Carcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial

Abstract

Measles virus (MV) vaccine strains have shown significant preclinical antitumor activity against glioblastoma (GBM), the most lethal glioma histology. In this first in human trial (NCT00390299), a carcinoembryonic antigen-expressing oncolytic measles virus derivative (MV-CEA), was administered in recurrent GBM patients either at the resection cavity (Group A), or, intratumorally on day 1, followed by a second dose administered in the resection cavity after tumor resection on day 5 (Group B). A total of 22 patients received study treatment, 9 in Group A and 13 in Group B. Primary endpoint was safety and toxicity: treatment was well tolerated with no dose-limiting toxicity being observed up to the maximum feasible dose (2×10⁷ TCID50). Median OS, a secondary endpoint, was 11.6 mo and one year survival was 45.5% comparing favorably with contemporary controls. Other secondary endpoints included assessment of viremia, MV replication and shedding, humoral and cellular immune response to the injected virus. A 22 interferon stimulated gene (ISG) diagonal linear discriminate analysis (DLDA) classification algorithm in a post-hoc analysis was found to be inversely (R = -0.6, p = 0.04) correlated with viral replication and tumor microenvironment remodeling including proinflammatory changes and CD8 + T cell infiltration in post treatment samples. This data supports that oncolytic MV derivatives warrant further clinical investigation and that an ISG-based DLDA algorithm can provide the basis for treatment personalization.

Fig. 1. Treatment-related adverse events.

Treatment was well tolerated with only grade 1 and 2 toxicity being observed (n = 22 evaluable patients).

Fig. 2. Baseline and posttreatment anti-measles virus (MV) antibody levels.

Error bars represent the standard error of the mean (SEM) A pre-treatment: n = 9 patients, mean =104.7 + /−13.0 SEM; A post treatment: n = 8 patients, mean=95.9 + /−14.6 SEM; B pre-treatment: n = 13 patients, mean=30.9 + /−10.4 SEM; B post treatment: n = 10 patients, mean=21.2 + /−10.2 SEM). Source data are provided as Source Data file.

Fig. 3. DLDA score correlation with viral replication in treated tumors.

DLDA scores calculated for all Group B patients were correlated with virus replication in the treated tumors (n = 12 patients with available virus replication data). Pearson’s correlation coefficient (r), 95% CI and two-sided P value based on a t-distribution with n-2 degrees of freedom. Source data are provided as Source Data file.

Fig. 4. Measles virus (MV) receptor expression in study patients.

Gene expression levels of the three known MV receptors CD46, SLAM and Nectin-4 were assessed in Group B patients (n = 13) and found to be comparable. Source data are provided as Source Data file.

Fig. 5. Differential gene expression in posttreatment samples of viral replication resistant versus permissive tumors (N = 13 patients).

A RNA was isolated from tumor biopsies before and after MV therapy, expression was analyzed by Nanostring and differentially expressed genes were used to determine differentially activated pathways. The heatmap shows gene expression intensity across samples (right panel) and biological processes enriched by each gene (left panel). Permissive tumors (N = 3 patients) are underlined with a black bar, intermediate permissiveness (N = 9 patients) with a green bar and resistant tumors (N = 1 patient) with a magenta bar at the bottom of the heat map. Expression of the genes presented in this plot was at least twofold different (up- or downregulated) with P value 0.05 or lower in the group of good responders vs poor responders after the treatment. B Bar plot depiction of adjusted P values corresponding to biological processes (BP) of the Gene Ontology (http://geneontology.org/): The 14 processes that are most differentially enriched post treatment in patients with replication permissive versus resistant tumors are shown here.

Fig. 6. Pre- versus posttreatment CD8 + T-cell infiltration and correlation with baseline DLDA scores in group B patients.

A There was a significant increase in CD8 + T-cell infiltration from baseline tumor samples to day 5 of treatment (CD8: Wilcoxon signed-rank test V = 57, P = 0.032, n = 11). B Development of CD8 + T-cell predominant lymphocytic infiltrates was observed in study patients following one dose of MV treatment, including patients with intermediate DLDA scores. Representative examples of two study patients are shown. C Correlation between DLDA score and CD8 + T-cell increase following treatment. Spearman’s rho = −0.46 (95% CI: −0.83 to 0.19, two-sided P value, P = 0.154, n = 11 patients with available log2 fold change CD8 data). D Lymphocytic cell infiltration was evaluated in tumor specimens obtained in subsequent surgeries following study completion in a subset of study patients; evolution of the percentage of CD8-positive cells is depicted. Source data are provided as Source Data file.

Fig. 7. Progression-free survival and overall survival outcomes in study patients.

A Progression-free survival in Group A and Group B patients. B Overall survival in Group A and Group B patients. Source data are provided as Source Data file.