The mean follow-up duration across the included studies was 40.0 months. Pooled rate of tumor control using the random effects model was 96% (95% CI: 95%-98%), and that of hearing preservation was 73% (95% CI: 66%-81%). The most common major complications following CKRS were trigeminal neuralgia, facial neuropathy, and hydrocephalus.

CONCLUSIONS

As studies on CyberKnife radiosurgery, one of the SRS modalities administered via LINAC, are far less common than studies on Gamma Knife radiosurgery for treatment of VS, more studies are needed in order to solidify the findings reported in the present meta-analysis. Although there are currently only 15 single-institution retrospective studies available in the neurosurgical literature, this study provides the most comprehensive and up-to-date analysis of highly relevant outcomes of interest in treatment of vestibular schwannoma via CyberKnife.
RADT-41. PREDICTION OF TREATMENT OUTCOME IN GAMMA KNIFE RADIOSURGERY OF BENIGN MENINGIOMAS
Authors: Yang Hye Jeong , Kim Tae Hoon , Seo Youngchan , Chung Hyun-Tai
Published: November 2023

Objective

This study aimed to assess the predictability of machine learning (ML) ensemble models for the success of Gamma Knife radiosurgery (GKRS) on non-skull base benign meningiomas.

METHODS

A total of 331 non-skull base benign meningiomas treated primarily with GKRS between 1997 and 2015 were retrospectively analyzed. When a tumor remained not larger than 125% of the initial volume at the last imaging follow-up and no significant change in the high signal intensity area around the tumor, it was classified as 'treatment success (TS).' Univariate correlation and multivariate logistic regression analyses were performed to identify statistically significant prognostic factors. Four ensemble algorithms were trained to predict the outcome of GKRS. The importance of features related to TS was analyzed.

RESULTS

The median MR imaging follow-up period was 8.6 years. The tumor control and signal change rates were 91.5% and 16.3%, respectively, and the TS rate was 77.6%. The conventional multivariate logistic regression model showed 83.7% accuracy and 37.8% specificity. The ML models had accuracies between 78.0% and 82.2% and specificities between 30.3% and 80.7%, and they were similar to those of conventional logistic regression analyses. The smaller brain volume absorbed more than 14 Gy, and the absence of signal change before GKRS was a favorable prognostic factor for TS in all models. The bagging algorithm with selected features showed the best specificity of 80.7% and the most significant AUC of 0.723.

CONCLUSION

A bagging ensemble algorithm with selected features had better specificity with similar accuracy than conventional multivariate logistic regression in predicting GKRS outcomes for non-skull base meningiomas.
RADT-42. STRATEGIES FOR TREATING RECURRENT GERM CELL TUMORS IN PATIENTS WHO HAVE UNDERGONE PRIOR CHEMORADIOTHERAPY AGAINST PRIMARY GERMINOMA
Authors: Yamasaki Fumiyuki , Kinoshita Yasuyuki , Takayasu Takeshi , Yonezawa Ushio , Taguchi Akira , Onishi Shumpei , Ozono Iori , Khairunnisa Novita Ikbar , Dowaki Ryosuke , Horie Nobutaka
Published: November 2023

BACKGROUND

Germinoma patients are thought to have a favorable prognosis due to their high sensitivity to chemotherapy and radiotherapy. However, it is also known that germinoma is at risk of recurrence after a long course of disease. Despite excellent sensitivity to chemotherapy and radiotherapy, there is no established standard treatment for patients with recurrent germinoma.

METHODS

Fourteen patients with recurrent germinoma treated in our institution from 1989 to 2022 were included in this retrospective study. All patients were treated for primary tumor with carboplatin-etoposide and 23.4 Gy of whole ventricle/whole brain irradiation. Twelve patients were treated at our institution at primary and first recurrence, and three patients were referred to our institutional for management against recurrent tumors. Medical records were examined to determine the course of the disease at the time of initial onset, the first recurrence, and the following course, including recurrence and survival.

RESULTS

There were 12 male and 2 female patients with recurrent germinoma, age at initial onset ranged from 11 to 29 years (median 18.5 years), and age at first recurrence ranged from 16 to 36 years (median 23.5 years). The time from the date of treatment initiation against primary tumor to first confirmed recurrence ranged from 4.2 to 272 months (median 79 months). Eleven patients had recurrences outside the irradiation field, with six experiencing spinal recurrence. Thirteen patients received chemotherapy, and 12 patients had radiotherapy, including eight patients treated with craniospinal irradiation (CSI). There were no reported cases of recurrence or mortality in the CSI-treated group. In contrast, the median PFS and OS in the group that did not receive CSI were 12 and 36 months, respectively, which were significantly different from the CSI-treated group (P < 0.05).

CONCLUSION

Our findings suggest that CSI has an important role in reducing the likelihood of future recurrence.
RADT-43. LONG TERM OUTCOMES OF PEDIATRIC AND ADULT CENTRAL NEUROCYTOMA—THE ROLE OF SALVAGE RADIOTHERAPY AND CONSERVATIVE MANAGEMENT
Authors: Yang Yufan , Wadhwani Nitin , Zheng Shuhua , Chandler James , Lesniak Maciej , Tate Matthew , Sonabend Adam , Kalapurakal John , Horbinski Craig , Lukas Rimas , Stupp Roger , Kumthekar Priya , Sachdev Sean
Published: November 2023

INTRODUCTION

Central Neurocytoma (CN) is a rare, WHO grade 2 brain tumor that predominantly affects young adults. Gross total resection (GTR) is often curative for CN, but the optimal treatment paradigm following subtotal resection (STR) and or scarcer pediatric cases has yet to be established—including the role of radiation therapy (RT). Herein, we reviewed the long-term outcomes of CN patients at our institution.

METHODS

Patients between the years 2001 and 2021 with a pathologic diagnosis of CN were reviewed. Demographic, treatment, and tumor characteristics (histopathological and molecular) were recorded. Recurrence free survival (RFS) and overall survival (OS) were calculated according to the Kaplan Meier-method. Post-RT tumor volumetric regression analysis was performed.

RESULTS

Seventeen adults (≥ 18 years old) and 5 children (< 18 years old) met the criteria for data analysis (n = 22). With a median follow-up of 6.9 years (range: 1.2-42.8 years), there was zero tumor-related mortality. Patients who received STR and/or had atypical tumors (criteria = Ki-67 >4%) experienced decreased RFS compared to those who received GTR and/or were without atypical tumors. RFS at 5 years was 67% for typical CNs and 22% for atypical CNs. Every pediatric tumor was atypical and 3/5 recurred within 5 years. Salvage RT following tumor recurrence led to 100% tumor control, with no further recurrences (median post-RT follow-up = 5.79 years); volumetric analysis for 3 recurrent tumors (8.59 cumulative years of serial scans) revealed an ~80% reduction in tumor (range: 76.3%-81.1%), at a mean rate of 2.49% per month.

CONCLUSION

We provide encouraging evidence that (1) CNs have limited long-term risk of tumor-related mortality and (2) RT after tumor recurrence conveys strong long-term tumor control, including for potentially more aggressive pediatric CNs. Our institutional experience supports the conservative management of CN, including withholding RT until signs of recurrence regardless of resection extent or Ki-67.
RADT-45. TREATMENT OF ATYPICAL CENTRAL NEUROCYTOMA WITH PROTON THERAPY
Authors: Singh Pawan
Published: November 2023

Central neurocytoma is a rare intraventricular tumor often thought to be benign but can demonstrate aggressive behavior such as recurrence or CNS dissemination with elevated MIB1 index. This is a clinical case presentation of a 19 year old male who presented with increased intracranial pressure and was found to have atypical central neurocytoma with Ki-67 of 5%. Given residual disease after second craniotomy and high risk for recurrence, patient was treated with a six week course of proton therapy. Patient responded to radiation therapy with stable disease and improvement of cognitive function. Outcome of disease stability with proton therapy is consistent with reported literature. This case adds further evidence for use of proton therapy in patients with atypical central neurocytoma.
RADT-46. STEREOTACTIC RADIOSURGERY FOR CYSTIC AND SOLID INTRACRANIAL HEMANGIOBLASTOMAS: A SINGLE-INSTITUTION RETROSPECTIVE SERIES
Authors: Yoo Kelly , Park David , Marianayagam Neelan , Pollom Erqi , Soltys Scott , Meola Antonio , Chang Steven
Published: November 2023

INTRODUCTION

Intracranial hemangioblastoma is a rare neoplasm that poses significant challenges in clinical management. Hemangioblastomas are characterized by unique radiological features into cystic or solid tumors. Out study aims to evaluate the role of SRS in the management of cystic and solid hemangioblastomas in a single institution setting.

METHODS

We conducted a retrospective analysis of clinical and radiological outcomes of patients with intracranial hemangioblastomas treated with CyberKnife SRS at our institute between 1998 and 2023. The follow-up data were available for 93 intracranial hemangioblastomas in 23 patients. Ten (43.5%) patients presented with 23 (25.6%) cystic hemangioblastomas, while 13 (56.5%) patients had 70 (75.3%) solid hemangioblastomas at the time of SRS treatment. The median age was 36 years and the median tumor volume accounted for 0.43 cc. The SRS was administered with the median single-fraction equivalent dose (SFED) of 20 Gy at the 77% of the median isodose line.

RESULTS

At a one-year follow-up, 11 initially solid hemangioblastomas developed cystic formation, resulting in a total of 34 (36.6%) cystic hemangioblastomas and 59 (63.4%) solid hemangioblastomas across 13 and 10 patients, respectively. Among these, 84.6% exhibited peritumoral edema prior to the onset of cystic formation. For 37 solid hemangioblastomas accompanied by peritumoral edema, SRS was administered before cystic transformation, remaining solid throughout the latest follow-up. Over a median follow-up period of 59 months (range: 3-260), 6 (17.6%) cystic and 13 (22%) solid hemangioblastomas progressed. The 5-year local tumor control (LTC) rate for intracranial hemangioblastomas was 84.7%, with 97% and 76.9% in cystic and solid lesions, respectively.

CONCLUSION

Our study illustrates the largest single-institutional long-term retrospective analysis of intracranial hemangioblastomas treated with SRS to date. Early SRS treatment at the time of edema may prevent cystic hemangioblastoma development and provides durable treatment outcomes for patients with both cystic and solid hemangioblastomas in long-term.
RADT-50. EVIDENCE-BASED MULTIVARIATE NORMAL TISSUE COMPLICATION PROBABILITY (NTCP) STUDY OF DOMAIN-SPECIFIC COGNITIVE DECLINE AFTER PARTIAL BRAIN RADIATION (RT)
Authors: Hopper Austin , Connor Michael , Salans Mia , Karunamuni Roshan , Unnikrishnan Soumya , Huynh-Le Minh , Tibbs Michelle , Reyes Anny , Stasenko Alena , McDonald Carrie , Moiseenko Vitali , El-Naqa Issam , Hattangandi-Gluth Jona
Published: November 2023

Beyond the hippocampus, there are no evidence-based dose constraints for eloquent brain structures which subserve cognitive domains. We performed a multivariate NTCP analysis of post-RT neurocognitive decline, examining dosimetric predictors of eloquent brain regions in a prospective longitudinal clinical trial. 83 patients with primary brain tumors receiving fractionated RT completed comprehensive neurocognitive evaluation and high-resolution volumetric and diffusion MRI at baseline and 6 months post-RT. Image processing using robust, validated automated segmentation parcellated individual white matter (WM) tracts, cortical regions, and hippocampi. Well-validated neurocognitive tests evaluating multiple cognitive domains were assessed with negative reliable change indices adjusted for practice effects between timepoints scored as decline. Univariate logistic regression and multivariate model building were performed examining dose to eloquent structures and clinical variables. Univariate analysis showed mean dose to the bilateral caudal anterior cingulate cortex and WM were correlated with decline in executive function. Attention/processing speed decline was correlated with mean/max dose to the posterior corpus callosum (CC), volume getting >20 Gy in the combined CC, as well as anti-epileptic use and chemotherapy. On multivariate analysis for attention automated bootstrapped logistic regression performance at nested cross-validation by AUC was 0.59 (0.54-0.65); LASSO model performance by AUC was 0.60 (0.54-0.66) with mean dose to combined CC being the most frequent variable in both. The top three most important variables in Random Forest by mean decrease in Gini coefficient were max dose to posterior and combined CC and mean dose to anterior CC. Model performance by AUC was 0.70 (0.64-0.75). Here we present the first, to our knowledge, NTCP model for decline in attention/processing speed, along with dosimetric predictors of executive function decline. We found that after partial brain RT, dose to several ROIs significantly correlated with post-RT impairment. These data can guide future cognitive-sparing strategies for brain RT.
RADT-51. RADIATION-INDUCED CEREBRAL CONTRAST ENHANCEMENTS STRONGLY SHARE RISK FACTORS WITH STROKE
Authors: Eichkorn Tanja , Lischalk Jonathan , Schwarz Robert , Bauer Lena Jasmin , Deng Maximilian , Regnery Sebastian , Jungk Christine , Herfarth Klaus , König Laila , Debus Jürgen
Published: November 2023

BACKGROUND AND PURPOSE

Radiation-induced cerebral contrast enhancements (RICE) are feared because frequent and potentially health-threatening. Risk factors are badly understood. Better understanding of RICE risk factors is critical to better face its risks by adapting therapy in the first place or patient care during follow-up.

MATERIALS AND METHODS

We analyzed consecutive 235 patients treated with proton radiotherapy (PRT; 54Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years.

RESULTS

The risk of RICE was significantly higher in patients with vascular risk factors (VRF) (p = 0.02). Especially age ≥50 years (vs. adults <50 years: two-fold risk; p = 0.02), hypertension (three-fold risk; p = 0.0001) and diabetes (6.7-fold risk; p = 0.007) were shown to be clearly associated to RICE occurrence. Dyslipidemia (2.4-fold), overweight (1.3-fold) and smoking (1.3-fold) was also more frequently observed in the cohort that developed RICE. History of previous stroke went along with a 1.7-fold risk for RICE but threshold for significance was not reached. If RICE occurred, Bevacizumab treatment was two-fold more frequently needed in the cohort with VRF, but RICE prognosis did not differ relevantly between the RICE subcohort with and without VRF.

CONCLUSIONS

These data firstly demonstrate that RICE strongly share risk factors with ischemic stroke which further enhances our vague understanding of multifactorial pathophysiology and opportunities of tackling RICE. Classical vascular risk factors, especially age, hypertension and diabetes correlated strongly with RICE risk. Risk-adapted screening and therapy can be directly derived from this data.
CTIM-01. NIVOLUMAB AND STEREOTACTIC RADIOSURGERY (SRS) FOR PATIENTS WITH BREAST CANCER BRAIN METASTASES: LONG TERM RESULTS AND CELL FREE DNA (CFDNA) ASSESSMENT FROM A NON-RANDOMIZED, OPEN-LABEL, PHASE IB STUDY
Authors: Ahmed Kamran , Kim Youngchul , Arrington John , Kim Sungjune , DeJesus Michelle , Soyano Aixa , Armaghani Avan , Costa Ricardo , Khong Hung , Loftus Loretta , Rosa Marilin , Caudell Jimmy , Diaz Roberto , Etame Arnold , Tran Nam , Soliman Hatem , Czerniecki Brian , Forsyth Peter , Yu Hsiang-Hsuan Michael , Han Hyo
Published: November 2023

BACKGROUND

We hypothesized treatment with nivolumab and SRS would be feasible and well tolerated and may improve intracranial tumor control over SRS alone for breast cancer brain metastases.

METHODS

The study is a phase Ib trial of nivolumab and SRS for breast cancer brain metastases. Clinical trial information: NCT03807765. Key eligibility criteria include breast cancer brain metastases of all subtypes, age ≥ 18, ECOG ≤ 2 with ≥ 10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg IV) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. Blood was collected at baseline and q4 weeks.

RESULTS

A total of 12 patients were treated to 17 brain metastases. Breast cancer subtypes included triple negative (50%), HR+/HER2- (33%), and HR-/HER2+ (17%). Median follow-up from start of protocol therapy is 44 months. Two lesions were noted to undergo local failure, both pathologically confirmed, for a 12-month local control of 94%. Median distant intracranial control was 7.4 months with a 12 month control rate of 33%. Median systemic progression free survival was 7.7 months with a 12 month rate of 42%. Median overall survival (OS) was 24.7 months with a 12 month OS of 75%. No cases of radionecrosis were noted. Most patients were noted to have an increase in cfDNA throughout study treatment, at week 5 compared to baseline (83%), week 25 compared to baseline (89%), and 100% at first follow-up. An increase in cfDNA 4 weeks post SRS was found to predict worse intracranial control (HR: 4.4; 95% CI: 1.1-18.5; p = 0.04).

CONCLUSIONS

Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. An increase in cfDNA 4 weeks post SRS was found to predict worse intracranial control and was eventually seen in all patients.
CTIM-04. TOPICAL DIPHENCYPRONE IMMUNOTHERAPY FOR CUTANEOUS NEUROFIBROMAS ASSOCIATED WITH NF1, A PHASE 1 STUDY
Authors: Brown Rebecca , Gulati Nicholas , Poplauski Dina , Young Jade
Published: November 2023

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome affecting ~1 in 2500 people. Affected patients develop peripheral nerve sheath tumors of the skin known as cutaneous neurofibromas (CN), with variable disease burden ranging from 0-1 tumors to over 10,000. Patients cite deformity, pain, and pruritus from CN as one of the most difficult features of the disease. To date, there are no practical or effective pharmacotherapies for these tumors. This is a single-center, phase I, open label trial to evaluate the safety, tolerability, and efficacy of diphencyprone (DPCP), a topical hapten compound that induces a delayed-type. Twelve adult patients with NF1 and >3 CN of maximum diameter >4 mm were enrolled. DPCP 0.04% ointment was administered topically once weekly to up to 20 cNFs in a localized body region for 10 weeks. Endpoints included (primary) safety and tolerability of DPCP ointment via CTCAE reporting and subjective scoring of symptoms. Efficacy was assessed using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines in conjunction with whole body photography and manual tri-axial tumor measurements. One treated tumor is tracked throughout the study with optical coherence tomography (OCT) imaging. Skin biopsies of a CN and surrounding tissue are collected at baseline, on Day 17 after treatment initiation, and four weeks post-treatment for exploratory endpoints qRT-PCR, single-cell RNA sequencing, and immunohistochemistry to detect differences in immune cell infiltration, tumor cell density, and transcriptional changes throughout the treatment course. Clinical trial information: NCT05438290.
CTIM-08. LOCAL IMMUNOTHERAPY WITH AUTOLOGOUS CIK CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH 20 YEARS FOLLOW-UP AND FAVORABLE FACTORS FOR LONG-TERM SURVIVAL
Authors: Duan Hao , He Zhenqiang , Chen Zhongping , Mou Yonggao
Published: November 2023

BACKGROUND

Between November 2002 and March 2004, a pilot study was conducted to evaluate the tolerance and survival following local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor resection cavity in 6 patients with high grade glioma (HGG) at Sun Yat-sen University Cancer Center.

METHODS

We reviewed the clinicopathological characteristics of these patients and updated their long-term follow-up. Profiles of tumor genome, transcriptome and immune microenvironment were also investigated by genomic target sequencing, RNA sequencing, electrochemiluminescence assay and immunohistochemistry (IHC) staining.

RESULTS

Four patients died from tumor progression and their overall survival ranged from 10.0 to 33.9 months. Remarkably, 2 patients, including one diagnosed as astrocytoma (IDH1 mutation, WHO 3) and the other diagnosed as diffuse hemispheric glioma H3 G34-mutant (G34-DHG), survived more than 19 years without evidence of recurrence. The distinctive clinical feature of the 2 long-term survivors was tumor gross total resection (GTR) before CIK therapy. Comparing with the short-term survivors, NTRK1 mutation was uniquely present and 353 genes were differentially expressed in the long-term survivors. These differential expression genes were highly associated with immune function. Electrochemiluminescence assay and IHC staining revealed higher expressions of cytokines and lower infiltrations of tumor-associated macrophages in the tumors of the long-term survivors.

CONCLUSION

These findings suggest that certain HGG patients can acquire long-term survival after local immunotherapy with CIK cells. Tumor GTR before CIK therapy and relatively weaker immunosuppressive tumor microenvironment may be the favorable factors for long-term survival.
CTIM-09. PHASE 1/1B TRIAL OF FC-ENGINEERED ANTI-CD40 AGONIST MONOCLONAL ANTIBODY (2141-V11) INFUSED WITH D2C7-IT IN ENHANCING DISEASE BY CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (RMG)
Authors: Desjardins Annick , Chandramohan Vidya , Landi Daniel , Peters Katherine , Johnson Margaret O , Low Justin , Khasraw Mustafa , Threatt Stevie , Bullock Chevelle , Herndon James , Lipp Eric , Friedman Allan , Friedman Henry , Ashley David , Osorio Juan , Ravetch Jeffrey , Bigner Darell
Published: November 2023

BACKGROUND

D2C7-IT is a dual-specific immunotoxin. Recombinant antibody fragments bind the wild-type epidermal growth factor receptor (EGFRwt) and its mutant EGFR variant III (EGFRvIII), triggering internalization and intracellular delivery of the Pseudomonas exotoxin, D2C7-IT cell-killing component. Single intratumoral delivery of D2C7-IT in animals generates an antitumor response by directly killing tumor cells and indirectly activating an adaptive T-cell response. However, tumor-associated macrophages (TAMs)-mediated immunosuppression limits its efficacy. Eliminating MG immunosuppression via CD40 co-stimulation enhances D2C7-IT-induced antitumor responses by activating a TAMs proinflammatory phenotype and promoting long-term tumor-specific CD8+ T-cell immunity. We initiated a phase 1 trial of D2C7-IT+2141-V11 (Fc-engineered anti-CD40 agonist) administered via CED in rMG patients.

METHODS

Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. Cohorts of 3 patients were treated with increasing doses of 2141-V11 to determine the recommended phase 2 dose (RP2D) when administered sequentially following D2C7-IT (166,075ng) via CED. Five dose levels (DLs) were evaluated (2141-V11 at: DL1: 0.70mg; DL2: 2.0mg; DL2**: 3.0mg; DL2*: 4.0mg; DL3: 7.0mg).

RESULTS

As of June 5, 2023, 27 patients had been treated (3 patients on DL1 and DL2; 2 on DL3 and DL2*; 17 on DL2**). No dose-limiting toxicities were observed; however, lower DLs were added due to higher frequency of adverse events (AEs) expected with D2C7-IT+2141-V11 within DL3 and DL2* (fever, neurologic symptoms). 13/27 patients remain alive (range 4-22months after therapy). No grade 4 or 5 AEs related to D2C7-IT+2141-V11 were observed, while grade 3 related AEs include one each of: dysphasia, encephalopathy, headache, hydrocephalus, paresthesia, and pyramidal tract disorder.

CONCLUSIONS

The RP2D for intratumoral infusion of D2C7-IT+2141-V11 via CED is identified. The protocol was amended to evaluate the addition of cervical perilymphatic injections of 2141-V11 post CED of D2C7-IT+2141-V11.
CTIM-10. A SURGICAL WINDOW-OF-OPPORTUNITY CLINICAL TRIAL EVALUATING THE PCSK9 INHIBITOR EVOLOCUMAB IN PATIENTS WITH GLIOMA
Authors: Singh Kirit , Hotchkiss Kelly , Foster Matthew , Railton Chelsea , Blandford Emily , Thomas Elizabeth , Miller Elizabeth S , Ashley David , Desjardins Annick , Friedman Henry , Johnson Margaret O , Friedman Allan , Keir Steve , Herndon James , Sampson John , Li Chuan-Yuan , Fecci Peter , Patel Anoop , Khasraw Mustafa
Published: November 2023

Gliomas evade the immune system by downregulating cell surface expression of major histocompatibility class (MHC)-I. Antagonism of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases MHC-I expression and can enhance checkpoint inhibition in vivo. Evolocumab is an FDA approved monoclonal antibody (mAb) for hyperlipidemia that inhibits PCSK9. However, large constructs such as mAbs typically have limited penetrance across the blood-brain-barrier. We report the preliminary results of a surgical window-of-opportunity study evaluating if Evolocumab administered subcutaneously pre-preoperatively is detectable in tumor tissue from patients with newly diagnosed or recurrent glioma (PESKe; NCT04937413). Twenty contemporaneous control samples are prospectively collected from patients undergoing craniotomy without receiving Evolocumab. Although non-randomized, these specimens provide valuable information for exploratory comparison of the treated and untreated specimens in terms of drug penetrance and MHC-I expression. To date, 24 patients have been enrolled (M: 14, F: 10) with a median age of 46.5. Of these, 5 received pre-procedure subcutaneous Evolocumab (420mg), while the remaining 19 were analyzed as controls. In treated patients, Evolocumab was detectable via mass spectroscopy (LC-MS/MS) in all analyzed cases, including in tumor tissue from both contrast-enhancing and non-contrast-enhancing regions. Ratios of drug in tumor relative to intra-operative blood were markedly higher in samples from contrast-enhancing regions compared to non-contrast enhancing regions (median ratio of tumor to blood of 0.1503 vs 0.0248 respectively). The tumor proteome was also analyzed using LC-MS/MS to quantitate MHC-I and MHC-II proteins. Initial analysis found increased MHC-I (HLA-A, HLA-B, HLA-C) quantitation via mass spectroscopic analysis of the tumor proteome in treated samples compared to contemporaneous untreated controls. No significant adverse events have been reported in those who received pre-procedure Evolocumab. Ongoing analyses will seek to determine whether increased MHC-I quantities in tumor correspond with increased cell surface expression via immunofluorescence and immunohistochemistry.
CTIM-16. DEVELOPING PATIENT SPECIFIC TUMOR INFILTRATING LYMPHOCYTES (TILS) WITH INCREASED TUMOR SPECIFICITY AS A THERAPY FOR GLIOBLASTOMA
Authors: Hotchkiss Kelly , Blandford Emily , Noldner Pamela , Zhou Ying , Singh Kirit , Patel Anoop , Fecci Peter , Antonia Scott , Shaz Beth , Khasraw Mustafa
Published: November 2023

Immunotherapy failure in glioblastoma results from three main hurdles; limited numbers of T cells within the tumor, T cell exhaustion and significant intra-tumoral and intra-patient heterogeneity leading to lack of T cell tumor recognition. Our group has developed an expansion protocol to isolate and expand less exhausted tumor infiltrating lymphocytes (TILs) from the tumor periphery, selecting for TILs that recognize tumor antigen ex vivo. This process will increase the number of T-cells specific for an individual patient’s diverse tumor neoantigens. We have successfully expanded glioblastoma associated TILs from 66% of the novel Lukens trap substrate, which collects TILs and tumor from the tumor periphery. Cells are expanded in two stages, preREP and REP, through novel methods based on a protocol with clinical success in lung cancer and modified to increase the percent of tumor specific T cells. Through co-culture with patient matched glioma neurospheres we have identified activated T cells from each stage of culture (initial product, preREP, REP) based on CD137+ expression and tumor specific cytokine release (IFNy+TNFa+IL2+IL17a+) by flow cytometry. Through 5’scRNA sequencing paired with TCR repertoire analysis we can identify activation specific TCRs. Overrepresented TCR alpha and beta chains will be linked by a P2A site, cloned into a lentiviral vector, and transduced into TCR negative Jurkat cells to confirm tumor reactivity. This strategy will allow us to enrich and assess tumor specific TCR activity compared to bystander activation in our TIL product. Following additional preclinical assessment of cytotoxicity against autologous tumor, we will evaluate safety and feasibility of by administering our novel TIL product intrathecally in patients with glioblastoma.
CTIM-18. NRG ONCOLOGY STUDY BN007: RANDOMIZED PHASE II/III TRIAL OF IPILIMIUMAB (IPI) PLUS NIVOLUMAB (NIVO) VS. TEMOZOLOMIDE (TMZ) IN MGMT-UNMETHYLATED (UMGMT) NEWLY DIAGNOSED GLIOBLASTOMA (NGBM)
Authors: Lassman Andrew , Polly Mei-Yin , Iwamoto Fabio , Sloan Andrew , Wang Tony , Aldape Kenneth , Wefel Jeffrey , Gondi Vinai , Gutierrez Alonson , Manasawala Mohammed , Gilbert Mark , Sulman Erik , Wolchok Jedd , Green Richard , Neil Elizabeth , Lukas Rimas , Goldlust Samuel , Snuderl Matija , Dignam James , Won Minhee , Movsas Benjamin , Mehta Minesh
Published: November 2023

BACKGROUND

New therapies are especially needed for uMGMT nGBM. NRG Oncology BN002 (phase I) demonstrated safety and preliminary efficacy of Ipi+Nivo for nGBM, leading to BN007 as phase II/III.

METHODS

Adults with uMGMT nGBM (WHO 2016) and KPS ≥ 70 were randomized to RT and concurrent and adjuvant Ipi+Nivo or TMZ, stratified by glioma-recursive partitioning analysis class (RPA), intent to use tumor-treating fields (NCT04396860). Phase II primary endpoint was progression-free survival (PFS), powered 95% to detect a hazard ratio (HR) ≤0.58 with 1-sided 0.15 significance after 100 events. If p < 0.15, then phase III would accrue with overall survival (OS) as primary endpoint. Corticosteroids were disallowed at Ipi+Nivo start. Histology, biomarkers, and PFS were assessed centrally.

RESULTS

Among 374 patients screened, 159 were randomized in phase II (79 Ipi+Nivo, 80 TMZ). Demographics (age median 60 years, range 28-79; male 66%, white 88%, not Hispanic/Latino 89%), KPS (90-100 61%), extent of resection (gross total 65% per local PI), and RPA (III 10%, IV 73%, V 17%) were well-balanced between arms. After 100 PFS events, the pre-planned phase II analysis demonstrated no improvement for Ipi+Nivo vs. TMZ [median 7.7 (95% CI: 6.5, 8.5) vs. 8.5 (95% CI: 7.1, 10.4) months; HR 1.47 (95% CI: 0.98-2.2); 1-sided p = 0.96]. OS is immature ( >50% alive, 13.7 months median follow-up) but without observed difference between arms [median ~13 months each; HR 0.95 (95% CI: 0.61-1.49); 1-sided p = 0.36]. On the Ipi+Nivo arm, treatment-related grade 3, 4, and 5 events were reported in 26 (33.3%), 4 (5.1%), and 2 (2.6%; colitis and autoimmune disorder, n = 1 each) patients.

CONCLUSIONS

Ipi+Nivo did not improve PFS for uMGMT nGBM. Accrual permanently closed after phase II. No new safety signals were identified. Molecular analyses and survival follow-up are ongoing. FUNDING: NCI Grants U10CA180868, U10CA180822, U24CA196067 (NRG Oncology Operations, SDMC, Specimen Bank).
CTIM-21. T-CELL RECEPTOR REPERTOIRE ANALYSIS IN PBMCS FROM PEDIATRIC PATIENTS WITH RECURRENT MEDULLOBLASTOMA DURING ADOPTIVE CELLULAR THERAPY
Authors: Yegorov Oleg , Yang Changlin , Yegorova Yanina , Mitchell Duane
Published: November 2023

BACKGROUND

Adoptive cellular therapy (ACT), which involves transferring tumor-specific lymphocytes, has shown promising clinical efficacy across various cancer types. However, accurately tracking these transferred cells has been challenging. To overcome this limitation, we utilized T-cell receptor (TCR) sequencing to investigate the TCR repertoire in peripheral blood mononuclear cells (PBMCs). Specifically, we examined PBMCs stimulated ex vivo using autologous dendritic cells (DCs) loaded with total tumor RNA, which we applied for infusion in pediatric patients. We also collected blood samples prior to and following immunotherapy to compare the TCR repertoire dynamics.

METHODS

We isolated total RNA from patient PBMCs obtained before the initiation of adoptive cellular therapy (ACT) and continued collection on a weekly basis for one month, followed by monthly collections after immunotherapy treatment. To generate cDNA, we used RACE technology with the addition of a common adapter at the 5' end. The raw sequencing data obtained was then preprocessed using MiXCR software. Subsequent TCR repertoire analysis was performed using the Immunarch R-package and VDJtools software. RESULTS&

CONCLUSIONS

The analysis of T-cell receptor (TCR) diversity across ex vivo extended T-cell samples showed a range of 593 to 34,000 unique CDR3 clones among 28 patients with recurrent medulloblastoma. The observed range suggests that different patients exhibit distinct levels of TCR diversity. Our results revealed significant instability in the TCR repertoire within the peripheral blood during the initial 28 days after ACT for all patients. Subsequently, the regeneration was mainly driven by de novo thymic production of naïve T-cells. TCR sequencing of PBMCs stimulated with autologous DCs loaded with total tumor RNA allowed us to gain a deeper understanding of the TCR repertoire in the context of immunotherapy. This approach enabled us to track and analyze the tumor-specific T-cells in the repertoire, providing valuable insights into their behavior and response to the treatment.
CTIM-23. SAFETY RUN-IN RESULTS OF A PHASE I/II STUDY TO EVALUATE ATEZOLIZUMAB IN COMBINATION WITH CABOZANTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Weathers Shiao-Pei , Kamiya-Matsuoka Carlos , Majd Nazanin , Ashu Alda , Thompson Chantell , Gachimova Evguenia , Aaroe Ashley , Patel Chirag , Loghin Monica , O'Brien Barbara , Alfred Yung W K , Puduvalli Vinay , de Groot John
Published: November 2023

BACKGROUND

Immune checkpoint inhibitor therapy has shown limited efficacy in the treatment of glioblastoma (GBM) in both newly diagnosed and recurrent disease which underscores the need for rational combinatorial strategies. Atezolizumab is a humanized monoclonal antibody that targets PD-L1 and has been shown to enhance the magnitude of tumor-specific T cell responses. Combining PD-L1/PD-1 axis inhibition with targeted therapy like cabozantinib which has both anti-tumoral and immunomodulatory properties may result in synergistic effects. Cabozantinib may modulate the myeloid cell population to overcome resistance to anti-PD-1/PD-L1 therapy.

METHODS

Eligibility criteria were those with recurrent GBM, age >18 yrs with 1st or 2nd recurrence who were naïve to antiangiogenic and receptor tyrosine kinase inhibitor treatment. The primary objective of the phase I run-in was to evaluate the safety of atezolizumab in combination with cabozantinib.

RESULTS

1 dose-limiting toxicity (DLT) of a grade 3 ALT elevation was observed in the first 6 DLT evaluable patients treated during the safety run-in phase. Regarding immune related adverse events, 1 of 6 patients developed atezolizumab-related grade 1 hypothyroidism. 1 of 6 patients developed study treatment-related grade 2 diarrhea. 2 patients after completion of 2 cycles of treatment had evidence of a partial radiographic response ( > 50% decrease). 1 patient had a near partial radiographic response (45% decrease). 2 patients had stable disease after completion of 2 cycles of the combinatorial treatment. 1 patient had only completed the first 28-day cycle, DLT period, and had not yet had imaging to reassess disease status.

CONCLUSIONS

The combination of atezolizumab with cabozantinib was tolerable, and no new safety signals were noted. In this small cohort of recurrent GBM patients, radiographic responses were observed. The phase II component of the trial is recruiting patients (n = 45) to evaluate clinical efficacy. Multi-omic correlative studies and fecal microbiome analyses are planned.
CTIM-30. A PHASE 1B, OPEN-LABEL, DOSE-ESCALATION TRIAL OF THE DELTA-LIKE LIGAND 3 (DLL3)/CD3 IGG-LIKE T CELL ENGAGER, BI 764532, IN PATIENTS WITH DLL3-POSITIVE GLIOMA
Authors: van den Bent Martin , Roth Patrick , Tabatabai Ghazaleh , Burger Michael C , Martinez-Garcia Maria , von Baumgarten Louisa , Greil Richard , Studeny Matus , Simetzberger Monika , Liu Meiruo
Published: November 2023

BACKGROUND

Patients with progressive diffuse gliomas have limited treatment options. DLL3, a Notch ligand, is expressed on most diffuse gliomas. BI 764532, a humanized IgG-like T cell engager, binds selectively to DLL3-positive cells and promotes T cell-mediated cytotoxicity. Preclinical data showed activity of BI 764532 against intracranial tumors. In an ongoing first-in-human trial in patients with DLL3-positive small-cell lung carcinoma and other neuroendocrine carcinomas (NECs) including extrapulmonary NECs and large-cell NECs of the lung (NCT04429087), BI 764532 exhibited promising efficacy and manageable tolerability. Here we describe a planned Phase Ib dose-escalation/expansion trial of BI 764532 monotherapy in patients with DLL3-positive refractory/relapsed diffuse glioma.

METHODS

The dose-escalation part will include ~12–20 patients (≥3 patients per dose level) from 12 sites across Europe/USA. Dose escalation will be guided by Bayesian logistic regression model with overdose control. BI 764532 will be administered intravenously. Treatment will continue until disease progression, undue toxicity, informed consent withdrawn, or other reasons requiring treatment discontinuation. Once a recommended dose for expansion is established, ~15 patients from Europe will be treated in a dose-expansion phase. Key inclusion criteria: ≥18 years old; histologically confirmed primary progressive diffuse glioma who have failed on standard-of-care therapies; DLL3-positivity by IHC on archived tumor tissue by central pathology review. Key exclusion criteria: extracranial metastatic or leptomeningeal disease; previous treatment with DLL3-targeting therapies; prior treatment with bevacizumab/other anti-VEGF/anti-angiogenic treatment ≤6 months prior to first administration of BI 764532; persistent toxicity from previous treatments that has not resolved to ≤CTCAE Grade 1; diagnosis of immunodeficiency, or intake of immunosuppressive therapy ≤7 days prior to first administration of BI 764532. Primary endpoints: dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (escalation phase); DLTs during the entire treatment period (expansion phase). Other objectives include pharmacokinetics, pharmacodynamics, preliminary efficacy and evaluation of DLL3 as a potential biomarker.
CTIM-33. EFFICACY AND SAFETY STUDY OF NEOADJUVANT EFINEPTAKIN ALFA (NT-I7) AND PEMBROLIZUMAB IN RECURRENT GLIOBLASTOMA
Authors: Webb Mason , Sener Ugur , Burns Terry , Twohy Erin , Kizilbash Sani H , Ruff Michael , Uhm Joon , Galanis Evanthia , D'Andre Stacy , Riviere-Cazaux Cecile , Lee Byung Ha , Flickinger Lynn , Parney Ian , Campian Jian
Published: November 2023

Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. Despite maximal surgical resection, irradiation, and chemotherapy, median overall survival (OS) for recurrent GBM (rGBM) remains at only 30 weeks. GBM tumors have an immune-suppressive microenvironment with low numbers of tumor-infiltrating lymphocytes (TILs). Interleukin 7 (IL-7) plays a key role in T cell homeostasis and survival, with IL-7 inducing T cell expansion in lymphopenic conditions. Efineptakin alfa (NT-I7), a long-acting IL-7, has been shown to increase effector CD8 T cells and reduce suppressor T-regulatory cells in murine GBM models, with subsequently improved OS. We recently completed a Phase I study in newly diagnosed GBM patients which showed that NT-I7 is safe, well-tolerated, and increased absolute lymphocyte counts (ALCs), and determined maximum tolerated dose for Phase II. We hypothesized that NT-I7 may not only mitigate GBM treatment-associated immune suppression, but also potentiate the effect of immune checkpoint blockade, leading to an increase in TILs and improved survival. The purpose of this study is to evaluate the safety and efficacy of combining NT-I7 and pembrolizumab in rGBM patients. This is an open-label, single arm one-stage Phase II study of NT-I7 and pembrolizumab as neoadjuvant and adjuvant therapy with surgery for adult patients with rGBM. We plan to enroll 30 evaluable patients, including a 6-patient safety run-in. The primary endpoint is the 9-month OS rate. Secondary endpoints include progression-free survival, objective response rate, changes in ALC, and adverse events profile. The correlative endpoints include studies to assess the anti-glioma immune response, changes in T cell subsets and functionality, peripheral cytokine quantification, and immunohistochemical analysis of GBM tissue. Longitudinal cerebrospinal fluid proteomics is optional. This study opened in Jan 2023. Six (6) of the planned thirty (30) patients had been enrolled by time of submission.
CTIM-36. IMMUNOHISTOCHEMISTRY EVALUATION ON PRE-TREATMENT TUMOR TISSUE PREDICTS TREATMENT RESPONSE TO MN-166 (IBUDILAST) AND TEMOZOLOMIDE COMBINATION THERAPY IN GLIOBLASTOMA PATIENTS
Authors: Lathia Justin , Lauko Adam , Matsuda Kazuko , Makhay Malath , Nayak Lakshmi , Chukwueke Ugonma , Lee Eudocia , Reardon David , Beroukhim Rameen , Batchelor Tracy , Aquilanti Elisa , Wen Patrick
Published: November 2023

STUDY DESIGN

MN-166-GBM-1201 is a Phase I/II open-label clinical trial to evaluate MN166 (ibudilast) and temozolomide (TMZ) combination treatment in newly diagnosed and recurrent glioblastoma (GBM) patients. 62 GBM patients (34 newly diagnosed and 28 recurrent) were enrolled in the study. All patients received MN-166 and TMZ combination treatment until disease progression or withdrawal from the study for other reasons.

METHODS

Pre-treatment tumor tissue at initial surgery from 24 study participants was evaluated to determine potential predictors of response to MN-166, which has been shown to inhibit the interaction between macrophage migration inhibitory factor (MIF) and CD74 with ERK phosphorylation downstream of CD74. We looked at CD11b and CD3 expression to characterize the immune profile within the tumors and Ki67 to determine percentage of proliferating tumor cells, all of which were calculated by a masked researcher. Then, patients were stratified based on progression within the first five months after receiving MN-166 and TMZ.

RESULTS

Patients who did not progress within 5 months had a significantly lower percentage of CD3+ T cell infiltration than nonresponding patients (p = 0.045), and CD74 expression was lower in patients with no progression (p = 0.16). The other markers demonstrated no differences. MN-166 and TMZ combination therapy was generally safe and well tolerated.

CONCLUSION

CD3 expression was a good predictor for tumor progression for five months in recurrent GBM patients treated with MN-166 and TMZ. T cell infiltration within GBM tumors has been an active area of research with the success of immune checkpoint blockade (ICB) therapies in other cancers. Moreover, MN-166 has been shown to impact immune suppressive myeloid cells, which are linked to the immune suppressive tumor microenvironment and a resistance mechanism to ICB. Collectively, we postulate that the efficacy of MN-166 for treatment of GBM could be further enhanced by co-treatment with ICBs.
CTIM-38. NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS
Authors: Karschnia Philipp , Arrillaga-Romany Isabel , Eichler April , Forst Deborah , Gerstner Elizabeth , Jordan Justin T , Ly Ina , Plotkin Scott R , Wang Nancy , Martinez-Lage Maria , Winter Sebastian F , Tonn Joerg-Christian , Rejeski Kai , von Baumgarten Louisa , Cahill Daniel , Nahed Brian V , Shankar Ganesh M , Abramson Jeremy S , Barnes Jeffrey A , El-Jawahri Areej , Hochberg Ephraim P , Johnson P Connor , Soumerai Jacob D , Takvorian Ronald W , Chen Yi-Bin , Frigault Matthew J , Dietrich Jorg
Published: November 2023

BACKGROUND

Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, efficacy data for patients with CNS involvement are limited. Also, there are concerns about increased neurotoxicities (denoted by the term 'ICANS') when the target antigen is present within the CNS.

METHODS

We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a five-year period.

RESULTS

Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe ICANS (grade 3-4) after 7/45 transfusions (15.6%). No fatalities were directly attributed to ICANS. A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Similar response rates were seen in both patients with parenchymal and leptomeningeal involvement. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010).

CONCLUSION

CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted to boost the success of such therapy.