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Context Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior. Objective We evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas. Design A prospective, phase 2a multicenter trial was conducted. Setting This study took place at a tertiary referral pituitary center. Patients Study participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy. Intervention Intervention included oral lapatinib 1250 mg/day for 6 months. Main Outcome Measures The primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety. Results Owing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients. Conclusions An oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma.

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-γ responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies.

Purpose: Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line. Patients and Methods: Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine. Results: For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay. Conclusions: In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.

BACKGROUND Many patients with CNS tumors express interest in initiating a ketogenic diet (KD). Following a discussion with the physician regarding the limited clinical evidence of KD for CNS tumors, interested patients were referred for evaluation by an oncology-certified dietitian. METHODS We performed a single institution retrospective chart review of patients with CNS tumors on a KD. Demographics, clinical characteristics, and diet information were extracted from patient charts. Descriptive statistics were conducted to summarize patterns of adherence to KD across patient characteristics. RESULTS From May 2016 to May 2018, 40 patients expressed interest in KD; 24 initiated it. M:F = 18:6, median age 46 (range 27–62). Diagnoses: 18 glioblastoma, 1 anaplastic astrocytoma, 2 grade 2 astrocytoma, 1 grade 2 oligodendroglioma, 1 spinal grade 2 astrocytoma, 1 chordoma. 18 tumors with methylated MGMT, 8 with mutant IDH1. At diet initiation, median KPS 80 (range 70–100); median BMI 25.6 (20.8–39). Median days on diet = 190 days; interquartile range 126–673 days; range 24–1479 days. Diet composition: 15 patients on 3:1 diet (grams fat: grams protein + carbs), 7 patients on 2:1, 2 patients on 1:1. 14 patients monitored blood ketone levels. 11 patients stopped KD: 5 for restrictiveness of diet (median 158 days, range 60–239); 1 for decreased KPS (673 days); 1 for excessive weight loss (108 days); 2 for disease progression (24 and 217 days); 2 lost to follow-up (109 and 125 days). In this small sample, no statistically significant associations between time on diet and age / gender / BMI / KPS / diet composition. However, trend toward longer adherence to diet in females, age < 50, 2:1 diet. CONCLUSION It is feasible for patients with CNS tumors to adopt KD. Results from prospective studies are needed to assess effects on QOL, neurocognition, performance status, and survival.

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

BACKGROUND Emerging evidence suggests that a ketogenic diet (KD) may limit neoplastic growth, but limited data exist regarding the effect of KD on daily activity, cognition, and health-related quality-of-life (HRQOL) for patients with glioblastoma. METHODS Newly diagnosed GBM patients participating in a single-arm phase 1 trial of a 16-week KD plus standard-of-care measured BID blood glucose and ketone levels (Keto-Mojo), captured continuous activity data (Fitbit), and completed quality-of-life (QLQ30) surveys and Montreal Cognitive Assessments (MoCA) at baseline, Week 8, and study end (up to 16 weeks). NCT03451799. RESULTS All patients (n = 14; 57% female; median age 55 years) maintained blood ketones above 0.3 mM > 50% of study duration (mean per-patient days in ketosis = 87%). Mean glucose (mg/dl) and ketone levels decreased through the study – Weeks 1/2: glucose 94.9 (SD:16.5), ketones 1.44 (SD:5.82); Weeks 3/4: glucose 94.1 (SD:12.9), ketones 1.34 (SD:0.9); Final two weeks: glucose 92.3 (SD:13.3), ketones 1.13 (SD:0.7). On average, patients walked 6,836 steps/day (SD:5,129), spending 14.3 hours sedentary (SD:6.45) and 43.6 minutes (SD:60.4) in high-intensity activity. Sleep duration was 6.8 hours (SD:2.26). Patients (n = 9) with OS > 14.6 mo from diagnosis demonstrated greater minutes of high-intensity activity (58.2 vs 20.7, p = 0.001), downtrending glucose (p = 0.001), and higher ketone levels (1.40 vs 1.11, p = 0.026). Activity data corroborated the tolerability of KD with stable-to-increased activity by study end. MoCA scores were stable from baseline (mean 23.4/30, SD:4.16) to study end (mean 24.8/30, SD:7.12; p = 0.38). When viewed as a composite score, HRQOL was stable-to-improving in 10/14 patients at Week 8 and EOS. CONCLUSION The use of wearable technology and at-home testing allowed for remote monitoring of activity and diet adherence. Good adherence and stable HRQOL and activity levels were observed in this phase 1 trial.

BACKGROUND Optimal management of progressive high-grade gliomas (HGG) is not fully defined and outcomes are poor. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme which converts tryptophan to kynurenines, which contribute to the immunosuppresive tumor microenvironment (TME). Targeting the TME by inhibiting IDO1 is a strategy for potential improvement in survival in HGG. METHODS A phase 1/2 trial using the IDO1 inhibitor indoximod was conducted in progressive grade 3 and 4 gliomas. The phase 1 cmponent used a 3 + 3 design escalating indoximod from 600mg po BID to 1200mg po BID in conjunction with temozolomide (150 mg/m2, 5/28 days). The phase 2 component consisted of 3 cohorts: A) indoximod+temozolomide B) indoximod+temozolomide+bevacizumab (patients already on bevacizumab) C) indoximod+temozolomide+stereotactic radiosurgery (SRS). Patients were treated until progression or toxicity. RESULTS 33.3% of patients developed indoximod TEAEs. There were no dose limiting toxicities in the phase 1 component (n=12). 1200 mg BID was established as the phase 2 dose of indoximod. In the phase 2 component (n=148) PFS6 was 74% (A), 93% (B), 70% (C). Median OS was 289 days [10.3 months](A), 159 days [5.7 months](B), 285 days [10.2 months](C). Correlative study results will be available for meeting presentation. CONCLUSIONS The IDO1 inhibitor indoximod proved safe and tolerable in conjunction with temozolomide, bevacizumab, and SRS in patients with progressive HGG. There was a trend toward better survival outcomes when indoximod was combined with temozolomide alone or temozolomide+SRS.

INTRODUCTION There is abundant interest in the potential therapeutic and supportive role of a ketogenic diet (KD) for glioblastoma patients. We conducted a single-arm phase 1 trial to assess the safety and feasibility of KD plus standard-of-care (SOC) in glioblastoma patients (NCT03451799). METHODS Adults within 3 months of diagnosis participated in a 16-week intervention of a classic 3:1 KD (grams fat : grams carbohydrate + protein) with dietitian support. Blood glucose and ketone levels were assessed twice daily (Keto-Mojo), with remote monitoring of daily weight and activity (Fitbit). The primary objective was to assess safety (weight stability, CTCAE) and feasibility (maintaining ketosis > 0.3mM for > 50% of study period). Secondary objectives included assessments of progression-free survival (PFS), overall survival (OS), health-related quality of life (HRQOL), and cognition (MoCA). RESULTS From 04/2018-02/2021, 14 patients were evaluable: female:male, 8:6, median age 55 years, KPS 80, BMI 24.5. MGMT promoter methylation: 6 present, 7 absent, 1 indeterminate. Adherence to KD was high, with all patients maintaining ketosis ( > 0.3mM) > 50% and 11 patients maintaining ketosis > 85% of study days. Adverse events (> Grade 2) potentially attributable to KD: appetite loss (Grade 2: 2); fatigue (Grade 2: 5); flu-like symptoms (Grade 2: 1); constipation (Grade 2: 5, Grade 3: 1). No patients were removed from study for safety reasons. HRQOL was stable, with improvements in role function (not statistically significant). MoCA score improved in 10/14 patients. Median PFS and OS from KD initiation were 11.7 and 29.1 months, respectively. CONCLUSION Our findings suggest that a supervised KD plus SOC is safe and feasible in glioblastoma patients. KD was well-tolerated with encouraging trends in HRQOL and cognition. PFS and OS in this small trial compare favorably to historical control. A multicenter phase 2 trial powered to assess efficacy is planned.

Introduction: Prolactinomas are usually benign and respond well to dopamine agonist therapy. However, approximately 20% are resistant, and 10% behave aggressively and persist or recur. Treatment resistance has been associated with ErbB receptor expression, prompting us to conduct a trial of ErbB targeted therapy in patients with aggressive prolactinomas. Objective: To evaluate efficacy of the EGFR/ErbB2 tyrosine kinase inhibitor lapatinib in patients with aggressive prolactinomas. Study design: We conducted a prospective 6-month phase IIa multicenter trial of oral lapatinib 1250 mg/d in adult patients with continued tumor growth on maximally tolerated dopamine agonist therapy. Pregnant women and patients with unstable visual fields were excluded. MRI was performed every 3 months. Primary endpoint was 40% reduction in tumor size; secondary endpoints were 50% PRL reduction, PRL normalization, % PRL reduction, % tumor size reduction, and immunohistochemical correlation of clinical response with ErbB receptor expression. A target sample size of 24 subjects was estimated to achieve power >80%, using one tailed hypothesis, an alpha of 0.10, and an effect size of 0.20. Numerical variables were summarized as median (range). Results: Due to rigorous inclusion criteria, 6 subjects were enrolled. Four were female; median age was 29 years (19-70) and median disease duration 8 years (1-30). Median tumor size was 40 mm (16-60) at diagnosis. Three subjects underwent 1 surgery and 3 had 2 surgeries; 1 had radiation therapy. At study start, median maximal tumor diameter was 25 mm (13-48) and baseline PRL was 379 ng/mL (114-11748). After 6 months on lapatinib, tumor size was stable in 3 subjects, decreased in 1 with 22% tumor volume reduction, and increased in 2. PRL decreased in 3 subjects, with a median decrease of 42% (-78% to -42%) and increased in 3 by 59% (28% to 103%). Median nadir PRL was 200 ng/mL (40-11753), for an overall 25% reduction (-87% to 25%). Final median PRL was 181 ng/mL (67-1726), with a median decrease of 7% (-79% to 103%). One subject with widely metastatic pituitary carcinoma initially experienced a 25% decrease in PRL but was withdrawn at 3 months when PRL increased and metastases progressed. Excluding this subject, overall median PRL decrease was 42% (-79% to 59%). EGFR and ErbB2 expression was not detectable in tumors derived from 3 subjects and did not correlate with treatment response. Lapatinib was well tolerated with reversible grade 1 transaminitis observed in 2 subjects, grade 2 rash in 4 subjects, and grade 1 asymptomatic bradycardia in 1 subject. Conclusions: Preliminary results suggest that lapatinib may be effective in controlling tumor growth in select patients with aggressive prolactinomas. Confirming the benefit of lapatinib in aggressive prolactinomas requires a larger cohort size.

There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix, including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (α4β1γ1) with higher tumor grade and with expression of cancer stem cell (CSC) markers, including Notch pathway members, CD133, Nestin, and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients. We also showed that depletion of laminin-411 α4 and β1 chains with CRISPR/Cas9 in human GBM cells led to reduced growth of resultant intracranial tumors in mice and significantly increased survival of host animals compared with mice with untreated cells. Inhibition of laminin-411 suppressed Notch pathway in normal and malignant human brain cell types. A nanobioconjugate potentially suitable for clinical use and capable of crossing blood–brain barrier was designed to block laminin-411 expression. Nanobioconjugate treatment of mice carrying intracranial GBM significantly increased animal survival and inhibited multiple CSC markers, including the Notch axis. This study describes an efficient strategy for GBM treatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma. Significance: Laminin-411 expression in the glioma microenvironment correlates with Notch and other cancer stem cell markers and can be targeted by a novel, clinically translatable nanobioconjugate to inhibit glioma growth.

BACKGROUND: Primary CNS Lymphoma (PCNSL) is an aggressive form of diffuse large B-cell lymphoma (DLBCL). Lenalidomide is an immunomodulatory agent which has shown activity in relapsed or refractory CNS and non-CNS DLBCL. The ideal dosing, timing as consolidation therapy, and role in maintenance therapy remain unclear. METHODS: We describe 3 elderly patients with R/R PCNSL who were treated with lenalidomide. All patients had a pathological diagnosis of PCNSL, immunocompetent status, failed at least 2 previous therapies including methotrexate and rituximab. One patient had also failed autologous stem cell transplant. Lenalidomide was administered orally, 25mg/day on days 1–21 of a 28-day cycle. RESULTS: Median age was 68 (range 65–71). Median KPS was 70 (range 60–70). Patient 1 achieved complete response (CR) after cycle 4, 2 additional maintenance cycles (20mg; reduced for Grade 3–4 Thrombocytopenia), and is in remission after 11 months. Patient 2 achieved partial response (PR) after cycle 1, CR after cycle 8, and 2 additional maintenance cycles; dose reduced at cycle 6 (20mg) for Grade 3–4 Neutropenia, and is in remission after 14 months. Patient 3 achieved PR after cycle 1, mixed response after cycle 2, and died 15 weeks after start of treatment; of note, patient was also on rituximab. Molecular and immunologic correlates are pending and will be presented with the abstract. CONCLUSIONS: This case series shows lenalidomide has single agent activity in heavily pre-treated R/R PCNSL. All the patients had clinical and radiographic response to treatment. Hematologic toxicities occurred at higher dose, however even at reduced dose, lenalidomide was effective in maintaining remission. In elderly patients, using lenalidomide at relapse and deferring neurotoxic treatment options may have a role in preserving good performance status. Further prospective studies are warranted to determine the efficacy and optimal dose of lenalidomide in patients with newly diagnosed and R/R PCNSL.

Glioblastomas (GBM) are the most aggressive and prevalent form of gliomas with abysmal prognosis and limited treatment options. We analyzed clinically relevant molecular aberrations suggestive of response to therapies in 1035 GBM tumors. Our analysis revealed mutations in 39 genes of 48 tested. IHC revealed expression of PD-L1 in 19% and PD-1 in 46%. MGMT-methylation was seen in 43%, EGFRvIII in 19% and 1p19q co-deletion in 2%. TP53 mutation was associated with concurrent mutations, while IDH1 mutation was associated with MGMT-methylation and TP53 mutation and was mutually exclusive of EGFRvIII mutation. Distinct biomarker profiles were seen in GBM compared with WHO grade III astrocytoma, suggesting different biology and potentially different treatment approaches. Analysis of 17 metachronous paired tumors showed frequent biomarker changes, including MGMT-methylation and EGFR aberrations, indicating the need for a re-biopsy for tumor profiling to direct subsequent therapy. MGMT-methylation, PR and TOPO1 appeared as significant prognostic markers in sub-cohorts of GBM defined by age. The current study represents the largest biomarker study on clinical GBM tumors using multiple technologies to detect gene mutation, amplification, protein expression and promoter methylation. These data will inform planning for future personalized biomarker-based clinical trials and identifying effective treatments based on tumor biomarkers.

Author(s): Mrugala, MM; Engelhard, HH; Dinh Tran, D; Kew, Y; Cavaliere, R; Villano, JL; Annenelie Bota, D; Rudnick, J; Love Sumrall, A; Zhu, JJ; Butowski, N

BACKGROUND There is abundant interest in the potential therapeutic and supportive role of a ketogenic diet (KD) in patients with glioblastoma (GBM). The KD is a high fat/low carbohydrate metabolic therapy that modulates several of the bioenergetic and biosynthetic pathways that are dysregulated in GBM. To date, studies of the KD in cancer patients have been limited in scope. This study will provide preliminary evidence on the safety and feasibility of a 16-week ketogenic diet in patients with GBM. METHODS This is an open-label single-arm feasibility trial being conducted at Cedars-Sinai Medical Center. We will recruit 20 recently diagnosed GBM patients who are receiving standard-of-care (SOC) treatment. Patients may enroll within 3 months of diagnosis, thus allowing patients who have already begun SOC chemoradiation the opportunity to participate. Excluded are patients with a KPS < 70, BMI < 22, or on high doses of steroids. Consenting patients will maintain a 16-week ketogenic diet (KD) supervised and monitored by study dietitians (RD). The primary outcome of safety will be assessed by monitoring weight, BMI, and adverse events. Secondary outcomes are: 1) Adherence to the KD, as assessed by BID blood glucose and ketone levels; 2) Time to progression and overall survival from date of KD initiation 3) Mean change in overall QOL, as measured using the QLQ30 and QLQ-BN20 questionnaires; and 4) Mean change in cognitive scores at 16 weeks from baseline. Exploratory outcomes include metabolic, inflammatory, and immune biomarkers; gut microbiota analysis; large oncosome analysis; and daily activity assessed with a wearable activity monitor. This novel trial incorporates multiple digital devices and mobile applications into the study design. Accrual is ongoing with 10 patients currently enrolled (NCT03451799).

Background This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor-associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). Methods TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1- and/or HLA-A2-positive patients with glioblastoma (GBM) were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals. Results Twenty-one patients were enrolled with 17 newly diagnosed (ND-GBM) and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33 % responders. TAA expression by qRT-PCR from fresh-frozen tumor samples showed all patient tumors expressed at least three TAA, with 75 % expressing all six. Correlations of increased PFS and OS with quantitative expression of MAGE1 and AIM-2 were observed, and a trend for longer survival was observed with gp100 and HER2 antigens. Target antigens gp100, HER1, and IL13Rα2 were downregulated in recurrent tumors from 4 HLA-A2+ patients. A decrease in or absence of CD133 expression was seen in five patients who underwent a second resection. At a median follow-up of 40.1 months, six of 16 ND-GBM patients showed no evidence of tumor recurrence. Median PFS in newly diagnosed patients was 16.9 months, and median OS was 38.4 months. Conclusions Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumors.

Atypical and anaplastic (WHO Grades II and III) meningiomas are aggressive tumors, and patients often progress despite surgery and radiation. There is no known effective chemotherapeutic option for these patients. Meningiomas have a high expression of vascular endothelial growth factor receptor (VEGFR). We sought to retrospectively study the activity of bevacizumab, which is an anti-angiogenic agent targeting the VEGF pathway in these tumors. This is a retrospective review of WHO Grade II and III meningiomas treated at four institutions, selecting only those patients who received bevacizumab. We analyzed radiographic response according to standard RANO criteria, progression-free survival (PFS) and overall survival from the initiation of bevacizumab therapy using Kaplan-Meier statistics. We identified 15 patients across four institutions who carried a diagnosis of atypical or anaplastic meningioma and were treated with bevacizumab. Best radiographic response was stable disease. MR perfusion studies showed decreased tumor blood volume in one patient. Three patients developed non-fatal intratumoral hemorrhage. Median PFS was 26 weeks (95 % CI, 10-29 weeks). Six month PFS rate was 43.8 % (95 % CI, 15.7-69.1 %). Bevacizumab was well-tolerated in our patients, and may be considered in patients who have exhausted radiation and surgical options. Prospective studies are required to define the safety and efficacy of bevacizumab in atypical and anaplastic meningiomas.

INTRODUCTION: We conducted a single-institution phase 1 trial of a dendritic cell immunotherapy targeting glioblastoma stem-like cells for patients with either newly diagnosed or recurrent glioblastoma. METHODS: Following gross total or near-gross total resection, patients who consented to participate in this trial underwent leukapheresis for isolation of peripheral blood mononuclear cells, which were then differentiated into dendritic cells in culture, pulsed with lysate derived from an allogeneic glioblastoma stem-like cell line, and administered by intradermal injection weekly x 4 weeks, then every other month until disease progression or vaccine depletion. Patients with newly diagnosed glioblastoma were treated with standard-of-care chemoradiation, with vaccine injections beginning 1 week following the completion of radiation therapy. Patients with recurrent disease received no other disease-directed therapy while on trial. RESULTS: From December 2013 to February 2018, 38 patients enrolled in this trial -- 12 patients with newly diagnosed glioblastoma and 26 with recurrent disease. Median age 57 (range 19–77), median KPS 80 (range 70–100), 66% male. Survival functions were estimated using the Kaplan-Meier method. For newly diagnosed patients, median Time-to-Progression (TTP) was 8.86 mo, and median Overall Survival (OS) was 21.1 mo. For patients with recurrent glioblastoma, median TTP was 3.14 mo and median OS was 12.0 mo. Treatment was well-tolerated with no related grade 3/4 toxicities. As of this analysis, 7 patients are still alive, and 2 patients in the newly diagnosed glioblastoma cohort are still progression-free. Immune response studies and tumor antigen profiling are ongoing. CONCLUSION: Consistent with other previously completed dendritic cell immunotherapy trials, this phase 1 trial demonstrates improved TPP and OS for patients with either newly diagnosed or recurrent glioblastoma compared to historical controls. Ongoing efforts include characterizing and expanding the subset of patients who most benefit from immunotherapy.

Adult, malignant brainstem gliomas are rare entities that often cause treatment conundrums due to the difficulty of surgical resection and, therefore, the absence of pathological diagnosis. This leads to a reliance on radiological imaging for diagnosis, which can often be unreliable. These shortcomings have made the treatment of brainstem gliomas challenging with unpredictable outcomes. The mainstay of treatment consists of chemotherapy and radiation; however, recurrence is inevitable. Predicting outcomes has been the major difficulty in treating these patients as adult malignant brainstem gliomas Grade II have a median survival between five to seven years while Grades III and IV are between 10-17 months (with some studies showing significantly longer survival in Grade III). Here, we present the case of a patient with the pathologic diagnosis of a right brachium pontis glioblastoma who had a remarkable survival of 73 months, whereas the expected median survival for these patients is 10-17 months.

The use of immunotherapy, specifically immune checkpoint inhibitors, is a rapidly emerging and evolving treatment modality for many solid tumor types. In this abstract, we describe a case of a 70 year old male with history of PD-L1 expressing metastatic poorly differentiated NSCLC treated with anti-PD-L1 therapy who was subsequently diagnosed with a glioblastoma with evidence of unexpected tumor infiltrating lymphocytes (TILs). The lung cancer was initially treated with combination chemotherapy with excellent response. This regimen was stopped prematurely due to significant treatment-related side effects. He then received the investigational anti-PD-L1 monoclonal antibody, MPDL3280A (Roche), under the Phase II Trial of MPDL3280A for PD-L1 positive locally advanced or metastatic NSCLC (NCT02031458). He experienced partial response without significant treatment-related side effects. Two weeks after completion of his 9th cycle of the study drug, he experienced altered mental status, personality changes, and confusion. A contrast brain MRI demonstrated a multifocal, rim-enhancing, left frontal lobe lesion with corpus callosal involvement. Of note, CT brain imaging prior to anti-PD-L1 study enrollment showed no evidence of abnormal enhancement. Stereotactic biopsy was performed with pathology showing glioblastoma with significant reactive lymphoid component noted (majority of lymphoid cells CD20 positive, scattered lymphocytes CD3 positive). He then underwent near image complete resection with pathology again demonstrating glioblastoma with 20-70% tumor necrosis, with 3 genomic alterations (CDKN2A/B loss; APCI1307K; TERT promoter – 124C > T) identified on Foundation One (Cambridge, MA) Next Generation Sequencing. This is the first reported case of a patient treated with anti-PD-L1 therapy for a high grade malignancy, who then developed a de novo glioblastoma with unusual biopsy findings of CD20 and CD3 positive TILs. Although more correlative studies are currently being performed, the immune implications for the use of immunotherapy for pre-treatment of glioblastomas may correspond to improved treatment response and patient outcomes.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

2059 Background: A hallmark of glioblastoma is the high incidence of tumor recurrence, thought to be triggered by cancer stem cells. These tumorigenic cells are resistant to irradiation and chemotherapeutic agents. The target antigen, CD-133, was chosen because it has been reported as a cancer stem cell antigen overexpressed in glioblastoma tumors and associated with shorter survival. Recent clinical trials suggest that the mean overall survival for these patients is roughly 5-9 months, emphasizing the important unmet medical need in this disease requiring additional strategic approaches. Dendritic cell immunotherapies such as ICT-121 could provide benefit to patients by educating their immune systems to induce the formation of cytotoxic T cells that attack tumor cells bearing the target antigen. In addition to immediate attack on tumor cells present at dosing, a long-term memory response effective against tumor recurrence might be induced. Immunotherapy, such as ICT-121, that targets cancer stem cells could be an important treatment for this disease. Methods: This Phase I multi-center trial of ICT-121 targeting CD133 was designed to assess safety and tolerability (primary endpoint) and to monitor overall survival and progression-free survival (secondary endpoints). ICT-121 is comprised of autologous dendritic cells that are loaded with two HLA-A2 restricted epitopes of the CD133 antigen. CD133 is overexpressed on glioblastoma cancer stem cells. The HLA-A2 patients that had undergone resection for recurrence of glioblastoma were treated with ICT-121 once a week for 4 weeks during the induction phase and then once every 2 months during the maintenance phase until disease progression, death, ICT-121 depletion or discontinuation. Results: A total of 20 patients were treated and eight of these patients are still alive. Immune response data with cytokine mRNA expression demonstrated a response to the CD133 epitopes. A total of 20 patients were treated and eight of these patients are still alive. Conclusions: The results from this Phase I trial suggest that ICT-121 is both safe and well-tolerated with an immune response seen in a subset of patients. Clinical trial information: NCT02049489.

BACKGROUND: Though glioblastoma is aptly considered a diffuse invasive disease, occasionally the blood supply to the tumor falls within the vascular distribution of a single artery. In these instances, patients who suffer a stroke in the region of brain involved with tumor can sometimes survive much longer than one might expect, even in the absence of treatment. METHODS: In this single-institution retrospective analysis, we identified four non-consecutive glioblastoma patients who experienced a stroke following diagnosis. Glioblastoma pathology was confirmed by review at our institution in patients who were initially diagnosed elsewhere. RESULTS: All four patients remain alive, with ages ranging from 31 to 74. Stroke occurred following initial diagnosis in 1 patient, after first recurrence in 1 patient, and after second recurrence in 2 patients. Stroke resulted in permanent KPS decline of 10-20 in all patients. Three of the 4 patients are still progression-free; in the fourth, progression occurred outside the infarcted area. Survival from diagnosis: 48.5 mo, 103.2 mo, 108.2 mo, and 145.8 mo. Survival from stroke: 14.5 mo, 102.7 mo, 67.8 mo, and 74.0 mo, respectively. Survival since last treatment (in the 3 patients who are progression-free): 27.1 mo, 47.8 mo, 74.0 mo. CONCLUSION: Long-term survival with glioblastoma is uncommon, particularly following recurrence, and particularly in the absence of ongoing treatment. Though stroke is in general a poor prognostic factor for patients with glioblastoma, here we highlight the possibility that the acute vascular disruption that results from strokes can occasionally arrest tumor growth. Although endovascular embolization is unlikely to ever be considered an appropriate treatment for glioblastoma, these findings support the notion that vascular disrupting agents and endovascular therapies that are limited to a single vascular territory may have a role in the treatment of select patients.

The NovoTTF-100A System is an anticancer treatment that emits alternating electric fields, at an intensity of 1 V/cm and a frequency of 200 kHz, which mimic the cytotoxic effect of chemotherapy by disrupting charged cytoplasmic proteins involved in the tightly orchestrated process of mitosis. The pivotal phase III trial demonstrated equivalent efficacy when the device was compared to conventional cytotoxic chemotherapies and bevacizumab, but without their systemic side effects. After the initial approval, patients were prescribed the device at 91 oncology centers in the United States from October 2011 to November 2013 and they provided consent to their protected health information for the patient registry. We then retrospectively analyzed their outcome and treatment-related adverse events. There were 147 women and 310 men (n = 457) and their median age was 55 (range 18-26) years. Over 70% of them had a Karnofsky performance score (KPS) of 70 or higher. Sixty percent were in their first or second recurrence while 27% were in their third or greater recurrence. More than 55% of patients had prior treatment with bevacizumab. The overall Kaplan-Meier median overall survival (OS) was 9.6 (95% confidence interval [CI] 8.0 to 13.7) months and the median treatment duration was 4.1 (95% CI 3.5 to 4.8) months. Favorable prognostic factors include ≥75% treatment compliance (

BACKGROUND: The anti-CTLA-4 monoclonal antibody ipilimumab is a potent immune modulator. However, experience treating high-grade glioma with ipilimumab is limited. METHODS: In this single-institution consecutive case series, we identified 7 patients with recurrent grade 3 (one patient) and grade 4 (6 patients) glioma who were treated with ipilimumab off-label between June 2012 and April 2014. RESULTS: Age at treatment: 39 to 66 years. Number of infusions: 1-6. Number of recurrences prior to starting ipilimumab: 1-5. Five patients received additional treatment in conjunction with ipilimumab, including 4 who received bevacizumab. Time to progression for the 6 glioblastoma patients: 1.1 mo, 1.2 mo, 2.7 mo, 2.8 mo, 6 mo, 19.5 mo. One patient (with anaplastic astrocytoma) is recurrence-free 3.2 months from treatment initiation. This patient, who has not received concurrent therapy, has had stable disease by RANO criteria, with improvement in FLAIR abnormality, steroid requirement, and functional status. Three patients have died, with survival of 1.3 mo, 2.2 mo, and 5.3 mo. Four patients are still alive at 3.2 mo, 3.7 mo, 13.3 mo, and 23.3 mo follow-up. One patient underwent repeat resection 3 months following treatment initiation, but no evidence of progressive disease was found. Increased granzyme B expression, suggestive of an immune response, was found on immunohistochemistry. Autoimmune-related adverse effects were grade 2 at maximum, and manageable with steroids. CONCLUSION: This case series highlights the potential use of ipilimumab for patients with recurrent high-grade glioma. Though optimal use has yet to be defined, a subset of patients do appear to benefit from treatment. Cases of radiographic response, clinical improvement, and evidence of immune response by pathology have all been seen. Some patients do well even beyond initial progression, a phenomenon that has been observed with other immunotherapies.

Recurrent glioblastoma multiforme (GBM) is a highly aggressive cancer with poor prognosis, and an overall survival of 6 to 7 months with optimal therapies. The NovoTTF-100A™ System is a novel antimitotic cancer therapy recently approved for the treatment of recurrent GBM, based on phase III (EF-11) trial results. The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received NovoTTF Therapy in a real-world, clinical practice setting in the United States between 2011 and 2013. Data were collected from all adult patients with recurrent GBM who began commercial NovoTTF Therapy in the United States between October 2011 and November 2013. All patients provided written consent before treatment was started. Overall survival (OS) curves were constructed for PRiDe using the Kaplan-Meier method. Median OS in PRiDe was compared for patients stratified by average daily compliance (≥75% v

e13033 Background: The NovoTTF-100A is a first-of-a-kind anticancer device, approved by the Food and Drug Administration in 2011, for the treatment of recurrent glioblastomas. It emits alternating ...

BACKGROUND: Dendritic cell vaccines are a promising treatment for glioblastoma. The glioblastoma stem-like cell subpopulation is refractory to standard chemotherapy and radiation treatment, but may be susceptible to immunotherapeutic targeting. METHODS: This single-institution phase I trial is designed to assess the safety, tolerability, and potential efficacy of an autologous dendritic cell vaccine pulsed with lysate derived from a glioblastoma stem-like cell line. Patients with newly diagnosed glioblastoma (Cohort A) receive standard radiation and temozolomide in addition to vaccine. Patients with up to third glioblastoma recurrence (Cohort B) receive vaccine alone, although patients previously treated with bevacizumab are allowed to continue bevacizumab on study. Prior to enrollment, patients must undergo a qualifying gross total or near-gross total resection. Treatment consists of a Vaccine Induction Phase (weekly vaccines x 4 – for Cohort A, given upon completion of radiation), followed by a Vaccine Maintenance Phase (vaccine every 8 weeks until supply depleted). Imaging is performed during Week 4 of the Induction phase and every 8 weeks thereafter until progression. The primary objective of safety and tolerability includes adverse event grading per NCI CTC. Clinical assessment includes progression-free survival at 6 months and overall survival. Immunological testing to assess cytotoxic T-lymphocyte response will be performed at predetermined intervals. Goal enrollment is 20 patients in each cohort. Stopping rules for safety and efficacy using Bayesian sequential design will be followed. RESULTS: To date, 18 patients (7 new GBM, 11 recurrent GBM) have enrolled in this trial. No adverse events related to vaccine have been noted. CONCLUSION: This single-institution phase I dendritic cell vaccine trial builds upon our previous research efforts by specifically targeting the glioblastoma stem-like cell subpopulation that is resistant to standard radiation and chemotherapy. Accrual is proceeding rapidly, and results will be published when available.

BACKGROUND: For patients with carcinomatous meningitis, treatment needs to be expedited, especially for patients with hematologic malignancies. Using neuroendoscopy as an adjunct at the time of ventricular reservoir placement allows immediate confirmation of catheter placement rather than waiting for a post-operative CT scan and waiting for contact from the surgeon. This confirmation allows delivery of intrathecal chemotherapy at the time of surgery saving the patient delays in chemotherapy delivery and potential side effects of the first chemotherapy delivery, as they are still under general anesthesia. Delay in confirmation of appropriate catheter placement or poor catheter placement delays treatment; this technique also allows the surgeon and oncologist to know definitively that the reservoir is properly positioned and functional at the time of surgery. METHODS: Five patients with carcinomatous meningitis who were candidates for intrathecal chemotherapy were prospectively followed. All of them had a ventricular reservoir placed with neuroendoscopy and immediate delivery of intrathecal chemotherapy. RESULTS: All five of the patients had a reservoir placed without incident. Four of the patients had chemotherapy delivered during surgery without incident. For one patient, there was a pharmacy delay, but the chemotherapy was delivered while the patient was still recovering from anesthesia. There were no complications related to the treatment. CONCLUSIONS: Neuroendoscopy has the power to immediately confirm proper ventricular placement of an Ommaya reservoir and to safely allow the delivery of intrathecal chemotherapy in the operating room. This technique eliminates delays in chemotherapy delivery and is safe.

Glioblastoma multiforme (GBM) is an aggressive tumor with 14.6 months median survival rate. We have previously shown that laminin-411, a vascular basement membrane (BM) protein is a marker of tumor blood vessels that correlates with aggressiveness of GBMs. The laminin-411 pathway involving its β1 chain-containing integrin receptors, and ligand Dll4 for cancer stem cell (CSC) Notch1 was studied in mouse xenograft models to better understand glial tumor growth and new vasculature system development. To confirm the importance of laminin-411 expression for GBM progression and outcome prediction, sections from formalin-fixed paraffin embedded human brain tumors were studied. Immunohistochemical analysis of 107 GBM samples has revealed 87% cases with overexpression of laminin-411, whereas it was only 34% for high-grade (III) and 10.6% for low-grade (I/II) gliomas. The median survival for patients with GBM overexpressing laminin-411 was 10 months, compared to 20.2 months for those expressing “normal” laminin-421. The median recurrence rate was 5.6 and 9.3 months respectively. Morphometric analysis of CSC Notch1, nestin, CD133, and c-myc was correlated with laminin-411 overexpression in patients with high-grade gliomas. Nanobioconjugate PolycefinTM was synthesized to block BM laminin-411 in mice bearing intracranial human U87MG-derived GBM. Two antisense oligonucleotides against laminin-411 α4 and β1 chains were covalently attached on polymalic acid nanoplatform. The nanodrug, PolycefinTM, was able to cross blood brain tumor barrier and delivered drugs into cancer cells (Ding et al. 2010, 2013) using pH-dependent endosome releasing unit Leu-Leu-Leu. Evidence of cross talk was observed between BM, CSCs and tumor proliferation when mice were treated with PolycefinTM. It is shown that blocking synthesis of laminin-411 leads to significally lower tumor expression of integrin β1 chain, Notch ligand Dll4, and Notch1. The CSC markers nestin, CD133, and c-myc that are known indicators of glial tumor progression also showed quantitative reduction by morphometric analysis in tumors of mice treated with anti-laminin-411 Polycefin compared to PBS-treated animals. The data point to the importance of laminin-411-integrin β1-Dll4-Notch1 pathway in GBM development and to the ability of Polycefin to negatively impact CSC as a possible mechamism of GBM inhibition. The results provide new insights in glioma microenvironment and tumor endothelial and parenchymal cell signaling suggesting a novel approach for future therapeutics to target CSCs in vivo through inhibition of laminin-411 to treat highly infiltrating GBMs. Citation Format: Pallavi R. Gangalum, Alexander V. Ljubimov, Alexandra Chesnokova, Bindu Konda, Hui Ding, Jose Portilla-Arias, Adam Mamelak, Serguei Bannykh, Surasak Phuphanich, Jeremy Rudnick, Jethro Hu, Keith L. Black, Julia Y. Ljubimova. Nanoconjugates for inhibition of laminin-411-integrin β1-Dll4-Notch1 pathway to treat glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2692. doi:10.1158/1538-7445.AM2014-2692

Aim: To present updated outcomes and toxicity data from patients with recurrent glioblastoma treated with the commercially available NovoTTF-100A System using patient registry database. Methods: The NovoTTF-100A device has been available by prescription at 126 oncology centers in the United States since November 2011. We retrospectively analyzed the outcomes and toxicity data from patients who were prescribed the device from November 2011 to November 2013 as treatment for recurrent glioblastoma. Overall survival (OS) was calculated based on social security death registry data. It was defined as the time from the treatment start until the date of death or last known date patient was alive. We analyzed performance status, compliance records, treatment history and adverse effects for all subjects. Results: There were 148 female and 309 male patients (n = 457) who were treated with NovoTTF-100A System. The median age was 55 years (range 18 to 86). Median Karnofsky Performance Status (KPS) was 80 (range 10-100) and 33% of patients were at their first recurrence when therapy was initiated. Over half of the patients (n = 252) received bevacizumab prior to NovoTTF- 100A therapy. The median OS was 9.6 (95% [CI] 8.0 to 13.7) months and the median treatment duration was 4.1 (95% [CI] 3.5 to 4.8) months. The average patient compliance with the use of the device was 70%. OS was positively correlated with higher compliance (= > 75%) and KPS (70-100), and negatively correlated with recurrence number and prior use of bevacizumab. Debulking surgery prior to the introduction of NovoTTF-100A therapy did not influence OS. The most common device-related adverse events included skin reactions (24.3%), neurological disorders (10.4%), heat sensation (8.9%), electric sensation (7.7%) and headache (5.7%). Conclusions: Treatment with NovoTTF-100A System, as prescribed in the neuro-oncology clinical practice to patients with recurrent glioblastoma offers favorable outcomes when compared to historical data. Patient compliance with the prescribed use of the system is high and positively correlates with improved survival. Bevacizumab naive patients benefit more while patients with poor KPS and multiple prior recurrences benefit less from this treatment. NovoTTF-100A System is well tolerated and has no new unexpected toxicities since its introduction to clinical practice. Disclosure: M.M. Mrugala: On Advisory Board of Novocure. PI on the clinical trial sponsored by Novocure; H.H. Engelhard: I have participated in Novocure's Advisory Boards; N. Butowski: I participated in Novocure's Advisory Board; D.D. Tran: I have received honorarium from Novocure for advisory board and speaker bureau; Y. Kew: I have participated in Novocure's Advisory Boards; R. Cavaliere: I have been a consultant for Novocure; J. Villano: Member of a speakers bureau and served on an advisory board for Novocure. D. Bota: Novocure Advisory Board; S. Kesari: I have received funding for advisory board meetings and clinical trials sponsored by Novocure; J. Rudnick: I have been a consultant for Novocure; A. Sumrall: I have been a Faculty Speaker and participated in an Advisory Board for Novocure; J.J. Zhu: Novocure Advisory Board; E.T. Wong: I received research funding from Novocure.

BACKGROUND: The NovoTTF-100A is a first-of-a-kind anticancer device, approved by the Food and Drug Administration in 2011, for the treatment of recurrent glioblastomas. It emits alternating electric fields, at an intensity of 1 V/cm and a frequency of 200 kHz, that mimic the cytotoxic effect of chemotherapy by disrupting charged cytoplasmic proteins involved in the tightly orchestrated process of mitosis. Past phase III trial demonstrated equivalent efficacy when the device was compared to conventional cytotoxic chemotherapies and bevacizumab, but without their systemic side effects. METHODS: The NovoTTF-100A device has been available by prescription at 91 oncology centers in the United States since November 2011. We retrospectively analyzed the outcome and toxicity data from patients who were prescribed the device from October 2011 to November 2013 as treatment for their recurrent glioblastomas. RESULTS: There were 147 female and 310 male patients (n = 457) who were treated with this device. The median age was 55 (range 18 to 86) years. The Kaplan-Meier median OS was 9.6 (95% confidence interval [CI] 8.0 to 13.7) months and the median treatment duration was 4.1 (95% CI 3.5 to 4.8) months. The most common device-related adverse events include skin reaction (24.3%), neurological disorders(10.4%), heat sensation (8.9%), electric sensation (7.7%) and headache (5.7%). CONCLUSIONS:Treatment with NovoTTF-100A, as prescribed in the general clinical setting to patients with recurrent glioblastomas, offers favorable outcomes compared to historical patient data. The adverse event profile of the device remains benign with no new unexpected toxicities.

e13010 Background: The anti-CTLA-4 monoclonal antibody ipilimumab is a potent immune modulator. Ipilimumab is FDA-approved for advanced-stage melanoma, and evidence of preclinical activity has been...

2019^ Background: Patients (pts) with GBM with unmethylated MGMT have a worse prognosis than those with methylated MGMT. Novel approaches for this poor risk group are warranted. The Brain Tumor Trials Collaborative (BTTC) performed a phase II trial evaluating standard chemoradiation followed by bevacizumab and erlotinib in patients with MGMT unmethylated GBM. EGFR and VEGFR are upregulated during radiation suggesting that this combination could be more effective than post-radiation adjuvant temozolomide (TMZ). Methods: After informed consent, adult patients with supratentorial GBM, KPS ≥ 70 and > 1 cm2 tumor block for MGMT promoter analysis were screened. Only tumors with confirmed unmethylated MGMT promoter were enrolled. All patients received RT + TMZ and then approximately 4 weeks after RT they received bevacizumab 10 mg/kg every 2 weeks and erlotinib 150 mg/day, continuously. One cycle was 4 weeks; evaluation by MRI was every 2 cycles. Treatment continued until disease progression or intolerable adverse events. Results: 115 patients were screened; 48 were enrolled (2 unevaluable: 1 for an infratentoral GBM and 1 withdrew after 7 days of treatment) with 29 men, 17 women. Median age was 56 yrs (29-75); median KPS was 90 (70-90). The median number of cycles was 8 (2-38) with 4 patients remaining on trial at the time of analysis. Objective responses: 4 CR, 12 PR and 30 SD. Median PFS is 7.3 months (95% CI (6.4, 11)) and median OS 14.2 months (95% CI (10.7, not reached)). There were no unexpected toxicities; grade 3/4 rate < 5%. Conclusions: Adjuvant bevacizumab and erlotinib in GBM with unmethylated MGMT is well tolerated. Preliminary efficacy data is comparable with outcomes in similar unmethylated MGMT patient populations from the EORTC/NCIC and RTOG 0525 studies. Tissue correlation is being performed. Clinical trial information: NCT00720356.

2080 Background: Glioblastoma patients who present with multifocal disease have an extremely poor prognosis – a recent analysis at our institution demonstrated a median survival of 6 months, versus 11 months for a cohort of unifocal glioblastoma patients matched for age, extent of resection, and KPS. Bevacizumab is frequently used to treat patients with recurrent or progressive glioblastoma. However, its benefit in the setting of multifocal disease is unproven, particularly in light of the concern that antiangiogenic treatment may promote a more invasive, multifocal, and potentially treatment-resistant phenotype. Methods: Between 2004 to 2010, 368 patients were diagnosed with glioblastoma at our institution. We identified 46 patients with multifocal disease on initial presentation, and retrospectively reviewed their clinical course and treatment history. Kaplan-Meier estimates and Wilcoxon tests were used to assess survival distribution. Results: Of the 46 patients with multifocal disease, 12 were treated with bevacizumab (7 upfront and 5 at first recurrence). All 12 bevacizumab-treated patients received external beam radiation therapy, and 11 received temozolomide. In the bevacizumab-treated cohort, median age at the time of surgery was 59 years, and median KPS was 80. For the 34 patients with multifocal disease who did not receive bevacizumab, median age was 69 years, and median KPS was 75. Median survival for the bevacizumab-treated patients was 12.9 months, with 12-month survival of 58.3%. By comparison, median survival for patients with multifocal disease who did not receive bevacizumab was 5.8 months, with 12-month survival of 20.6%. The difference in survival between the two groups was statistically significant, with p-value of 0.045 by the Wilcoxon test. Conclusions: This single-institution retrospective analysis suggests that bevacizumab treatment is associated with a survival benefit for glioblastoma patients who present with multifocal disease. One can infer that the clinical benefit of bevacizumab in this setting outweighs any potential concerns regarding the ability of bevacizumab to promote an invasive, treatment-resistant tumor phenotype.

2087 Background: This study evaluated the safety and immune responses to an autologous dendritic cell vaccine pulsed with class I peptides from tumor associated antigens (TAA) expressed on gliomas and overexpressed in their cancer stem cell population (ICT-107). These TAA epitodes AIM-2. TRP-2, HER2 and AIM-2, are also overexpressed on glioblastoma multiforme (GBM) cancer stem cells. Methods: TAA epitopes included HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2. HLA-A1 and/or HLA-A2 positive glioblastoma (GBM) patients with gross total resection were eligible. Mononuclear cells from leukapheresis were differentiated into dendritic cells, pulsed with TAA peptides, and administered intradermally three times at two-week intervals in the axilla region after a standard treatment with concurrent temozolomide (TMZ) and radiation therapy for newly diagnosed (ND-GBM). Results: Twenty-one patients were enrolled with 17 ND-GBM and three recurrent GBM patients and one brainstem glioma. Immune response data on 15 newly diagnosed patients showed 33% responders. TAA expression by qRT-PCR showed all patient tumors expressed at least three TAA with 75% expressing all six. Correlations of increased PFS and quantitative expression of MAGE1, AIM-2, gp100 and HER2 were observed. A decrease or absence of CD133 expression was seen in five patients who underwent a second resection. As of February 1, 2012, six of 16 ND-GBM patients showed no evidence of tumor recurrence (44-63 months). Median progressive free survival (PFS) in newly diagnosed patients was 16.9 months with a two-year PFS rate was 43.8% (95%CI,19.8-66.0 ). The median overall survival rate (OS) was 38.4 months and a two-year OS was 80.3% (95%CI,58.6-96.7). Conclusions: Expression of four ICT-107 targeted antigens in the pre-vaccine tumors correlated with prolonged overall survival and PFS in ND-GBM patients. The goal of targeting tumor antigens highly expressed on glioblastoma cancer stem cells is supported by the observation of decreased or absent CD133 expression in the recurrent areas of gadolinium-enhanced tumor.

2084 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers and have a modest impact to extend overall survival. We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu, and this is a presentation of the final results of our clinical trial. Methods: Patients with glioblastoma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Twenty three patient with glioblastoma received therapy including 8 with newly diagnosed disease (35%) and 15 with recurrent disease (65%) were evaluable. Immune response data is available for 20/23 patients although survival data is present for all. One grade 3 SAE of fever and chills was noted otherwise therapy was well tolerated. Within the newly diagnosed GBM cohort the median overall survival (OS) was 25.5 months (15,31+), and within the recurrent GBM cohort, the median OS was 16 months (8,23+). Among the recurrent GBM an increase of >1.5 X baseline interferon gamma production post vaccination was associated with a prolonged median OS 22 months (8,40) in 4/12 patients versus 17 months (9,27) in 8/12 patients. Conclusions: We were able to generate an immune response in 25% of patients which is lower than what we have seen in previous trials and suggests a limited synergy with local control. However, within the recurrent GBM cohort we did find prolonged survival in both groups with an increased survival noted in immune responders demonstrating the potential for this therapy.

Introduction Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed. Methods Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age, extent of resection, Karnofsky performance scale (KPS), and treatment on overall survival. Results Sixty-five percent of patients were men with median age of 63 years, and 70% had KPS≥80. Most patients (81%) received standard treatment (temozolomide with concurrent radiation). A total of 72 (47%) patients had retained PTEN expression. Median overall survival (OS) was 19.1 months (95% CI: 15.0–22.5). Median survival of 20.0 months (95% CI: 15.0–25.5) and 18.2 months (95% CI: 13.0–25.7) was observed in PTEN retained and PTEN loss patients, respectively (p = .71). PTEN loss patients were also found to have amplifications of EGFR gene more frequently than patients with retained PTEN (70.8% vs. 47.8%, p = .01). Multivariate analysis showed that older age (HR 1.64, CI: 1.02–2.63, p = .04), low KPS (HR 3.57, CI: 2.20–5.79, p

e13008 Background: Increased expression of α4 and β1 chain-containing vascular protein laminin-411 (α4β1γ1) correlated with tumor invasion and progression and was associated with glioma patients’ poor prognosis and survival. Therefore, laminin-411 may be a promising target for glioma diagnosis and treatment. Methods: 1. A clinical trial for laminin-411 vs. a normal laminin-421 is underway at Cedars-Sinai Medical Center for evaluating laminin-411 overexpression in gliomas. The clinical material used comprises 194 primary gliomas: 106 glioblastomas multiforme, 28 anaplastic astrocytoma, 7 anaplastic oligoastrocytoma, 20 astrocytoma grade II, 19 oligodendroglioma grade II, 4 ependymomas grade I-II, pilocystic astrocytoma I-II, 4 microglial activation tissues. 2. Targeted nanobiopolymer for angiogenesis inhibition of gliomas was synthesized for systemic treatment in vivo. The drug is based on polymalic acid for efficient and specific delivery of antisense oligonucleotides and monoclonal antibodies. The mechan...

2042 Background: Active immunotherapy offers the potential for high tumor-specific toxicity and sustained tumoricidal activity. We developed a dendritic cell (DC) immunotherapy to target specific g...

2097 Background: Active immunotherapy offers the potential for high tumor-specific toxicity and sustained tumoricidal activity. We therefore have developed this protocol to exploit the most current...

2033 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers extend overall survival from 11.6 to 13.9 months. Methods: We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu. Patients with high-grade glioma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis is used to isolate mononuclear cells which are differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines are administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Eighteen patients have been enrolled (7 Male, 11 Female) between April 2007 and February 2009 with one screen failure and two patients with clinical progression prior to vaccination. The median patient age was 57 years (26 to 74 ) and median Karnofsky performance status was 90% (80–100). The histology included 3 newly diagnosed glioblastoma multiforme (GBM), 8 recurrent GBM, 2 newly diagnosed anaplastic astrocytoma (AA), and 2 recurrent AA. 15 patients were successfully treated by vaccine injections with 12 patients receiving vaccine every 2 weeks x 3 followed by adjuvant chemotherapy. Our preliminary data on 15 patients and 39 courses of Dendritic Cell vaccines demonstrate one grade 3 toxicity of fever/chest pain. A stable disease interval of 13 to 90 weeks was observed for patients who received vaccine. The 3 newly diagnosed GBM patients have stable disease (18 to 71 weeks). In the recurrent GBM cohort 7/8 patients had progression within 6 months from the post-vaccination MRI. Conclusions: This phase I study demonstrates the safety, feasibility of dendritic cell vaccination with biodegradable carmustine (BCNU) wafers with one grade 3 AE. Immunological data is pending to determine potential synergy of dendritic cell vaccination with intracranial chemotherapy. No significant financial relationships to disclose.

2032 Background: Previous immunotherapy trials for malignant glioma (Yu, J.,et al, Cancer Res. 2001;61:842–7 and 2004;64;4973–9) have demonstrated efficacy in generating a tumor specific immune response. Here we set out to determine feasibility and immunogenecity of dendritic vaccination with specific glioma-associated antigens. Methods: The goal of this study is to use tumor associated antigens (TAA) known to be expressed on gliomas and pulse dendritic cells with these antigens in an MHC compatible fashion using epitopes of HER-2, TRP-2, gp100, MAGE-1, IL13R alpha, and AIM-3. In this phase I trial, HLA-A1 and/or HLA-A2-positive patients with newly diagnosed or recurrent glioblastoma were eligible. Leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells in culture, pulsed with tumor peptide, and then administered intradermally three times at 2-week intervals. Results: Twenty patients, 15 males and five females, were enrolled between November 2006 and December 2008 with one screen failure. The median patient age was 47 years (range: 26–65) and patients had a median Karnofsky performance status of 90% (range: 90–100). There were 16 newly diagnosed and three recurrent glioblastoma multiforme (GBM) patients, who underwent surgery prior to vaccination. Our data on 19 patients and 54 courses of dendritic cell vaccines demonstrate zero grade 3 /4 toxicities that were attributable to the vaccination. Thirteen patients continue to have stable disease (ranging from 15 to 115 weeks), six patients have demonstrated tumor progression. Median survival from surgery was 60 weeks (ranging from 26 to 115 weeks). Of 15 patients tested to date, six patients demonstrated an antigen-specific cytotoxic T-cell response to at least one antigen after vaccination. Only 17% of CTL responders (1/6) demonstrated tumor progression compared to 56% (5/9) of nonresponders to date. Conclusions: This phase I study demonstrated the feasibility, safety, and bioactivity of a TAA-pulsed dendritic cell vaccine for patients with glioblastoma progression free survival correlated with CTL response. [Table: see text]

2088 Background: Glioblastoma multiforme (GBM) overexpresses the epidermal growth factor receptor (EGFR) and gefitinib is an EGFR tyrosine kinase inhibitor (TKI). The protein mammalian target of ra...