Recurrent Malignant Glioma Research Articles

Boron neutron capture therapy in clinical application:Progress and prospect

<p indent="0mm">Boron neutron capture therapy (BNCT) is an emerging radiotherapeutic modality aimed at selectively concentrating boron compounds in tumor cells and then subjecting the tumor cells to neutron beam radiation. Treatment with BNCT is based on the nuclear capture and fission reactions that occur when nonradioactive boron-10 (¹⁰B) is irradiated with neutrons to yield an alpha particle (helium, ⁴He) and a recoiling lithium-7 (⁷Li) nuclei. The ⁴He particle has a range of <sc>9 μm</sc> and the ⁷Li particle <sc>5 μm</sc> in tissue. In theory, the short range of this reaction limits the damage to malignant cells while sparing adjacent normal cells. The development of BNCT is still constrained by the progress in developing boron delivery agents with a high tumor uptake, low normal tissue uptake, and optimizing the dosing paradigms and quantitative estimation of the ¹⁰B concentrations. It is widely recognized that the second generation boron-containing agents, sodium borocaptate (BSH) and boronophenylalanine (BPA), are less than ideal. New and more effective boron-containing agents are urgently required for clinical use to deliver the requisite amounts of boron to tumor cells. The delivery of boron-containing agent can also be optimized to improve cancer cell uptake and subcellular distribution. Additionally, it is crucial to design high intensity neutron sources and establish hospital-based BNCT. Compared with nuclear reactors, accelerator-based neutron sources are more realistic to be applied in clinical practice. In future, the critical issues regarding novel boron-containing agents, the appropriate delivery strategies, and neutron sources of BNCT for clinical use must be addressed. Two clinical trials with newly diagnosed glioblastoma have been reported, BNCT alone after surgery provided a mean survival time of 17.7 and <sc>19.5 months</sc> respectively. The survival outcomes were good as compared to the current standard of care which is post-operation fractionated radiotherapy with concomitant and adjuvant TMZ. Several clinical studies of BNCT in the treatment of recurrent head and neck cancer have been reported, with high response rate and acceptable toxicity. To date, BNCT has been clinically evaluated as an alternative to conventional radiotherapy for the treatment of several tumor types, including newly diagnosed glioblastoma, recurrent glioma, recurrent head and neck tumors, meningioma, malignant melanoma, and liver metastasis. Recently, accelerator-based neutron source has been used in clinical trials for recurrent malignant gliomas and head &amp; neck cancers. Although initial results with BNCT are promising, high-quality prospective clinical trials are still lacking. Well-designed phase II/III clinical research is necessary to define the efficacy and safety of BNCT in various tumor types. Meanwhile, studies comparing the outcomes of BNCT with other standards of care are needed for the further development of BNCT. Based on the previous studies, the BNCT clinical trials in glioblastoma can be initiated with newly diagnosed glioblastoma patients. For other tumor types, late-stage patients with recurrent or metastatic disease after the first-line treatment might be recruited. Last but not the least, in the era of comprehensive treatment for malignant tumor, it is necessary to explore the combined treatment mode of BNCT. For the future research, BNCT may be coupled with a variety of anti-tumor modalities, including traditional photon radiotherapy, immunotherapy, targeted therapy and chemotherapy. It is also possible to explore a variety of drug delivery methods to improve the uptake of boron-containing agents by tumor sites. Multidisciplinary model is needed to jointly promote BNCT to become a routine clinical treatment modality.

DDRE-09. MULTI-INSTITUTION RETROSPECTIVE EXPERIENCE WITH LENVATINIB FOR PROGRESSIVE MALIGNANT GLIOMA

Abstract Despite treatment with radiation and temozolomide chemotherapy, malignant gliomas inevitably recur after treatment and have poor prognosis. Clinical trials should be offered when available, but effective treatment options for multiply recurrent tumors is sparse. In our multi-institutional retrospective cohort, we looked at recurrent malignant gliomas treated with Lenvatinib multi-kinase inhibitor. Patients consented to an IRB-approved study protocol that allows for longitudinal history review and analysis at our institution. Lenvatinib is a targeted therapy that is FDA approved for Differentiated Thyroid Cancer, Renal Cell Carcinoma, Hepatocellular Carcinoma, and Endometrial Carcinoma. Lenvatinib binds to tyrosine kinase receptors inhibiting kinase activity by VEGFR1-3, FGFR1-4, PDGFRa, FGF, KIT, and RET. In this cohort, patients received radiation and temozolomide chemotherapy, N=15, median age was 45.5, and 47% were male. At time of surgery 40% underwent biopsy, 40% had STR, and 20% had GTR. Glioblastoma was the most common tumor type at 87%, 6.7% were recurrent anaplastic astrocytoma, and 6.7% were recurrent glioma NOS. IDH mutation was seen in 13% of our cohort, and MGMT methylation was seen in 27%, all patients had available IDH and MGMT data. Patients were heavily treated, median number of recurrences was 3. Patient mean PFS was 2.7 months, and median OS was 24.0 months. Clincal Benefit Rate (PR+SD) to Lenvatinib in recurrent disease was 57%, with 29% Partial Responses and 29% Stable Disease as best radiographic response. This retrospective cohort supports further evaluation of the efficacy of Lenvatinib in recurrent malignant glioma in a clinical trial.

Efficacy and safety of nivolumab in Japanese patients with first recurrence of glioblastoma: an open-label, non-comparative study

BackgroundAn open-label, non-comparative study assessed the efficacy and safety of nivolumab in Japanese patients with first recurrence glioblastoma.MethodsPatients with first recurrence of histologically confirmed World Health Organization Grade IV glioma, after treatment with temozolomide and radiotherapy, received nivolumab 3 mg/kg every 2 weeks until confirmed disease progression (Response Assessment in Neuro-Oncology criteria) or toxicity. Primary endpoint was 1-year overall survival rate assessed by Bayesian approach. The prespecified efficacy criterion was that the Bayesian posterior probability threshold for exceeding the 1-year overall survival of bevacizumab (34.5%) from the Japanese phase 2 study (JO22506) would be 93%.ResultsOf the 50 enrolled patients, 44 (88.0%) had recurrent malignant glioma (glioblastoma, gliosarcoma), and of these, 26 (59.1%) had at least one measurable lesion at baseline. The Bayesian posterior mean 1-year overall survival (90% Bayesian credible intervals) with nivolumab was 54.4% (42.27–66.21), and the Bayesian posterior probability of exceeding the threshold of the 1-year overall survival rate of bevacizumab (34.5%) was 99.7%. Median (90% confidence interval) overall and progression-free survival was 13.1 (10.4–17.7) and 1.5 (1.4–1.5) months, respectively. One partial response was observed (objective response rate 1/26 evaluable patients [3.8%]). Treatment-related adverse event rates were 14.0% for Grade 3–4 and 2.0% for Grade 5; most adverse events resolved and were manageable.ConclusionsThe 1-year overall survival with nivolumab monotherapy in Japanese patients with glioblastoma met the prespecified efficacy criterion. The safety profile of nivolumab was consistent with that observed in other tumor types.Clinical Trial RegistrationJapicCTI-152967.

358P Anlotinib plus temozolomide for recurrent glioma: A single-center, retrospective study of 30 cases

The prognosis of patients with recurrent malignant glioma (rMG) is quite poor. According to the NCCN guidelines, bevacizumab is recommended drug for rMG. Anlotinib is a multitarget tyrosine kinase inhibitor that can inhibit tumor angiogenesis and tumor cell growth. We report results from this retrospective study to determine the efficacy and tolerability of Anlotinib plus temozolomide (TMZ) as a first-line treatment for rMG.

Hitchhiking to brain tumours: stem cell delivery of oncolytic viruses.

Three studies have reported the results of phase 1 clinical trials of virotherapy for malignant gliomas, underscoring the momentum in the field. In the first study,1 investigators used a replication-competent, tumour-selective adenovirus to treat patients with recurrent glioblastomas. In a group in which patients received virus treatment only (n=25), 20% of the patients survived more than 3 years after treatment, and three patients had tumour volume reductions of 95% or more. In the second study,2 intratumoural infusion of a tumour-selective poliovirus into patients with recurrent malignant glioma improved overall survival, which reached a plateau of 21% at 24 months that was sustained at 36 months.

Alterations of the Gut Microbiome in Recurrent Malignant Gliomas Patients Received Bevacizumab and Temozolomide Combination Treatment and Temozolomide Monotherapy.

The online version contains supplementary material available at 10.1007/s12088-021-00962-2.

Abstract 1912: Evasion of neutralizing antibodies and enhanced anti-tumor effects of hexon-modified Delta-24-RGD oncolytic adenovirus

Abstract Oncolytic viruses are a new form of cancer immunotherapy that harnesses the combined abilities of the virus to directly lyse cancer cells and to induce immunogenic environments to activate anti-tumor immunity. Our oncolytic adenovirus Delta-24-RGD has demonstrated significant clinical benefits for a subset of patients with recurrent malignant gliomas in a recent phase 1 clinical trial. However, the backbone of Delta-24-RGD is derived from adenovirus serotype 5 to which 40 percent of the human population has prior exposure and harbor neutralizing antibodies that can block virus infection and replication. We hypothesized that replacing the major targets of antibodies in the oncolytic virus will protect it from neutralizing antibodies, resulting in enhanced efficacy of the cancer virotherapy. Because hexon hypervariable regions are the dominant targets of antibodies, we replaced these regions with those from a lesser prevalent serotype 43 to create a hybrid virus called Delta-24-RGD-H43m. Transmission electron microscopy imaging of the viruses revealed the assembly of viable virions after infection with either Delta-24-RGD or Delta-24-RGD-H43m in human and mouse cancer cell lines, signifying successful virus replication, that was corroborated by quantification of viral replication using hexon-staining dilution method. Accordingly, the inherent anti-tumor effect of the virus was not perturbed after the genetic modification, as Delta-24-RGD and Delta-24-RGD-H43m showed comparable efficacies both in vitro (P= 0.568) and in vivo using mice without prior immunity to adenovirus (P= 0.228). Importantly, the oncolytic ability of Delta-24-RGD-H43m was not compromised by neutralizing antibodies generated against adenovirus serotype 5 that efficiently neutralized Delta-24-RGD (P&amp;lt; 0.0001) as assessed by measuring cell viability after virus infection. In immunized mice with prior adenovirus exposure, Delta-24-RGD-H43m treatment yielded higher occurrences of complete tumor remission compared to Delta-24-RGD (89% versus 67%). Despite our growing understanding of viruses, the immune system, and cancer, the specific interaction between oncolytic viruses and the host immune system is still very limited. Strategies to protect the therapeutic viruses from virus-specific immune responses should prolong their persistence in tumors and result in better therapeutic outcomes. Further research in this field will aid the development of enhanced cancer virotherapies. Citation Format: Dong Ho Shin, Teresa T. Nguyen, Hong Jiang, Xuejun Fan, Yanhua Yi, Sagar S. Sohoni, Sumit Gupta, Ashley Ossimetha, Candelaria Gomez-Manzano, Juan Fueyo. Evasion of neutralizing antibodies and enhanced anti-tumor effects of hexon-modified Delta-24-RGD oncolytic adenovirus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1912.

Maintenance of WT1 expression in tumor cells is associated with a good prognosis in malignant glioma patients treated with WT1 peptide vaccine immunotherapy.

We have previously revealed the overexpression of Wilms' tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4+/CD8+ tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3+ or CD8+ T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4+ T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy.

EPCT-01. A NOVEL PEPTIDE VACCINE DIRECTED TO CMV PP65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL

IntroductionThe cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma. MethodsVaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly. ResultsTo date, 22 patients have been enrolled. Diagnoses include medulloblastoma (n=2), glioblastoma (n=12), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=3), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 45% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 1.7,4.5) and median OS is 6.5 months (95% CI 3.3, 7.9). Immune response to pp65 as determined by ELISpot was found in 75% of patients. On MRI 6 of the 11 evaluable patients have had at least stable disease with three of those having a partial response. ConclusionsPreliminary results demonstrate that PEP-CMV is well-tolerated and elicits an immune response in heavily pretreated, multiply recurrent patients. A multi-institutional Phase II trial is scheduled to open fall 2021.

Effect of temozolomide combined with radiotherapy on survival and MGMT protein expression in recurrent malignant glioma patients

Purpose: To investigate the effect of temozolomide (TMZ) combined with radiotherapy (RT) on O-6- methylguanine-DNA methyltransferase (MGMT) protein and survival of recurrent malignant glioma patients.&#x0D; Methods: Ninety-two patients with malignant glioma in our hospital from January 2014 to January 2015 were assigned to study and control groups using the random table method. Subjects in the control group received radiotherapy (total dose in the range of 60 – 75 Gy), while those in the study group were given TMZ orally (75 mg/m2) daily in addition to radiotherapy, as well as TMZ at 150 – 200 mg/m2. After treatment, clinical effectiveness was compared for the two groups. Changes in methylation of MGMT gene were determined in the two groups. The patients were followed up for 3 years, and the degrees of survival and recurrence were recorded.&#x0D; Results: Total effectiveness of clinical treatment was markedly higher in the study group (76.09 %) than in the control group (45.65 %; p &lt; 0.05). One month after radiotherapy, significant decrease in MGMT gene methylation was seen in patients in the study group, relative to control patients (p &lt; 0.05). Patients in the study group had lower median recurrence but higher degree of survival in the 2nd and 3rd years, relative to control patients (p &lt; 0.05).&#x0D; Conclusion: The combination of temozolomide and radiotherapy is more effective than radiotherapy in the treatment of recurrent malignant glioma. The combined treatment significantly inhibits tumor recurrence in patients, and improves their prognosis and standard of life.

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

Glioblastoma

Glioblastoma, the most malignant and most common form of glioma, is known to portend very poor prognosis with the median overall survival of approximately 1.5 years. Its treatment requires a multidisciplinary approach, which consists of maximal safe resection followed by radiotherapy and chemotherapy with temozolomide. Bevacizumab is approved for newly diagnosed as well as recurrent malignant glioma in Japan. NovoTTF is a novel medical device that emits alternating electric fields; it inhibits the proliferation and growth of the tumor by interfering with tumor cell mitosis at anaphase. A photodynamic therapy with talaporfin sodium has been approved for primary malignant brain tumor including glioblastoma in Japan. For epilepsy secondary to glioblastoma, a novel class of antiepileptics such as levetiracetam and lacosamide is preferred given the lack of drug-drug interactions. Perampanel is a selective antagonist of AMPA receptors, the major subtype of ionotropic glutamate receptors; it may be a preferred antiepileptics for glioblastoma, given the in vitro and in vivo analyses suggesting that it decreases the proliferation and invasion of tumor cells. In this chapter, I describe the overview of the multidisciplinary treatments of glioblastoma. I also describe the future perspectives.

Accelerator-based BNCT for patients with recurrent glioblastoma: a multicenter phase II study.

BackgroundBoron neutron capture therapy (BNCT) utilizes tumor-selective particle radiation. This study aimed to assess the safety and efficacy of accelerator-based BNCT (AB-BNCT) using a cyclotron-based neutron generator (BNCT 30) and 10B-boronophenylalanine (SPM-011) in patients with recurrent malignant glioma (MG) (primarily glioblastoma [GB]).MethodsThis multi-institutional, open-label, phase II clinical trial involved 27 recurrent MG cases, including 24 GB cases, who were enrolled from February 2016 to June 2018. The study was conducted using the abovementioned AB-BNCT system, with 500 mg/kg SPM-011 (study code: JG002). The patients were bevacizumab-naïve and had recurrent MG after standard treatment. The primary endpoint was the 1-year survival rate, and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results were compared to those of a previous Japanese domestic bevacizumab trial for recurrent GB (JO22506).ResultsThe 1-year survival rate and median OS of the recurrent GB cases in this trial were 79.2% (95% CI: 57.0–90.8) and 18.9 months (95% CI: 12.9–not estimable), respectively, whereas those of JO22506 were 34.5% (90% CI: 20.0–49.0) and 10.5 months (95% CI: 8.2–12.4), respectively. The median PFS was 0.9 months (95% CI: 0.8–1.0) by the RANO criteria. The most prominent adverse event was brain edema. Twenty-one of 27 cases were treated with bevacizumab following progressive disease.ConclusionsAB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG. AB-BNCT may increase the risk of brain edema due to re-irradiation for recurrent MG; however, this appears to be controlled well with bevacizumab.

Clinical Experience using Osimertinib in Patients with Recurrent Malignant Gliomas Containing EGFR Alterations.

Background:EGFR alterations are commonly observed in malignant gliomas (MG). Osimertinib, an irreversible EGFR-tyrosine kinase inhibitor, effectively penetrates the blood brain barrier and achieves therapeutic concentrations in brain tissue.Materials and Methods:This retrospective chart review identified six patients with recurrent MG and EGFR alterations who received osimertinib.Results:Four patients were assessed for response. One patient had a partial response, two patients achieved stable disease and one was refractory. One patient with an EGFR vIII rearrangement remained on treatment for 236 days and a second patient with an EGFR vIII mutation remained on treatment for 294 days and continued on treatment at the time of analysis. Thrombocytopenia occurred in two patients, one patient developed grade 1 diarrhea and pneumonia, and another patient developed grade 1 mucositis.Conclusion:Osimertinib had a tolerable safety profile in this heavily pretreated brain tumor population. Osimertinib may benefit select patients with recurrent MG containing EGFR alterations.

DDEL-08. CONVECTION-ENHANCED DELIVERY OF NIMUSTINE HYDROCHLORIDE (ACNU) AGAINST PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMAS

Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Intracerebral infusion technique of convection-enhanced delivery (CED) for patients with brain tumors could offer a novel approach for effective chemotherapy. We have been working to develop an effective chemotherapy using nimustine hydrochloride (ACNU) with this drug delivery method. After several studies targeting supratentorial recurrent malignant gliomas and recurrent gliomas affecting brainstem, we conducted phase 1 study to evaluate the safety of combination of convection-enhanced delivery of nimustine hydrochloride and systemic temozolomide against recurrent gliomas affecting brainstem. In this study, we demonstrated the safety and feasibility of CED of ACNU as well as real time monitoring of drug distribution by mixing ACNU with contrast agent; Gd-DOTA. We also defined the maximum tolerable concentration in this study and proceeded to phase 2 trial against recurrent gliomas affecting brain stem. However, these trials revealed the difficulty of treating pediatric DIPG at the time of recurrence. Therefore, we decided to treat pediatric DIPG cases at their initial diagnosis in the subsequent study. Aiming at obtaining Shonin approval both for intraparenchymal infusion catheter and drug to infuse into brain parenchyma, we are now conducting Phase II physician-led trial against initially diagnosed pediatric DIPG cases.

Maintenance of Energy Homeostasis during Calorically Restricted Ketogenic Diet and Fasting-MR-Spectroscopic Insights from the ERGO2 Trial

Simple SummaryThe glioblastoma is a highly malignant brain tumor with very limited treatment options up to date. Metabolism of this tumor is highly dependent on glucose uptake. It is believed that glioblastoma cells cannot metabolize ketone bodies, which are found in the blood during periods of fasting or ketogenic dieting. According to this hypothesis, dieting could lead to cancer cell starvation. The ERGO2 (Ernaehrungsumstellung bei Patienten mit Rezidiv eines Glioblastoms) MR-spectroscopic imaging subtrial was designed to investigate tumor metabolism in patients randomized to calorically restricted ketogenic diet/intermittent fasting versus standard diet. The non-invasive investigation of tumor metabolism is of high clinical interest.Background: The ERGO2 (Ernaehrungsumstellung bei Patienten mit Rezidiv eines Glioblastoms) MR-spectroscopic imaging (MRSI) subtrial investigated metabolism in patients randomized to calorically restricted ketogenic diet/intermittent fasting (crKD-IF) versus standard diet (SD) in addition to re-irradiation (RT) for recurrent malignant glioma. Intracerebral concentrations of ketone bodies (KB), intracellular pH (pHi), and adenosine triphosphate (ATP) were non-invasively determined. Methods: 50 patients were randomized (1:1): Group A keeping a crKD-IF for nine days, and Group B a SD. RT was performed on day 4–8. Twenty-three patients received an extended MRSI-protocol (1H decoupled 31P MRSI with 3D chemical shift imaging (CSI) and 2D 1H point-resolved spectroscopy (PRESS)) at a 3T scanner at baseline and on day 6. Voxels were selected from the area of recurrent tumor and contralateral hemisphere. Spectra were analyzed with LCModel, adding simulated signals of 3-hydroxybutyrate (βOHB), acetone (Acn) and acetoacetate (AcAc) to the standard basis set. Results: Acn was the only reliably MRSI-detectable KB within tumor tissue and/or normal appearing white matter (NAWM). It was detected in 4/11 patients in Group A and in 0/8 patients in Group B. MRSI results showed no significant depletion of ATP in tumor tissue of patients at day 6 during crKD-IF, even though there were a significant difference in ketone serum levels between Group A and B at day 6 and a decline in fasting glucose in Group A from baseline to day 6. The tumor specific alkaline pHi was maintained. Conclusions: Our metabolic findings suggest that tumor cells maintain energy homeostasis even with reduced serum glucose levels and may generate additional ATP through other sources.

DDRE-17. INITIAL CLINICAL EXPERIENCE USING OSIMERTINIB IN PATIENTS WITH RECURRENT MALIGNANT GLIOMAS WITH EGFR ALTERATIONS

Abstract EGFR alterations are commonly observed in malignant gliomas (MG), especially glioblastomas, making this pathway an appealing therapeutic target. Unlike other EGFR tyrosine kinase inhibitors (TKIs), osimertinib (osi), a third-generation, irreversible EGFR-TKI commonly used to treat EGFR-mutant lung cancer, is able to effectively penetrate the blood brain barrier (BBB) and achieve therapeutic concentrations in brain tissue. METHODS: A retrospective chart review identified six patients (pts) aged 46–74 years with recurrent MG and known EGFR alterations identified by next generation sequencing who received at least one dose of osi between 1/1/2018 and 5/26/2020. Patients received osi 80 mg by mouth once daily and continued treatment until disease progression, the development of unacceptable side effects, medical complications, or death. RESULTS: All patients had EGFR amplification. Other EGFR alterations identified included EGFRvIII (1 pt), deletion of introns 1–7 (3 pts) and deletion of introns 13–15 (2 pts). Four of the six patients were evaluable for response. Three patients (75.0%) had stable disease (SD) as best response and one patient (25.0%) was refractory to treatment. One patient with an EGFRvIII mutation achieved stable disease on osi and remained on treatment for 236 days. Thrombocytopenia developed in 2 patients (grade 2 (1), grade 3 (1) in patient also on concurrent bevacizumab) and 1 patient developed grade 1 diarrhea and pneumonia. Overall, this heavily pretreated patient population tolerated osi therapy and half of the patients had a best response of SD which lasted from 77 to 236 days. CONCLUSIONS: Osi has a tolerable safety profile in this heavily pretreated brain tumor population, and it may benefit selected patients with recurrent MG containing EGFR alterations. Further clinical investigations are needed, particularly in patients whose tumors express an EGFRvIII mutation, to identify which EGFR alterations may sensitize tumors to this BBB penetrant EGFR-TKI.

CTNI-26. ACCELERATOR-BASED BNCT IN RESCUE TREATMENT OF PATIENTS WITH RECURRENT GBM: A MULTICENTER PHASE II STUDY

Abstract BACKGROUND Boron neutron capture therapy (BNCT) is tumor-selective particle radiation and theoretically efficacious especially for tumors with infiltrative nature, such as glioblastoma (GBM). The aim of this study is to assess safety and efficacy of accelerator-based BNCT (AB-BNCT) using cyclotron-based neutron generator, BNCT30, and 10B-boronophenylalanine (borofalan(10B)) agent, SPM-011, in patients with recurrent malignant gliomas, chiefly GBM. METHODS The multi-institutional open-label, phase II clinical trial for recurrent 27 cases of malignant gliomas (MG) (24 cases were GBM) was conducted with above AB-BNCT system, using 500mg/kg of SPM-011 (study code, JG002). The patients were enrolled from February 2016 to June 2018. The inclusion criteria are bevacizumab-naïve MG, recurrent after standard treatment composed of XRT and chemotherapy with TMZ. Neutron-irradiation time were determined not to exceed to 8.5 Gy-Eq for scalp dose. Primary endpoint was 1-year survival rate and secondary ones were median overall survival (mOS), median progression free survival (mPFS). The results were compared to previous Japanese domestic bevacizumab trial for recurrent GBM (JO22506) which had the similar inclusion criteria with JG002. RESULTS 1-year survival rate and mOS of recurrent GBM cases in JG002 was 79.2% (95% CI:57.0–90.8) and 18.7 months (95% CI:12.9–23.4) respectively, while those of JO22506 was 34.5% (90% CI:20.0–49.0) and 10.5 months (95% CI:8.2–12.4), respectively. Median PFS of JG002 and JO22506 were 0.9 and 3.3 months, respectively. Most important adverse event in JG002 was brain edema. Brain edema in 21 out of 27 cases was treated with bevacizumab after progress disease. CONCLUSIONS AB-BNCT demonstrated acceptable safety and prolonged survival for recurrent MG chiefly GBM. AB-BNCT might produce brain edema somewhat after the treatment, which might be the unavoidable adverse event of re-irradiation for recurrent MG, however that seemed to be controlled well with bevacizumab.

EXTH-39. HEXON SWAPPING MITIGATES ANTI-VIRAL IMMUNE RESPONSE DURING BRAIN TUMOR VIROTHERAPY

Abstract Cancer virotherapy is a paradigm-shifting treatment modality based on the capabilities of virus-mediated oncolysis to elicit an anti-tumor immune response. Phase 1 and 2 clinical trials have demonstrated the safety and efficacy of our oncolytic adenovirus DNX-2401 (Delta-24-RGD) for patients with recurrent malignant gliomas. While a subset of the patients showed significant benefits, our goal is to improve the response rate. Clearance of the therapeutic virus by dominant anti-viral immune responses may contribute to the observed limits of the virotherapy. Adenovirus serotype 5 that provides the backbone of most oncolytic adenoviruses is highly prevalent in the human population and neutralizing antibodies against the capsid protein hexon may inhibit viral infection and replication. In this study, we showed using immunofluorescence that in mice bearing orthotopic syngeneic glioblastoma GSC005 treated with Delta-24-RGD, IgG antibodies crossed the disrupted blood-brain barrier and infiltrated the brain tumor parenchyma to colocalize with the viral hexon, suggesting that the systemic immune response may eradicate the virus within the infected tumor. To overcome this obstacle, we generated a chimeric virus called Delta-24-RGD-H43m with hexon hypervariable regions replaced with those from a lesser prevalent serotype 43 to avoid recognition by antibodies generated against serotype 5. The molecular swapping of the hexon did not significantly interfere with virion assembly nor attenuate its anti-glioma effect. Thus, the two viruses showed comparable efficacy in vitro (P= 0.568) and in vivo for animals without prior virus exposures (P= 0.228). Importantly, Delta-24-RGD-H43m evaded neutralizing antibodies generated against Delta-24-RGD and maintained its oncolytic ability (P&amp;lt; 0.0001). We conclude that hexon swapping strategies may improve virotherapy by alleviating the dominant immune response against the virus. Despite limited understanding of the interaction between oncolytic viruses and the host immune system, further research on strategies to circumvent virus-specific immune responses should aid the development of enhanced, glioma-targeted virotherapies.

CTIM-21. PEPTIDE VACCINE DIRECTED TO CMV pp65 FOR TREATMENT OF RECURRENT MALIGNANT GLIOMA AND MEDULLOBLASTOMA IN CHILDREN AND YOUNG ADULTS: PRELIMINARY RESULTS OF A PHASE I TRIAL

INTRODUCTIONThe cytomegalovirus (CMV) antigen, pp65, is ubiquitously expressed in malignant glioma and medulloblastoma but not in healthy brain. The objective of this Phase I trial (NCT03299309) was to assess the safety and feasibility of a novel pp65 peptide vaccine (PEP-CMV) in children and young adults with recurrent medulloblastoma and malignant glioma.METHODSVaccines contain a synthetic long peptide (SLP) of 26 amino acids encoding multiple potential class I, class II, and antibody epitopes of CMV pp65 across several haplotypes. This SLP is administered as an emulsion in Montanide ISA 51. Patients receive a single course of temozolomide to induce lymphopenia, tetanus/diphtheria toxoid site preconditioning, then vaccines administered intradermally every two weeks for 3 doses, then monthly.RESULTSTo date, 17 patients have been enrolled. Diagnoses include medulloblastoma (n=1), glioblastoma (n=9), anaplastic oligodendroglioma (n=2), anaplastic astrocytoma (n=2), and malignant glioma NOS (n=3). Mean number of prior treatment regimens is 4.9 (range 1–12). Mean age is 22yo (range 6–35) and 41% of patients are male. The median KPS is 80. The median number of vaccines given at time of analysis is 3.3 (range 1–12). There have been no ≥ 3 Grade toxicities related to the vaccine. One patient developed nausea, vomiting, palpitations, and tachycardia after vaccination and had elevated inflammatory cytokines consistent with cytokine release syndrome. Median PFS is 2.5 months (95% CI: 0.8, not estimable) and median OS is 6.5 months (95% CI 1.8, not estimable). Interim analysis of immune monitoring bloodwork and perfusion MRI to quantify responses to PEP-CMV has been delayed due to COVID-19. However, adults with GBM who received PEP-CMV (NCT02864368) had significant (p≤0.05) increases in GCSF, GM-CSF, IFN-γ, IL-10, IL-2, IL-8, MIP1-α, and TNF-α levels.CONCLUSIONSPreliminary results demonstrate that PEP-CMV is feasible and well-tolerated in heavily pretreated, multiply recurrent patients.