First Results on Survival from a Large Phase 3 Clinical Trial of an Autologous Dendritic Cell Vaccine in Newly Diagnosed Glioblastoma

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.https://deepblue.lib.umich.edu/bitstream/2027.42/144529/1/12967_2018_Article_1552.pd

Endoplasmic reticulum chaperones and their roles in the immunogenicity of cancer vaccines

The endoplasmic reticulum (ER) is a major site of passage for proteins en route to other organelles, to the cell surface, and to the extracellular space. It is also the transport route for peptides generated in the cytosol by the proteasome into the ER for loading onto major histocompatibility complex class I (MHC I) molecules for eventual antigen presentation at the cell surface. Chaperones within the ER are critical for many of these processes; however, outside the ER certain of those chaperones may play important and direct roles in immune responses. In some cases, particular ER chaperones have been utilized as vaccines against tumors or infectious disease pathogens when purified from tumor tissue or recombinantly generated and loaded with antigen. In other cases, the cell surface location of ER chaperones has implications for immune responses as well as possible tumor resistance. We have produced heat shock protein/chaperone protein-based cancer vaccines called CRCL (Chaperone-Rich Cell Lysate) that are conglomerates of chaperones enriched from solid tumors by an isoelectric focusing technique. These preparations have been effective against numerous murine tumors, as well as in a canine with an advanced lung carcinoma treated with autologous CRCL. We also published extensive proteomic analyses of CRCL prepared from human surgically-resected tumor samples. Of note, these preparations contained at least ten ER chaperones and a number of other residents, along with many other chaperones/heat shock proteins. Gene ontology and network analyses utilizing these proteins essentially recapitulate the antigen presentation pathways and interconnections. In conjunction with our current knowledge of cell surface/extracellular ER chaperones, these data collectively suggest that a systems-level view may provide insight into the potent immune stimulatory activities of CRCL with an emphasis on the roles of ER components in those processes

Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery

Rationale and design of the 500-patient, 3-year, and prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT registry

Implantation of biodegradable wafers impregnated with carmustine (BCNU) is one of the few chemotherapeutic modalities that have been evaluated in Phase III trials and approved by the US FDA for treatment of newly diagnosed high-grade glioma and recurrent glioblastoma. Enrolling up to 500 patients for 3-year follow-up at over 30 sites, the prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT (VIGILANT) registry (NCT02684838) will evaluate BCNU wafers for treatment of CNS malignancies in contemporary practice and in the new era of molecular tumor analysis. Subgroup analyses will include tumor type, molecular marker status, and treatment combinations. Interim analyses from the VIGILANT registry will be reported until complete results are available in 2024

Patterns of care for adults with newly diagnosed malignant glioma

CONTEXT: Patients with malignant glioma (grade III or IV) face a poor prognosis, and few evidence-based treatment guidelines are available. There is a dearth of prospective data on patterns of care for these patients. OBJECTIVE: To provide benchmark data to enable comparison of individual practice patterns and outcomes. DESIGN, SETTING, AND PATIENTS: The Glioma Outcomes (GO) Project enrolled 788 patients at 52 clinical sites, both academic and community practices, between December 1997 and July 2000. The enrollment criteria included adult patients with primary grade III or IV glioma undergoing a first or second operation for diagnosis or treatment. The data collection instruments included questionnaire forms given at enrollment, during the perioperative period, and at follow-up intervals of 3 months until death or a maximum of 24 months. Of the patients recorded in the GO database, 565 patients with newly diagnosed tumors were used for this analysis. MAIN OUTCOME MEASURES: Patterns of care (surgical management, perioperative care, postoperative management). RESULTS: Most patients underwent magnetic resonance imaging (n = 518; 92%) and an attempt at tumor resection (n = 425; 75%). Cortical mapping (n = 107; 19%) and intraoperative image guidance (n = 161; 29%) were uncommon. Most received perioperative corticosteroids (n = 535; 99%) and antiepileptic medications (n = 497; 88%), but few received antidepressants (n = 38; 8%) or prophylactic heparin (n = 42; 7%). Most received adjuvant radiation therapy (n = 479; 87%), but fewer received chemotherapy (n = 300; 54%). Practice patterns varied significantly between academic and community settings. CONCLUSIONS: Reliance on magnetic resonance imaging, surgery, and radiation is generally accepted; however, relatively infrequent chemotherapy use may conflict with published literature, and frequent use of prophylactic antiepileptic medications contradicts established practice guidelines. Other practice patterns involving surgical adjuncts, prophylactic heparin, and antidepressants require further investigation to clarify appropriateness. Establishing further clinical guidelines may help reduce variability in practice patterns

Phenotype and neuronal cytotoxic function of glioblastoma extracellular vesicles

No abstract available