Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Bota DA

PROVIDER: S-EPMC9749349 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Bota Daniela A DA Taylor Thomas H TH Piccioni David E DE Duma Christopher M CM LaRocca Renato V RV Kesari Santosh S Carrillo Jose A JA Abedi Mehrdad M Aiken Robert D RD Hsu Frank P K FPK Kong Xiao-Tang XT Hsieh Candace C Bota Peter G PG Nistor Gabriel I GI Keirstead Hans S HS Dillman Robert O RO

Journal of experimental & clinical cancer research : CR 20221214 1

<h4>Background</h4>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.<h4>Methods</h4>Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) ...[more]

PMID: 36517865

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Project description:Abstract In primary glioblastoma (GBM), overall survival (OS) is poor despite standard aggressive therapy. Adjunctive AV-GBM-1 vaccine immunotherapy may improve OS. In this multi-institutional phase II trial, key eligibility criteria for intent-to-treat (ITT) enrollment were: (1) primary GBM, (2) age < 70 years when GBM was resected, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) KPS > 70 post-surgery, and (6) plan to treat with concurrent RT/TMZ. Dendritic cells (DC) were differentiated from monocytes by culturing in IL-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). AV-GBM-1 consisted of autologous DC incubated with autologous tumor antigens contained in the lysate of irradiated cultured GBM cells. After recovery from RT/TMZ, doses were admixed with 500 mcg GM-CSF; up to 8 doses were injected subcutaneously over 6 months. Patients were not excluded by apparent progression or pseudo-progression post RT/TMZ. OS and progression-free-survival (PFS) were calculated from ITT enrollment. The success rate was 97% for both GBM cell cultures and collection of monocytes; 60/60 vaccines were successfully manufactured. Median age was 59 years. 57 patients received 392 injections. After two weekly injections there were significant increases in plasma lipocalin-2 and angiopoietin-1, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The most common adverse events attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). With follow up from 15.2 to 32 months, median PFS and OS were 10.3 (8.5,11.6 95% CI) and 16.0 (13.0,21.3 95% CI) months respectively. OS was better in the 25 patients who had methylguanine-methyltransferase (MGMT) methylation and/or isocitrate dehydrogenase (IDH) mutation. Age was not independently correlated with survival. From date of first injection, OS was not increased in 14 patients who were treated with alternating electrical tumor-treating fields. CONCLUSION: feasibility, safety, and PFS were encouraging. A phase III trial is in development. Clinicaltrials.gov NCT03400917.

Project description:BackgroundTumor-treating fields (TTFields) therapy and radiotherapy may have synergistic anti-glioma effect based on preclinical studies. The combination of chemoradiation therapy (CRT) with TTFields therapy has noticeably attracted clinicians' attention. This study aimed to provide insights into the clinical outcomes of patients with newly diagnosed glioblastoma who received either concurrent CRT and TTFields therapy or adjuvant TTFields therapy following CRT. The findings were based on a cohort of patients who were treated at Huashan Hospital (Shanghai, China).MethodsThis retrospective study analyzed ndGBM patients' clinical outcomes who were treated at Huashan Hospital and received TTFields therapy. Patients were categorized into two groups: one group received adjuvant TTFields therapy after completing CRT (referred to as the A-TTF group), while the other received TTFields therapy concurrently with CRT and continued TTFields after treatment (referred to as the CA-TTF group). The study evaluated treatment efficacy and toxicities, comparing outcomes between the two groups. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. To mitigate confounding factors, efficacy was assessed using the Cox proportional hazards regression model, propensity score matching, and inverse probability of treatment weighting (IPTW) based on the propensity score.ResultsA total of 72 patients with ndGBM were included in the study. Among them, 41 patients received concurrent and adjuvant TTFields therapy in combination with CRT (CA-TTF group), and 31 patients received adjuvant TTFields therapy with temozolomide (A-TTF group). The median follow-up time was 18.0 months. No significant differences were observed in median PFS (14.2 vs. 15.0 months, P = 0.92) or OS (20.8 vs. 20.0 months, P = 0.92) between the CA-TTF and A-TTF groups. Skin toxicity was common, while manageable, with no significant difference between the two groups. Following IPTW adjustment, the hazard ratios for PFS and OS indicated a potential advantage for the CA-TTF group, although this difference was not statistically significant.ConclusionConcurrent CRT and TTFields therapy emerged safe for newly diagnosed GBM patients. Although no significant survival differences were found between the CA-TTF and A-TTF groups, the potential benefit of concurrent TTFields warrants further investigation through large-scale clinical trials.

Dataset Information

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

Methods

Results

Conclusions

Trial registration

Publications

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

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