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Univariate and multivariate survival analysis.

S1 shows intratumor mutation heterogeneity between two specimens of one tumor. S2 describes mutational load of the patient cohort. S3 shows survival difference based on histology. S4 shows mutational signature.

Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here, we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2,485 somatic mutations, including single-nucleotide substitutions and small indels, using a validated in-house protocol. Sixty-one percent of the mutations were contributed by 12 hypermutators. The hypermutators were enriched for recurrent tumors and had comparable outcome, and most were associated with temozolomide exposure. TP53 was the most frequently mutated gene in our cohort, followed by IDH1 and EGFR. We detected at least one EGFR mutation in 23% of LGGs, which was significantly higher than 6% seen in The Cancer Genome Atlas, a pattern that can be partially explained by the different patient composition and sequencing depth. IDH hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%). Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of IDH mutation. We predicted 1p/19q status using the panel sequencing data and received only modest performance by benchmarking the prediction to FISH results of 50 tumors. Targeted therapy based on the sequencing data resulted in three responders out of 14 participants. In conclusion, our study suggests ultradeep targeted sequencing can recapitulate previous findings and can be a useful approach in the clinical setting.

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Purpose:Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets.Patients and Methods:Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106–1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment.Results:We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0–8.3 months]; 6-month PFS was 19% (95% CI, 7%–52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas.Conclusions:Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

Supplementary Figure 3

Background Medulloblastoma in adults is rare and treatment decisions are largely driven from pediatric literature. We sought to characterize recurrent medulloblastoma in adults. Methods From a single-institution dataset of 200 adult patients diagnosed with medulloblastoma during 1978–2017, those with recurrence were analyzed for clinical features, treatment, and outcome. Results Of the 200 patients, 82 (41%) with median age of 29 years (18–59) had recurrence after a median follow-up time of 8.4 years (95% CI = 7.1, 10.3). Of these, 30 (37%) were standard-risk, 31 (38%) were high-risk, and 21 (26%) had unknown-risk diseases at the time of initial diagnosis. Forty-eight (58%) presented with recurrence outside the posterior fossa, of whom 35 (43%) had distant recurrence only. Median Progression-free survival (PFS) and OS from initial surgery were 33.5 and 62.4 months, respectively. Neither PFS nor OS from initial diagnosis differed between the standard-risk and high-risk groups in those who experience recurrence (P = .505 and .463, respectively). Median OS from first recurrence was 20.3 months, also with no difference between the standard-risk and high-risk groups (P = .518). Recurrences were treated with combinations of re-resection (20 patients; 25%), systemic chemotherapy (61 patients; 76%), radiation (29 patients; 36%), stem cell transplant (6 patients; 8%), and intrathecal chemotherapy (4 patients; 5%). Patients who received radiation at recurrence had better OS (32.9 months) than those who did not (19.2 months) (P = .034). Conclusions Recurrent medulloblastoma in adults has a poor prognosis irrespective of initial risk stratification. Recurrence commonly arises outside the posterior fossa years after initial diagnosis.

Background Patients with high‐grade glioma (HGG) face unique challenges toward the end of life (EoL), given their aggressive trajectory and neurologic deterioration. Aggressiveness of medical care at EoL has been identified as an important quality metric for oncology patients. At this time, limited data exist around the nature of EoL care of patients with HGG. Methods Patients with HGG and palliative care (PC) referral seen between 2010 and 2015 were identified (N = 80). Of these, N = 52 met inclusion criteria. Random selections of patients with (1) HGG not referred to PC (n = 80), and (2) non‐CNS cancers with PC referral (n = 80) were identified for comparison. A composite score of aggressiveness of medical care at EoL was calculated for each patient from predetermined variables. A time of eligibility for PC was defined for each patient when predetermined criteria based on symptom burden, functional status, and prognosis were met. Results Among the patients analyzed with HGG referred to PC, 59.6% (N = 31) were referred as inpatients, and 53.8% (N = 28) were referred within the last 12 weeks of life. Patients with HGG had similar aggressiveness of care at EoL regardless of PC referral, and HGG patients had less aggressive care at EoL than patients with non‐CNS cancers (p = 0.007). Care was more aggressive at EoL in HGG patients who received late versus early PC referrals (p = 0.012). Motor weakness at time of eligibility (OR = 2.55, p = 0.002) and more disease progressions (OR = 1.25, p = 0.043) were associated with less aggressive care at EoL. Conclusions Early clinical‐ and disease‐related features predict the aggressiveness of medical care at EoL in patients with HGG. Formal PC consultation is used infrequently and suboptimally in patients with HGG. Our data suggest that the role of PC in improving EoL outcomes in HGG warrants further evaluation., Aggressiveness of medical care at end of life (EoL) has been identified as an important quality metric for EoL care; however, to date, this has not been studied in patients with high‐grade glioma. This retrospective study finds less aggressive medical care at EoL in patients with glioma compared with other cancers. We also found that palliative care is often used late and in the inpatient setting in this population, limiting its clinical impact.

Despite their significant distress, supportive care interventions for caregivers of glioma patients are generally lacking. And, whether caregivers are more likely to benefit from interventions targeting patient-caregiver dyads or caregivers individually is unknown. This pilot randomized controlled trial compared the feasibility and preliminary efficacy of a dyadic yoga (DY) versus an individual caregiver yoga (CY) intervention as a supportive care strategy for family caregivers.Patient-caregiver dyads were randomized to a DY, CY or usual care (UC) arm. DY and CY interventions were delivered over 15 sessions. Caregivers completed assessments of their depressive symptoms, quality of life (QOL), and caregiving reactions at baseline, 6 weeks, and 12 weeks, and a subset completed qualitative interviews at 12 weeks.With a consent rate of 63%, 67 dyads were randomized. Attendance in the DY was higher than in the CY group (session means, DY = 12.23, CY = 9.00; p = 0.06). Caregivers (79% female; 78% non-Hispanic White; mean age, 53 years) reported significantly more subjective benefit in the CY arm than in the DY arm (d = 2.1; p .01), which was consistent with the qualitative assessment. There were medium effect sizes for improved mental QOL (d = 0.46) and financial burden (d = 0.53) in favor of the CY over the UC group. Caregivers in the CY group reported more caregiving esteem (d = 0.56) and less health decline (d = 0.60) than those in the DY group.Individual rather than dyadic delivery may be a superior supportive care approach for this vulnerable caregiver population. A larger, adequately powered efficacy trial is warranted.

Treatment of recurrent gliomas is especially challenging, as many of these patients have previously been treated with extensive surgery, radiation, or systemic therapy. Due to this, the optimum therapy for patients with recurrent glioma is controversial, with widely variable practice patterns. In this opinion piece, a multidisciplinary panel of experts provides rationale for their treatment approach in a patient with recurrent glioma following subtotal resection with adjuvant chemoradiation for an anaplastic astrocytoma. In summary, the consensus of the panel was to recommend re-resection if possible with hypofractionated radiotherapy schedules, with re-irradiation and systemic therapy as directed by a multidisciplinary team through repeat analysis of the tumor specimen for an updated mutational burden.

Objectives Although patients with primary and metastatic brain tumors and their partners are at risk of experiencing high symptom burden, they are often excluded from psychosocial intervention studies. Thus, we sought to examine the feasibility and preliminary efficacy of a couple-based meditation (CBM) program targeting symptom and well-being outcomes. Methods Couples completed baseline measures assessing symptom and well-being outcomes and were randomized to the CBM or a usual care control group. Couples in the CBM groups attended four weekly (60 minutes each) therapist-led sessions that were delivered via FaceTime (Apple Inc, Cupertino, CA). The CBM program focused on cultivating mindfulness, compassion, gratitude and purpose, and integrated emotional disclosure exercises. Both groups were reassessed six and 12 weeks after baseline. Results We approached 60 eligible dyads, of which 37 (62%) consented, 35 (95%) were randomized, and 22 (63%) completed all assessments. Couples in the CBM group attended a mean of 3.33 sessions (SD 1.09). For patients, significant group differences in favor of the CBM group were found for cognitive (d = 1.05) and general disease symptoms (d = 0.93), and relationship well-being (d = 0.68) and compassion (d = 0.96). No significant group differences were revealed for partners. Conclusion It seems to be feasible, acceptable, and possibly efficacious to deliver a dyadic intervention via FaceTime to brain tumor couples. Although both patients and partners in the CBM group rated the intervention as beneficial, significant group differences with medium-to-large effect sizes were only found for patients.

Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard of care treatment, with a median overall survival of 3-9 mo. after recurrence. There are limited treatment options available upon progression of disease which may include potential participation in clinical trials. However, patients may not meet the strictly defined entry criteria to participate in these clinical trials. VAL-083 is a first-in-class bifunctional alkylating agent that acts independent of O6-methylguanine-DNA-methyltransferase (MGMT) methylation status. Under an Expanded Access (EA) program, we have treated 24 patients with recurrent GBM, who were not eligible to participate in clinical trials with VAL-083. Four (4/24; 17%) patients had leptomeningeal disease (LMD) at time of enrolment. While safety data was assessed for all patients, those without LMD (20 patients) were evaluated for efficacy. All patients evaluated for efficacy received chemoradiation with TMZ, and the mean number of adjuvant TMZ cycles was 5 (± 6.2). The median time from last progression to start of VAL-083 was 0.65 mo. (95%CI: 0.32-1.55) and median KPS was 80 (25-75P: 70-90). Eight (8/20; 40%) patients had 2 or more prior recurrences, 9/20 (45%) patients had multifocal disease, and 5/20 (25%) had prior lomustine. Eighteen (18/20; 90%) patients had unmethylated promoter status for MGMT and 18/20 (90%) were IDH wild type. All patients had at least 1 mutation, with 11/20 (55%) having 5 or more mutations, and one patient had hypermutator phenotype with MSH6 mutation. The most common mutations were, TERT 11/20 (55%), PTEN 9/20 (45%), and TP53 6/20 (30%). All patients started treatment with VAL-083 at 30 mg/m2 administered on 3 consecutive days every 21 days. Seven patients received bevacizumab concurrently with VAL-083. VAL-083 was well tolerated and the main adverse events were consistent with prior experience, i.e., thrombocytopenia and neutropenia. Eight (8/24; 33%) patients had a dose reduction, 7 of which were due to thrombocytopenia, and 1 due to neutropenia. Five patients with thrombocytopenia had prior lomustine. As of cut-off date (05 Jan, 2023), median progression free survival (mPFS) and median overall survival (mOS) from last disease progression was 5.9 mo (95%CI: 3.9-7.9) and 9.4 mo (95%CI: 3.0-14.3), respectively. In patients without multifocal disease mOS was even longer, 14.3 mo (95%CI: 3.9-14.3). Use of VAL-083 in this expanded access study showed benefit in the treatment of recurrent GBM patients even those who have had multiple recurrences and were not candidates for the treatment through clinical trial. Additional safety and efficacy measures will be presented at the meeting.Clincialtrials.gov Identifier: NCT03138629. All EA treatment requests and plans were approved by MD Anderson Cancer Center IRB. Citation Format: Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Rebecca A. Harrison, Nazanin K. Majd, Ashley E. Aaroe, Stephanie Knight, Teresa Hanna, Timothy A. Gregory, John Langlands, Dennis Brown, Vinay K. Puduvalli. VAL-083 in patients with recurrent glioblastoma treated under expanded access program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB127.

BACKGROUND This pilot RCT compared the feasibility and preliminary efficacy of a dyadic versus individual yoga intervention as a supportive care strategy for family caregivers of high grade glioma patients. METHODS Caregivers completed self-reported assessments of QOL (SF-36) and caregiver burden (CRA) and were then randomized to a patient-caregiver dyadic yoga (DY), caregiver yoga (CY) or usual are (UC) arm while patients were undergoing standard radiotherapy. Both yoga programs were delivered over 15 sessions either in-person or via videoconference (Zoom). All groups were re-assessed at the end of treatment and then again 3-months later. RESULTS We consented 76 dyads (59%) and randomized 23 to the DY, 22 to the CY, and 22 to the UC arm. Attendance in the DY was higher than in the CY group (means, DY=12.23, CY=9.00, P=.06, d=.57). Caregivers reported significantly more overall subjective benefit in the CY compared to the DY arm (means, CY=1.39, DY=1.81, P< .05, d=1.45). Caregivers slightly favored the in-person delivery (means, in person: 1.48; zoom: 1.82, P=.10; d=.77). A clinically significant, medium effect size was found for improved QOL in favor of the CY over the DY group (means, CY=49.45, DY=44.45; F=3.58, P=.07; d=.67). Caregivers in the CY group reported less caregiving-related health declines compared to the DY group (means, CY=2.18; DY=2.48; F=4.23, P< .05; d=.42). Caregivers in the CY group reported less caregiving-related financial burden than the UC group (means: CY=2.79; UC=3.21; F=3.32, P=.08; d=.35). CONCLUSION Despite lower attendance, caregivers in the CY arm reported greater subjective overall benefit, experienced better mental QOL and less caregiver burden compared with those in the DY and UC comparison arms. It appears that individual rather than dyadic delivery may be a superior supportive care approach for this vulnerable caregiver population. An adequately powered, larger trial of this intervention strategy is warranted.

Background We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. Methods In an open-label, single-center, single-arm phase II “window-of-opportunity” trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor. Results No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients’ recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages. Conclusions Immune analyses indicated that pembrolizumab anti–programmed cell death 1 (PD-1) monotherapy alone can’t induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.

// Shelli R. Kesler 1 , 2 , * , Rebecca A. Harrison 3 , * , Melissa L. Petersen 3 , Vikram Rao 1 , 2 , Hannah Dyson 3 , Kristin Alfaro-Munoz 3 , Shiao-Pei Weathers 3 and John de Groot 3 1 Cancer Neuroscience Laboratory, School of Nursing, The University of Texas at Austin, Austin, Texas, USA 2 Department of Diagnostic Medicine, Dell School of Medicine, The University of Texas at Austin, Austin, Texas, USA 3 Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA * These authors contributed equally to this work Correspondence to: Shelli R. Kesler, email: srkesler@austin.utexas.edu Keywords: MRI; IDH; glioma; machine learning; connectomics Received: July 04, 2019 Accepted: October 21, 2019 Published: November 05, 2019 ABSTRACT Background Gliomas are the most common type of malignant brain tumor. Clinical outcomes depend on many factors including tumor molecular characteristics. Mutation of the isocitrate dehydrogenase (IDH) gene confers significant benefits in terms of survival and quality of life. Preoperative determination of IDH genotype can facilitate surgical planning, allow for novel clinical trial designs, and assist clinical counseling surrounding the individual patient’s disease. Methods In this study, we aimed to evaluate a novel approach for non-invasively predicting IDH status from conventional MRI via connectomics, a whole-brain network-based technique. We retrospectively extracted 93 connectome features from the preoperative, T1-weighted MRI data of 234 adult patients (148 IDH mutated) and evaluated the performance of four common machine learning models to predict IDH genotype. Results Area under the curve (AUC) of the receiver operator characteristic were 0.76 to 0.94 with random forest (RF) showing significantly higher performance ( p < 0.01) than other algorithms. Feature selection schemes and the addition of age and tumor location did not change RF performance. Conclusions Our findings suggest that connectomics is a feasible approach for preoperatively predicting IDH genotype in patients with gliomas. Our results support prior evidence that RF is an ideal machine learning method for this area of research. Additionally, connectomics provides unique insights regarding potential mechanisms of tumor genotype on large-scale brain network organization.

BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (>20 years old) and seven pediatric (

Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here, we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2,485 somatic mutations, including single-nucleotide substitutions and small indels, using a validated in-house protocol. Sixty-one percent of the mutations were contributed by 12 hypermutators. The hypermutators were enriched for recurrent tumors and had comparable outcome, and most were associated with temozolomide exposure. TP53 was the most frequently mutated gene in our cohort, followed by IDH1 and EGFR. We detected at least one EGFR mutation in 23% of LGGs, which was significantly higher than 6% seen in The Cancer Genome Atlas, a pattern that can be partially explained by the different patient composition and sequencing depth. IDH hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%). Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of IDH mutation. We predicted 1p/19q status using the panel sequencing data and received only modest performance by benchmarking the prediction to FISH results of 50 tumors. Targeted therapy based on the sequencing data resulted in three responders out of 14 participants. In conclusion, our study suggests ultradeep targeted sequencing can recapitulate previous findings and can be a useful approach in the clinical setting.

Background It is estimated only 8–11% of patients with glioblastoma (GBM) enrol in clinical trials, limiting treatment development. We analysed the clinical and demographic features of patients with GBM enroled in clinical trials at the University of Texas MD Anderson Cancer Center (MDACC). Methods We reviewed the records of adult patients treated for primary GBM between 2007 and 2012 at the MDACC. A total of 755 patients were identified: 133 were deemed non-eligible, 111 were deemed trial eligible but received standard care and 511 participated in a clinical trial (311 for newly diagnosed glioblastoma [nGBM] and 200 for recurrent glioblastoma [rGBM]). Population characteristics were analysed using descriptive statistics, and survival end-points were evaluated with the Kaplan–Meier method. Results The median age of clinical trial participants and trial eligible patients was 53.2 years (standard deviation 12.1). Most patients (49.4%) were enroled in a clinical trial protocol for nGBM. The majority of nGBM trial participants were male patients (65.1%), white (86.3%), married (84.4%) and in state (59.9%). Employment status, education, symptoms, tumour location, performance status, extent of resection and treatment facility differed between nGBM trial participants and non-participants. Patients who were eligible but did not enrol tended to be older, have worse performance status and live farther away from the MDACC. Conclusion Numerous disease and demographic barriers exist in trial enrolment in patients with GBM. This study highlights some of these obstacles, which require attention to improve patient enrolment to clinical trials. Patient and physician engagement in novel therapeutic strategies is essential to improving outcomes in this disease.

In efforts to understand financial distress (FD) associated with advanced cancer care from the perspective of both patients with incurable disease and their spousal caregivers, we assessed FD in both members of the couple, identified symptom and quality of life (QOL) correlates, and examined the potential role of illness communication.Patients undergoing treatment for stage III/IV lung cancer or a grade III/IV primary brain tumor and their spousal caregivers (n = 76 dyads) completed measures of somatic and affective symptoms including FD, physical and mental QOL, and ease of engaging in illness communication. Patients and caregivers additionally rated their perception of each other's symptoms, including FD.FD was endorsed by both patients (any FD 62.7%; high FD 24%) and spousal caregivers (any FD 64.7%; high FD 32.3%). Self-reported FD was significantly correlated (partial r = .52, p .001) within couples. FD was associated with greater symptoms of anxiety (r = .29, p = .01; r = .31, p = .01), depression (r = 29, p = 01; r = .39, p = .001), and poorer physical QOL(r = - .25, p = .03; r = - .25, p = .001) for patients and caregivers, respectively. For patients, FD was additionally associated with poorer mental QOL(r = - .44, p .001). Caregivers accurately perceived patient FD, yet patients tended to underreport their caregiver's FD by almost an entire point (t = 2.8, p = .007). A 3-way interaction (FD X role X illness communication) revealed (b = .40, p = .041) that illness communication moderated the association between FD and physical QOL for spouses so that spouses who reported less ease of illness communication demonstrated a stronger association between financial distress and physical QOL (b = - 2.08, p .001) than those reporting greater ease of engaging in illness communication (b = .49, p = .508).In the advanced cancer setting, FD is prevalent in both patients and their spousal caregivers and associated with psychological distress and poor physical QOL. Results suggest that optimal FD assessment should include patients and spouses, and spouse's ease of engaging with illness communication may be a potential target for future intervention studies.

Background There is an urgent need for additional therapies to treat recurrent glioblastoma (GBM). Preclinical studies suggest that high dose macitentan, an oral dual endothelin receptor antagonist, enhances the cytotoxic effects of temozolomide (TMZ) in GBM, improving survival. This phase I trial investigated the maximum tolerated dose of macitentan combined with TMZ in patients with recurrent GBM and assessed the safety and tolerability of high dose macitentan in these patients (NCT01499251). Methods Adults with recurrent GBM received ascending doses of macitentan from 30 mg once daily concomitantly with TMZ. Safety and tolerability were assessed in addition to exploratory efficacy and pharmacokinetic endpoints. An ancillary study examined biomarker expression following macitentan treatment prior to surgical resection of recurrent GBM. Results Thirty-eight patients with recurrent GBM were administered macitentan doses up to 300 mg once daily; no dose-limiting toxicities were observed, and a maximum tolerated dose was not determined. All patients experienced at least one treatment-emergent adverse event (TEAE), the majority associated with GBM or TMZ treatment. TEAEs related to macitentan and TMZ were reported for 16 (42.1%) and 26 (68.4%) patients, respectively, with no serious macitentan-related TEAEs. Macitentan concentrations increased with dose, with no plateau in exposure. Substantial heterogeneity was observed in the expression of efficacy biomarkers within tumors. The Kaplan-Meier estimate of median overall survival across all dose groups was 9.4 (95% CI 8.5, 13.4) months. Conclusion High-dose macitentan was well tolerated in recurrent GBM patients concomitantly receiving TMZ. TEAEs were consistent with those seen in patients receiving either drug individually.

Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard of care treatment, with a median survival after recurrence of 3–9 months. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA repair. This trial is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-radiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1); and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2), compared to historical controls in both groups. Tumor response will be assessed by MRI every 42 days, using RANO criteria. The initial starting dose in this study was 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle, which was subsequently reduced to 30 mg/m2/d to improve tolerance due to myelosuppression. As of June 2-2020, 35 patients with recurrent GBM (Group 1) have received 40 mg/m2/d and 39 patients have received 30 mg/m2/d VAL-083. In the adjuvant setting (Group 2), 25 patients have been enrolled (30 mg/m2/day). Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

BACKGROUND WHO grade II and III IDH wild-type astrocytomas behave more aggressively than their IDH mutated counterparts. A subpopulation shares molecular features with the novel entity proposed in cIMPACT-NOW Update 3 “Diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma (GBM), WHO IV”. METHODS We performed a retrospective analysis of clinical and molecular features, management and survival of 134 adult patients treated for grade II and III IDH wild-type astrocytoma between 06/2012 and 12/2018 at MD Anderson Cancer Center (MDACC - 112) and UT Health Science Center at Houston (UTHSC - 22). All patients had IDH1 sequenced, all but 2 had IDH2 sequenced, and 73 had further next generation sequencing. RESULTS Median age at diagnosis was 53 (interquartile range 18-83). 82 patients (61%) were male. 31 patients were histologically diagnosed with grade II astrocytoma, 102 with grade III astrocytoma, and one with diffuse glioma (insufficient tissue to render histologic grade or perform sequencing). EGFR alterations were found in 31 patients and TERT promoter mutations in 22. 84 (63%) received concurrent chemoradiation and adjuvant temozolomide (grade II, n=9; grade III, n=74; NOS, n=1). PFS overall was 12.0 months (grade II = 17.9; grade III = 10.7). OS in patients treated with concurrent chemoradiation and adjuvant temozolomide was 17.1 months versus 17.7 in patients treated with sequential radiation and temozolomide (p = NS), and 10.6 in patients treated with RT alone or surveillance (p< 0.016). The highest 2-year OS was seen in grade II patients treated with concurrent chemoradiation and adjuvant temozolomide (60%). CONCLUSIONS WHO grade II and III IDHwt astrocytoma survival is similar to historical GBM cohorts. The proportion meeting molecular criteria for GBM is yet undefined. Groups who received chemotherapy may perform better than those who do not. Further analysis of MGMT methylation and other molecular factors is ongoing.

BACKGROUND Patients with high-grade gliomas (HGG) face unique challenges toward the end of life (EoL), given their aggressive disease trajectory and progressive neurologic deterioration. The discipline of supportive care (SC) has been beneficial in improving quality of EoL care in patients with non-CNS cancers, however data on its contribution to EoL care in patients with HGG is lacking. METHODS We retrospectively reviewed charts of MDA patients from 2010-2017 to compare the demographic factors and clinical and quantitative EoL outcomes between patients with HGG--who were either referred (n=54) or not referred (n=85) to SC--and patients with non-CNS cancers who were referred to SC (n=72). A composite score for poor EoL quality outcomes was used with the following variables: death in hospital, chemotherapy within 14d of death, ≥2 hospitalizations, ≥2 ER visits, ICU admission and >14 days hospitalization within the last 30 days of life. Patients were eligible for SC based on poor/declining performance status, < 6 month prognosis, or recurrent GBM. RESULTS Patients with HGG had similar EoL quality regardless of SC referral, and these patients in general had better EoL quality than patients with non-CNS cancers (p=0.005). EoL quality was significantly worse in HGG patients who received late versus early SC referrals (p=0.0066). Both weakness (OR=1.27, p=0.0289) and number of disease progressions (OR=2.618, p=0.001) at the time of eligibility for SC were predictive of poorer quality of EOL. The majority of HGG patients (61.2%) eligible for SC were not referred. CONCLUSIONS EoL outcomes in patients with malignant gliomas are overall better than those of patients with non-CNS cancer, however certain clinical features and later SC referral remain significantly associated with poorer EoL quality. Our data suggest that the role of SC in improving EoL outcomes in our patient population warrants further evaluation.

Cerebral edema following chimeric antigen receptor (CAR) T-cell therapy can be fatal. ZUMA-2 is a pivotal phase 2, multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T-cell therapy, in relapsed/refractory mantle cell lymphoma. We describe a 65-year-old patient in ZUMA-2 who developed cerebral edema following CAR T-cell therapy and had complete recovery after multimodality clinical intervention including rabbit antithymocyte globulin (ATG). Biomarker results show early and robust CAR T-cell expansion and related induction of inflammatory cytokines, followed by rapid declines in CAR T-cell and proinflammatory cytokine levels after ATG administration. This clinical profile highlights a potential relevance of ATG in treating severe CAR T-cell-related neurotoxicity.

We describe the institutional guidelines of a major tertiary cancer center with regard to using hypofractionated radiation regimens to treat glioblastoma as a measure to minimize exposure to coronavirus disease 2019 (COVID-19) while not sacrificing clinical outcomes. Our guidelines review level one evidence of various hypofractionated regimens, and recommend a multidisciplinary approach while balancing the risk of morbidity and mortality among individuals at high risk for severe illness from COVID-19 infection. We also briefly outline strategies our department is taking in mitigating risk among our cancer patients undergoing radiation.

Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard-of-care treatment, with a median survival of 3-9 months after recurrence. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independently of MGMT DNA repair. This trial is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated, bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1); and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2), compared to historical controls in both groups. Tumor response is assessed by MRI every 42 days, using RANO criteria. The initial starting dose in this study was 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle, which was subsequently reduced to 30 mg/m2/d to improve tolerance due to myelosuppression. As of May 2021, Group 1 (Recurrent GBM) is fully enrolled: 35 evaluable patients have received 40 mg/m2/d and 48 evaluable patients have received 30 mg/m2/d VAL-083. In the adjuvant setting (Group 2), 35 evaluable patients have been enrolled (30 mg/m2/day). Enrollment, safety data and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

BACKGROUND Checkpoint inhibitor therapy has demonstrated overall limited efficacy in the treatment of GBM. Mechanisms of resistance to checkpoint blockade need to be better elucidated. Analysis of the tumor microenvironment is critical to identify correlates of response to immune checkpoint blockade. 60 newly diagnosed GBM patients unselected for MGMT status underwent treatment with concurrent atezolizumab with radiation therapy and TMZ followed by adjuvant atezolizumab and TMZ (NCT03174197). Clinical data has been reported previously. METHODS Tissue image immunoprofiling was conducted using 2 multiplex immunofluorescence (mIF) panels against; CD3, CD8, PD-1, PD-L1, Granzyme B, FOXP3, CD45RO, CD68, and GFAP antibodies. PDL-1 (Clone SP263) malignant cells expression was assessed by immunohistochemistry. Correlations between mIF biomarkers co-expressions, IHC PD-L1, and clinical outcome including OS, radiographic response, and PFS were evaluated. RESULTS Of 60 patients enrolled, image immunoprofiling was performed successfully on pre-treatment tissue in 48 patients. 20 of 60 patients underwent re-resection for suspected recurrent disease of which 10 patients had immunoprofiling performed successfully on pre and post treatment samples. An analysis of CD3CD8+ cytotoxic T lymphocytes was consistent with prior work, showing no or relatively low levels at baseline, and no association with clinical outcome. PDL-1 expression by IHC, at thresholds of >1% or >5%, was not associated with clinical outcome. Tumors with a higher number of GFAP-expressing cancer cells had a significantly lower tumor response (p< 0.05) and median OS (430 vs. 799 days, p< 0.01). CONCLUSIONS For newly diagnosed GBM patients treated with standard of care radiation and temozolomide in combination with atezolizumab, T-cell levels and PDL-1 expression were not predictive of outcome. GFAP may represent a novel predictive biomarker of overall survival. Ongoing studies to evaluate the gut microbiome and tumor genomic (WES, CNA) and transcriptomic (RNAseq) features of these and matched tumors are underway.

156 Background: Seeking to address the well-documented burden of caring for a loved one with a high-grade glioma, this pilot RCT compared the feasibility and preliminary efficacy of a dyadic versus individual yoga intervention as a supportive care strategy for family caregivers. Methods: Caregivers completed self-reported assessments of QOL (SF-36) and caregiver burden (CRA) at baseline. Then, patients and caregivers were randomized to either a dyadic yoga (DY) arm in which caregivers attended the sessions together with the patient, a caregiver yoga (CY) arm in which the caregiver attended all sessions individually or a usual care (UC) arm. Both yoga programs were delivered over 15 sessions either in-person or via videoconference (Zoom) concurrently while patients were undergoing standard radiotherapy. All arms were re-assessed at the end of treatment and then again 3-months later. Results: We consented 76 patient-caregiver dyads (59%) and randomized 23 dyads to the DY, 22 to the CY, and 22 to the UC arm. Attendance in the DY was higher than in the CY group (session means, DY = 12.23, CY = 9.00; P =.06, d =.57). Caregivers (80% female; 78% non-Hispanic White; mean age = 53 yrs) reported significantly more overall subjective benefit in the CY compared to the DY arm (means, CY = 1.39, DY = 1.81, P

Despite continued research efforts, glioblastoma multiforme (GBM) remains the deadliest brain tumor. Immunotherapy offers a novel way to treat this disease, the genetic signature of which is not completely elucidated. Additionally, these tumors are known to induce immunosuppression in the surrounding tumor microenvironment via an array of mechanisms, making effective treatment all the more difficult. The immunotherapeutic strategy of using tumor vaccines offers a way to harness the activity of the host immune system to potentially control tumor progression. GBM vaccines can react to a variety of tumor-specific antigens, which can be harvested from the patient's unique pathological condition using selected immunotherapy techniques. This article reviews the rationale behind and development of GBM vaccines, the relevant clinical trials, and the challenges involved in this treatment strategy.

Purpose: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets. Patients and Methods: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106–1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment. Results: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0–8.3 months]; 6-month PFS was 19% (95% CI, 7%–52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas. Conclusions: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.