Abstract BACKGROUND Myeloid-derived suppressor cells (MDSCs) exacerbate immunosuppression and immune exhaustion in glioblastoma (GBM) and promote resistance to chemoradiotherapy. Preclinical data demonstrate that inhibiting the receptor for advanced glycation end-products (RAGE) pathway using azeliragon, when combined with radiation therapy (RT), can modulate MDSC accumulation in the tumor microenvironment and improve tumor control. CAN-401 is a phase II study evaluating the safety and preliminary clinical efficacy of combining azeliragon with RT for newly diagnosed IDH-wildtype MGMT-unmethylated glioblastoma (GBM). METHODS This multi-institutional, single-arm, open-label phase II study combines azeliragon with RT (60 Gy/30 fractions). Azeliragon is administered orally with a loading dose of 30 mg twice daily for 6 days before RT, followed by 20 mg daily during and after RT. If more than one dose-limiting toxicity occurs during the safety run-in of 6 patients, additional patients will be treated at de-escalated dose levels using the rolling six design. The study hypothesizes that azeliragon and RT will improve median progression-free survival (PFS) to 9.7 months compared to historical control of 5.7 months, corresponding to a hazard ratio of 0.58. The study aims to enroll 30 evaluable patients. RESULTS From December 2023 to May 2024, 10 patients were enrolled and treated with 20 mg of azeliragon daily, including 6 patients in the safety run-in. No dose-limiting toxicity was observed, hence no dose de-escalation was needed. The most common treatment-related adverse events (AEs) were grade 1, including fatigue and lymphopenia. There were no dose modifications or discontinuations due to treatment-related AEs. Enrollment is ongoing, and updated clinical outcomes will be reported. CONCLUSIONS Azeliragon at 20 mg per day with concurrent RT is well tolerated in patients with GBM. The phase II study is currently enrolling across 8 institutions in the United States (NCT05986851).

Introduction Secondary central nervous system lymphoma (SCNSL) complicates the management of 5-15% of patients (pts) with aggressive B-cell lymphoma. Optimal management of SCNSL requires adequate treatment of both systemic and CNS disease. Prognosis remains poor, with historical cohorts reporting median overall survival (OS) of 30-60 months (mos) despite chemoimmunotherapy and autologous stem cell transplant (ASCT). To optimize treatment of both systemic and CNS disease, we adopted a modified protocol based on Ferreri et al (JCO, 2015) as our institutional approach to SCNSL. We report our single-center analysis of outcomes using the modified Ferreri (mFerreri) protocol. Methods We conducted a retrospective study of adult SCNSL pts treated with mFerreri at the University of Colorado between January 1, 2015, and December 31, 2024. Treatment consisted of an initial cycle (C) of R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) plus intrathecal (IT) methotrexate (MTX) for systemic debulking. C2 and C3 consisted of intravenous (IV) MTX (3.5g/m² on day (D) 1), cytarabine (2g/m² every 12 hours on D2–3), and rituximab (500mg/m² on D3 and 11). C4 consisted of R-EPOCH plus IT MTX for further systemic therapy. C5 consisted of cytarabine (2g/m² every 12 hours on D1, 3, 5) and rituximab (500mg/m² on D3). Pts in complete (CR) or partial remission (PR) could proceed to ASCT with thiotepa-based conditioning. Primary outcome was OS. Progression-free survival (PFS) and CR rate were also assessed. Outcomes were evaluated using Kaplan-Meier analysis and Cox regression. Results 39 pts with SCNSL were treated with mFerreri. Median age at diagnosis was 58 years (range, 26–83). 14 (36%) were female. ECOG was ≤1 at diagnosis in 37 (95%). Histologic subtypes included DLBCL (N=27, 69%), high-grade B-cell lymphoma (HGBL) in 9 pts (23%), including 7 (18%) with double-hit or triple-hit and 2 (5%) with HGBL-NOS. Burkitt and transformed lymphoma in 2 (5%) and 4 (10.3%) pts, respectively. Twenty pts (51.3%) had germinal center B-cell subtype. Most pts (97%) had stage III/IV at diagnosis. IPI score was ≥3 in 28 pts (73.7%). Of 39 pts, 25 had received 1st line of therapy (LOT; R-CHOP, R-EPOCH, or polatuzumab + R-CHP) prior to mFerreri. The median time from 1st LOT to progression was 7 mos (range, 5–13.2). Median number of mFerreri cycles was 3 (IQR 2-5); 16 pts received 2 or fewer cycles. In assessable pts, the systemic CR and PR rates were 67.1% (N=19) and 17.9% (N=5), respectively, and CNS CR and PR rates were 56.2% (N=18) and 15.6% (N=5), respectively. After median follow-up of 28.9 mos, median OS was 64.6 mos (10.4-NA) and median PFS was 21.4 mos (3.9-NA). Notably, pts who proceeded to ASCT (N=16) had a 2-year OS and PFS of 100% (100-100) and 93.3% (81.5-100), respectively, whereas pts that did not proceed to ASCT had 2-year OS and PFS of 20.9% (8.8-50) and 10.2% (2.8-37.6), respectively. Pts with CNS involvement at initial diagnosis had significantly improved median PFS (64.6 mos, 64.6-NA) compared to patients with CNS disease first detected at relapse within 12 mos (4.0 mos; 1.1-NA) or >12 mos (21.4 mos 1.3-NA) from diagnosis (p=0.04). Of the 23 pts who did not proceed to ASCT, reasons were progressive disease (PD; 39%, N=9), pt preference (26%, N=6), poor performance status (22%, N=5), hospice (35%, N=8), and alternative therapy (26%, N=6). In univariate analysis, variables associated with improved OS included ASCT (HR 0.05, CI: 0.006–0.35, p < 0.01), treatment with more cycles of mFerreri prior to ASCT (HR 0.3, CI: 0.2–0.5, p < 0.001), CNS involvement at diagnosis (vs at relapse; HR 0.3, CI: 0.09–0.9, p = 0.03), and non-GCB origin (HR 0.3, CI: 0.1–0.9, p = 0.04). In contrast, PD on PET (HR 17.1, CI: 3.0-98.1, p<0.01) or MRI (HR 14.3, CI: 3.4-60.2, p<0.001) after mFerreri, CNS relapse within 12 mos of 1st LOT (HR 6.9, CI: 1.8–25.5, p < 0.01) and ECOG ≥2 (HR 13.5, CI: 1.9–93.5, p < 0.01) were associated with inferior OS. Similar findings were observed for PFS. Multivariate analysis was limited by sample size. Conclusions Among fit pts with SCNSL, mFerreri demonstrates efficacy against both systemic and CNS disease, resulting in excellent outcomes in responders who proceed to ASCT. Additionally, pts with CNS disease detected at initial diagnosis experience improved survival, underscoring the importance of CNS staging in high-risk pts.

H3 altered gliomas represent a rare subtype of glioma most commonly seen in children but increasingly recognized in adults. Due to the rarity of these tumors, randomized controlled clinical trials have not been performed, and the ideal treatment regimen is unknown. Radiation therapy alone may not be inferior to radiation with chemotherapy. Patients diagnosed with an H3 altered glioma after the year January 1, 2017 were retrospectively identified. Sixteen patients with H3 K27-altered pathology were identified (8 female) with a median age of 30 years (R=17-42) and KPS at diagnosis of 80% (R=60-100). Five patients (3 female) with H3 G34-mutated pathology were identified with a median age of 18 years (R=17-31) and median KPS of 90% (90-100). Among the patients with H3 K27-altered gliomas, four underwent resection, eleven had biopsy alone, and one underwent laser interstitial therapy at initial diagnosis. All patients underwent radiation therapy, three without concomitant or adjuvant temozolomide. The remainder received temozolomide either concomitantly or adjuvantly along with other treatments such as Novo-TTF. All patients with H3 G34-mutated pathology underwent resection followed by focal radiation therapy with concomitant and adjuvant temozolomide, median of 12 adjuvant cycles (R=3-22). Two patients received at least one dose of CCNU with temozolomide, and one received an experimental vaccine. Patients with H3 K27-altered tumors had a median PFS and OS of 10 months and 24 months, respectively. Patients with H3 G34-mutated tumors had a median PFS and OS of 25 months and 37 months, respectively. At recurrence, 10/12 patients with H3 K27-altered glioma received salvage therapy with a median of 1 line of salvage therapy (R=1-4), while 3/4 patients with H3 G34 mutated glioma progressed and received a median of 2 lines of salvage therapy (R=1-2). Additional characteristics, molecular characterization and survival outcomes will be presented.

Myeloid-derived suppressor cells (MDSCs) contribute to immunosuppression and treatment resistance in glioblastoma (GBM). A prior phase I study showed that phosphodiesterase-5 inhibition during chemoradiotherapy reduced peripheral MDSCs, particularly in patients with a baseline absolute lymphocyte count (ALC) <2000/mm3. Preclinical data suggest that inhibiting the receptor for advanced glycation end-products (RAGE) pathway with azeliragon, when combined with radiation therapy (RT), modulates MDSC accumulation in GBM and improves tumor control. CAN-401 (NCT05986851) is a phase II study evaluating the safety and preliminary efficacy of azeliragon with RT for newly diagnosed, MGMT-unmethylated GBM. In this multi-institutional, single-arm, open-label phase II trial, patients with unmethylated GBM received azeliragon with RT (60 Gy/30 fractions) without temozolomide or tumor-treating fields. Azeliragon was administered as a 30 mg BID for six days before RT, followed by 20 mg daily during and after RT. A six-patient safety run-in was conducted, with seamless accrual to a total of 30 patients. The primary hypothesis was that azeliragon plus RT would improve median progression-free survival (PFS) to 9.7 months compared to a historical control of 5.7 months (HR: 0.58). From 12/2023 to 9/2024, 35 patients were screened, 30 enrolled, and 29 were evaluable. No dose-limiting toxicities, dose modifications, or discontinuations due to treatment-related adverse events were observed. At a median follow-up of 6.9 months, 22 patients had progressed, and 7 had died. Median PFS was 6.0 months (95% CI: 3.0-9.0), with a 6-month PFS rate of 48%. Patients with baseline ALC <2000/mm3 (n=19) had non-significantly longer PFS than those with ALC ≥2000/mm3 (median PFS 7.2 vs, 4.3 months; 6-month PFS 63% vs, 30%, p=0.18). The combination of azeliragon and RT was well tolerated but did not improve PFS. Patients with lower baseline ALC may benefit from MDSC modulation, warranting further investigation.

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity through the nuclear retention and reactivation of tumor suppressor proteins, reduced translation of oncogenes, and decreased expression of anti-apoptotic proteins. As a single agent, SEL has demonstrated brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS Through an NCI Project Team, we developed a multi-institutional phase I/II clinical trial which opened across the NCI Experimental Therapeutics Clinical Trial Network. Eligibility included histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. We evaluated safety, tolerability, and dose finding with an IQ 3 + 3 design of TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. RESULTS From October 2022 to March 2024, we enrolled 12 patients (n=11 evaluable) into phase I of the study. Patient characteristics included 82% male, median age 62 (range 50-77), 64% white. The median number of cycles administered was 6 (range 1-12). Two dose levels (SEL 60mg and SEL 80mg) were evaluated. No dose-limiting toxicities (DLTs) were observed. The most common treatment related adverse events were nausea (58%), decreased platelet count (50%), fatigue (50%), constipation (42%), vomiting (25%), decreased lymphocyte count (25%), and decreased neutrophil count (25%). Grade 3+ treatment related adverse events included nausea, grade 3 (n=1); decreased lymphocyte count, grades 3-4 (n=2); and anorexia, grade 3 (n=1). Phase I has completed enrollment and the recommended phase II dose will be SEL 80mg. Additional results will be presented. CONCLUSION Results suggest that a sequential dosing regimen of SEL+TMZ is feasible, well-tolerated, and may minimize the cumulative toxicity of SEL. The phase II randomized portion of this trial is enrolling nationwide and will investigate efficacy and candidate molecular signatures of vulnerability (NCI #10505, NCT05432804).

Abstract BACKGROUND Banan et al (PMID 2776277) recently identified infratentorial IDH-mutant astrocytomas (Inf-IDHmt) as a distinct subtype in which 80% have non-canonical mutations, precluding the use of IDH1 R132H immunohistochemistry (IHC) for diagnosis. They note “molecular testing is critical for detection of these tumors”. Only 47% have ATRX loss by IHC and only 56% have MGMT promotor methylation. Thus, it is critical that neurosurgeons take this into account during surgical planning due to the requirement for adequate tissue sample volume necessary for diagnosis. We review these diagnostic challenges in our recent single institution experience with these tumors. METHODS Database text word searches were conducted for the years 2007-2023 to generate cases, coupled with chart review. RESULTS 7 cases were identified: 3 male and 4 female, ages 27-44. All cases were small stereotactic biopsies. The histological diagnosis was made exceptionally challenging by paucity of tumor cells (especially in grade 2), coupled with the fact that 5 of 7 had non-canonical IDH-mutation and 5 of 7 showed ATRX retention by IHC, necessitating a very high index of suspicion on the part of the pathologist to send for next-generation sequencing (NGS). Due to the rare co-expression of IDH and histone mutations in this subtype, 6 of 7 had H3 K27M IHC conducted; all were negative. Due to small tissue volumes, MGMT promotor methylation testing could only be conducted on 3 of 7 cases; testing was uninformative on these 3. CONCLUSION Preoperative high index of suspicion is required to obtain maximal safe biopsy volumes of tissue for molecular and MGMT methylation testing, which should be conducted on virtually all brainstem and cerebellar biopsies.

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity via tumor suppressor protein nuclear localization and reactivation, oncoprotein translation suppression, and DNA repair inhibition. As a single agent, SEL has demonstrated adequate brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS We developed in vitro and in vivo studies to rationally design a phase I/II trial to evaluate the safety and efficacy of the sequential combination of SEL+TMZ. Sequential treatment of U87 cells and intracranial mouse xenografts demonstrated superior DNA damage (ɣH2A.X, cleaved PARP) and overall survival compared to combination or single-agent therapy (HR 0.25 [95% CI, 0.07-0.84]; p = 0.01, log-rank). We used the top-scoring pair method to identify a 6 gene-pair RNAseq signature associated with response to SEL. RESULTS Based on preclinical findings, we developed and opened a multi-institutional phase I/II clinical trial in October 2022. Eligibility includes histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. Primary objectives are safety and preliminary efficacy. Secondary objectives are overall response rate, efficacy, and prospective validation of a molecular signature of response. Phase I dose finding by IQ 3 + 3 (n = 12) involves TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. Phase II will involve randomization (n = 72) to the RP2D of SEL+TMZ versus monotherapy TMZ. Using proportional hazards regression, RHR 0.5 with p < 0.1 will demonstrate sufficient efficacy. We have enrolled 3 participants in dose level 1 (SEL 60mg) with no dose-limiting toxicities (DLTs) observed. Additional preliminary results will be presented. CONCLUSION Preliminary results suggest that a sequential dosing regimen of SEL+TMZ is feasible and initial dose is well-tolerated and may minimize the cumulative toxicity of SEL. The trial is currently enrolling nationwide (NCI #10505, NCT05432804).

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Abstract Recent review has emphasized that glioblastoma (GBM) in persons living with human immunodeficiency virus (HIV)(PLWH) is “severely underreported in the literature” (PMID 35857248), since only 24 cases could be identified. This 2022 study concluded that overall survival in this patient group is less than in persons who are HIV-negative. Given the predominantly single-case reports in the literature, it is not surprising that “data remains limited”. To this end, we report our 15-year experience with patients with HIV-positivity diagnosed at our institution. Text word search of Department of Pathology databases, 2008-2023, with review of histological sections and the medical record. 7 patients living with PLWH were identified, all males, ages at diagnosis 44-61 years, median 58 years. 3 had tumors that met histological criteria for GBM, IDH-wildtype, WHO grade 4, 1 had GBM by modern molecular criteria and 2 had astrocytoma, IDH-mutant, WHO grade 4. One of the latter had co-existent diffuse high grade B cell lymphoma intimately admixed within his glioma while the final patient had multifocal brain lesions of different neuroimaging appearances, with the bifrontal tumor consistent with GBM and posterior frontal lesions suspicious for progressive multifocal leukoencephalopathy. At the time of tumor diagnosis, 1 had HIV for 20+ years, a second was well controlled with normal CD4 count and a third had not yet been on anti-retroviral agents. Survival was poor, with 2 PLWH with IDH-mutant tumors succumbing at 2 and 4 months and 3 with GBMs at 7, 12 and 32 months; a 4th is alive at 6 months. PLWH can develop various glial tumor types including both IDH-mutant and IDH-wildtype tumors, strongly suggesting co-incident rather than causal relationship. Tumors may be first diagnosed at varying stages of their immunodeficiency disorder; survival is poor even for PLWH with IDH-mutant grade 4 tumor.

Abstract IDH 1 and IDH 2 are crucial metabolic enzymes which covert isocitrate to alpha-ketoglutarate. During this process, NADP is reduced to NADPH. Mutant IDH produces an oncometabolite, D-2 hydroxyglutarate (2-HG). Elevated 2-HG levels interfere with epigenetic regulation and cellular metabolism leading to oncogenesis and have been postulated to play a role in multiple malignancies. Mutations in IDH1 and IDH2 have been found in AML, cholangiocarcinoma, myeloproliferative, myelodysplastic syndromes, and low-grade gliomas. IDH inhibitors, although not FDA approved for treatment of glioma, have shown promise as a treatment for low-grade gliomas with IDH mutation in clinical trials. Ivosidenib is an orally available inhibitor of IDH1. We examined patients with oligodendroglioma treated off-label with ivosidenib. RANO criteria for low grade glioma was used to determine radiographic response following ivosidenib initiation. Patient ages 28 , 37 , and 37 females with oligodendroglioma, IDH1 mutated, 1p/19q co-deleted, WHO grade 2 were treated with ivosidenib. Treatment was initiated between August 2022 and March 2023. Two patients had two prior recurrences each while the third patient was treated in the neoadjuvant setting following subtotal resection. Two had stable disease as best response at follow-up of 7 and 17 months while the third is awaiting interval follow up. Duration of ivosidenib therapy was 9, 19, and 3 months respectively and is ongoing in all patients. Only grade 1 leukopenia was observed in one patient which resolved without intervention. No seizures since surgery were observed in two patients, while yearly focal seizures occurred in the third patient. Median progression free survival was not able to be determined, however preliminary data reveals stable disease as best response in all three patients without side effects or increased seizure frequency. IDH inhibitors continue to be an area of interest and ongoing research in the treatment of low-grade glioma.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

Purpose To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults. Methods ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature. Results Fifty-nine randomized trials focusing on therapeutic management were identified. Recommendations Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)–mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for MGMTpromoter unmethylated tumors), or TMZ alone (for MGMT promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines.

2068 Background: There is a lack of effective therapy for recurrent high-grade meningiomas who relapsed after prior radiation therapy (RT). ETCTN 10186 is a phase I/II study to evaluate the feasibility and preliminary clinical efficacy of combining reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab for recurrent high-grade meningiomas. The preliminary results from the phase I portion are reported here. Methods: Recurrent grade II-III meningioma patients were treated with radiosurgery plus nivolumab with or without ipilimumab. Key eligibility criteria include age ≥ 18 years; ECOG score ≤ 2; tumor diameter 1-5 cm; prior radiation dose ≤ 70 Gy; normal organ function; no active autoimmunity. During the phase I portion, eligible patients were treated according to treatment-escalation schema following the modified 3+3 design (Table 1). The maximum tolerated combination (MTC) will be the regimen at which ≤ 1/6 patients experience dose-limiting toxicity (DLT) within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. The primary endpoint of the phase I portion is to determine the MTC. Objective radiological responses (ORRs) are defined as per the Macdonald criteria. One cycle of immunotherapy is defined as 4 weeks of nivolumab with or without concurrent ipilimumab. Results: From 7/2019 to 3/2021, 13 patients were enrolled in the phase I, including 6 with regimen A and 7 with regimen B (Table). The median prior RT dose was 56 Gy (18-70) at a median interval of 2.8 years (1.3-13.3). There was no DLT in either cohort, so regimen B was deemed the MTC. The median cycles of immunotherapy completed were not significantly different between cohort A and B (11 vs. 6, p = 0.41, respectively). Three cohort A patients and 2 cohort B patients completed all planned doses of immunotherapy. Most patients stopped due to progression, and only one cohort B patient stopped due to treatment-related toxicity (grade 3 hypophysitis and encephalitis after 6 cycles of immunotherapy). After a median follow-up of 11.1 months, there have been 5 progressions and 4 deaths. The 6 month-PFS and 12 month-PFS rates are 62% and 54%, respectively. Two ORRs have been reported by institutional assessment, and central radiology review is ongoing and will be reported. Conclusions: Reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab are well tolerated for radiation-relapsed high-grade meningiomas. Phase II study of regimen B is currently enrolling. Clinical trial information: NCT03604978. [Table: see text]

Annals of NeurologyVolume 92, Issue 2 p. 159-160 ANA podcasts & Webinars ANA Investigates: The Future of Biomarkers in Alzheimer Disease Suzanne E. Schindler MD, PhD, Suzanne E. Schindler MD, PhD Deparment of Neurology, Washington University School of Medicine, St. Louis, MO & Knight Alzheimer Research Center, Washington University School of Medicine, St. Louis, MOSearch for more papers by this authorDouglas E. Ney MD, Corresponding Author Douglas E. Ney MD [email protected] orcid.org/0000-0001-7273-8141 Departments of Neurology and Neurosurgery, University of Colorado School of Medicine, Aurora, CO Address correspondence to Ney, Departments of Neurology and Neurosurgery, University of Colorado School of Medicine, 12700 E. 19th Ave,Research 2 Building, MS B-182, Aurora, CO 80045. E-mail: [email protected]Search for more papers by this authorAdeline L. Goss MD, Adeline L. Goss MD Department of Neurology, University of California San Francisco, San Francisco, CASearch for more papers by this authorGil Rabinovici MD, Gil Rabinovici MD Departments of Neurology, Radiology & Biomedical Imaging, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CASearch for more papers by this author Suzanne E. Schindler MD, PhD, Suzanne E. Schindler MD, PhD Deparment of Neurology, Washington University School of Medicine, St. Louis, MO & Knight Alzheimer Research Center, Washington University School of Medicine, St. Louis, MOSearch for more papers by this authorDouglas E. Ney MD, Corresponding Author Douglas E. Ney MD [email protected] orcid.org/0000-0001-7273-8141 Departments of Neurology and Neurosurgery, University of Colorado School of Medicine, Aurora, CO Address correspondence to Ney, Departments of Neurology and Neurosurgery, University of Colorado School of Medicine, 12700 E. 19th Ave,Research 2 Building, MS B-182, Aurora, CO 80045. E-mail: [email protected]Search for more papers by this authorAdeline L. Goss MD, Adeline L. Goss MD Department of Neurology, University of California San Francisco, San Francisco, CASearch for more papers by this authorGil Rabinovici MD, Gil Rabinovici MD Departments of Neurology, Radiology & Biomedical Imaging, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CASearch for more papers by this author First published: 11 June 2022 https://doi.org/10.1002/ana.26437Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. 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Glioblastoma and other high-grade gliomas (HGGs) are the most common and deadly primary brain tumors. Due to recent advances in immunotherapy and improved clinical outcomes in other disease sites, the study of immunotherapy in HGG has increased significantly. Herein, we summarize and evaluate existing evidence and ongoing clinical trials investigating the use of immunotherapy in the treatment of HGG, including therapeutic vaccination, immune checkpoint inhibition, adoptive lymphocyte transfer, and combinatorial approaches utilizing radiation and multiple modalities of immunotherapy. Special attention is given to the mechanisms by which radiation may improve immunogenicity in HGG, why this motivates the study of radiation in combination with immunotherapy, and how to determine optimal dosing and scheduling of radiation. Though larger randomized controlled trials have not consistently shown improvements in clinical outcomes, this area of research is still in its early stages and a number of important lessons can be taken away from the studies that have been completed to date. Many studies found a subset of patients who experienced durable responses, and analysis of their immune cells and tumor cells can be used to identify biomarkers that predict therapeutic response, as well as additional glioma-specific targets that can enhance therapeutic efficacy in a challenging tumor type.

Glioblastoma and other high-grade gliomas (HGGs) are the most common and deadly primary brain tumors. Due to recent advances in immunotherapy and improved clinical outcomes in other disease sites, the study of immunotherapy in HGG has increased significantly. Herein, we summarize and evaluate existing evidence and ongoing clinical trials investigating the use of immunotherapy in the treatment of HGG, including therapeutic vaccination, immune checkpoint inhibition, adoptive lymphocyte transfer, and combinatorial approaches utilizing radiation and multiple modalities of immunotherapy. Special attention is given to the mechanisms by which radiation may improve immunogenicity in HGG, why this motivates the study of radiation in combination with immunotherapy, and how to determine optimal dosing and scheduling of radiation. Though larger randomized controlled trials have not consistently shown improvements in clinical outcomes, this area of research is still in its early stages and a number of important lessons can be taken away from the studies that have been completed to date. Many studies found a subset of patients who experienced durable responses, and analysis of their immune cells and tumor cells can be used to identify biomarkers that predict therapeutic response, as well as additional glioma-specific targets that can enhance therapeutic efficacy in a challenging tumor type.