Preclinical assessment of MAGMAS inhibitor as a potential therapy for pediatric medulloblastoma.

Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and non-SHH group3 subtypes. MAGMAS (Mitochondrial Associated Granulocyte Macrophage colony-stimulating factor Signaling molecules) encode for mitochondrial import inner membrane translocase subunit and is responsible for translocation of matrix proteins across the inner membrane. We previously reported that a small molecule MAGMAS inhibitor, BT9, decreases cell proliferation, migration, and oxidative phosphorylation in adult glioblastoma cell lines. The aim of our study was to investigate whether the chemotherapeutic effect of BT9 can be extended to pediatric medulloblastoma. Methods: Multiple in vitro assays were performed using human DAOY (SHH activated tp53 mutant) and D425 (non-SHH group 3) cells. The impact of BT9 on cellular growth, death, migration, invasion, and metabolic activity were quantified using MTT assay, TUNEL staining, scratch wound assay, Matrigel invasion chambers, and seahorse assay, respectively. Survival following 50mg/kg BT9 treatment was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells. Results: Compared to control, BT9 treatment led to a significant reduction in medulloblastoma cell growth (DAOY, 24hrs IC50: 3.6uM, 48hrs IC50: 2.3uM, 72hrs IC50: 2.1uM; D425 24hrs IC50: 3.4uM, 48hrs IC50: 2.2uM, 72hrs IC50: 2.1uM) and a significant increase in cell death (DAOY, 24hrs p=0.0004, 48hrs p<0.0001; D425, 24hrs p=0.0001, 48hrs p=0.02). In DAOY cells, 3uM BT9 delayed migration, and significantly decreased DAOY and D425 cells invasion (p < 0.0001). Our in vivo study, however, did not extend survival in xenograft mouse model of group3 medulloblastoma compared to vehicle-treated controls. Conclusions: Our in vitro data showed BT9 antitumor efficacy in DAOY and D425 cell lines suggesting that BT9 may represent a promising targeted therapeutic in pediatric medulloblastoma. These data, however, need to be further validated in animal models.

Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment.

BACKGROUND: Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival. METHODS: Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 µg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration. RESULTS: Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%. CONCLUSIONS: AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted. TRIAL REGISTRATION: NCT, NCT03400917 , Registered 10 January 2018.

Planning for post-pandemic cancer care delivery: Recovery or opportunity for redesign?

The delivery of cancer care has never changed as rapidly and dramatically as we have seen with the coronavirus disease 2019 (COVID-19) pandemic. During the early phase of the pandemic, recommendations for the management of oncology patients issued by various professional societies and government agencies did not recognize the significant regional differences in the impact of the pandemic. California initially experienced lower than expected numbers of cases, and the health care system did not experience the same degree of the burden that had been the case in other parts of the country. In light of promising trends in COVID-19 infections and mortality in California, by late April 2020, discussions were initiated for a phased recovery of full-scale cancer services. However, by July 2020, a surge of cases was reported across the nation, including in California. In this review, the authors share the response and recovery planning experience of the University of California (UC) Cancer Consortium in an effort to provide guidance to oncology practices. The UC Cancer Consortium was established in 2017 to bring together 5 UC Comprehensive Cancer Centers: UC Davis Comprehensive Cancer Center, UC Los Angeles Jonsson Comprehensive Cancer Center, UC Irvine Chao Family Comprehensive Cancer Center, UC San Diego Moores Cancer Center, and the UC San Francisco Helen Diller Family Comprehensive Cancer Center. The interventions implemented in each of these cancer centers are highlighted, with a focus on opportunities for a redesign in care delivery models. The authors propose that their experiences gained during this pandemic will enhance pre-pandemic cancer care delivery.