Intramuscular (IM) INO-5401 + INO-9012 with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma.
David A. Reardon, Steven Brem, Arati Desai, Stephen Bagley, Sylvia C. Kurz, Macarena I. de la Fuente, Seema Nagpal, Mary Welch, Adı́lia Hormigo, Peter Forsyth, Jacob Mandel, Simon Khagi, Robert Aiken, Tobias Walbert, Frank S. Lieberman, Jana Portnow, James Battiste, Elisabeth Gillespie, Israel Lowy, Jeffrey Skolnik
Abstract
2004 Background: Novel T cell-enabling therapies plus checkpoint inhibition may improve OS in GBM. INO-5401 (synthetic DNA plasmid encoding hTERT, WT-1, PSMA) plus INO-9012 (synthetic DNA plasmid encoding IL-12), with cemiplimab (PD-1 inhibitor), was given to patients with newly diagnosed GBM with MRD to evaluate tolerability, efficacy, and immunogenicity. Median OS and immunogenicity at 18 months (OS18) are reported. Methods: This is a phase I/II, single arm, two cohort (A: unmethylated MGMT and B: methylated MGMT) study. Primary endpoint is safety; efficacy and immunogenicity are secondary. Nine mg INO-5401 plus 1 mg INO-9012 (4 doses Q3W, then Q9W) was given IM with EP in combination with cemiplimab (350 mg IV Q3W). Hypofractionated RT (40 Gy over 3 weeks) with TMZ was given to all patients, followed by maintenance (Cohort B only), which was a novel therapeutic approach. Immunogenicity was assessed by quantifying INO-5401-specific peripheral cellular immune responses via IFN-g ELISpot and flow cytometry. Intra-tumoral gene expression was analyzed by RNA-Seq of FFPE GBM tissue. Differences in gene expression were analyzed using the Wilcoxon rank sum test. Results: Fifty-two subjects were enrolled: 32 in Cohort A; 20 in Cohort B (35% women; median age 60 years [range 19-78 years]). The adverse event profile was consistent with known single-agent (INO-5401, INO-9012, EP or cemiplimab) events; most events were ≤Grade 2 and no related events were Grade ≥4. Median OS durations in Cohorts A and B were 17.9 months (95% CI 14.5-19.8) and 32.5 months (95% CI 18.4-not reached), respectively. Flow cytometry revealed activated, antigen specific CD4+CD69+PD1+ and CD8+CD69+PD1+ T cells, the latter with lytic potential as defined by presence of perforin and granzyme A. Both subsets exhibited HR < 1.0 and p < 0.05 when accounting for a 0.1% T cell frequency change, translating to a 23% and 28% reduced risk of death, respectively. Gene expression levels in pre-treatment tissues were similar between alive and deceased groups for INO-5401 antigens and immune cell markers; however, the alive group displayed significantly reduced expression of genes associated with anti-apoptosis, pro-proliferation, and immune response suppression. Post-treatment tumor tissue displayed altered gene expression for immune-related markers versus pre-treatment tissue, including markers of T cell infiltration, activation, and lytic potential. Conclusions: INO-5401 + INO-9012 has an acceptable risk/benefit profile and elicits robust immune responses that correlate with enhanced survival when administered with cemiplimab and RT/TMZ to newly diagnosed GBM patients. Pre-treatment gene expression signatures in MGMT-unmethylated patients were statistically associated with OS18. Overall, INO-5401 elicits antigen-specific T cells that can infiltrate GBM tumors. Clinical trial information: NCT03491683.