Long-Term Follow-Up of Gemogenovatucel-T (Vigil) Survival and Molecular Signals of Immune Response in Recurrent Ovarian Cancer

Rodney P Rocconi, Laura Stanbery, Luciana Madeira da Silva, Robert A Barrington, Phylicia Aaron, Luisa Manning, Staci Horvath, Gladice Wallraven, Ernest Bognar, Adam Walter, John Nemunaitis, Rodney P Rocconi, Laura Stanbery, Luciana Madeira da Silva, Robert A Barrington, Phylicia Aaron, Luisa Manning, Staci Horvath, Gladice Wallraven, Ernest Bognar, Adam Walter, John Nemunaitis

Abstract

Aim: To determine the relationship between gene expression profile (GEP) and overall survival (OS) by NanoString following treatment with Vigil.

Patients and methods: Recurrent ovarian cancer patients (n = 21) enrolled in prior clinical trials.

Results: GEP stratified by TISHIGH vs. TISLOW demonstrated OS benefit (NR vs. 5.8 months HR 0.23; p = 0.0379), and in particular, MHC-II elevated baseline expression was correlated with OS advantage (p = 0.038). Moreover, 1-year OS was 75% in TISHIGH patients vs. 25% in TISLOW (p = 0.03795). OS was also correlated with positive γ-IFN ELISPOT response, 36.8 vs. 23.0 months (HR 0.19, p = 0.0098).

Conclusion: Vigil demonstrates OS benefit in correlation with TISHIGH score, elevated MHC-II expression and positive γ-IFN ELISPOT in recurrent ovarian cancer patients.

Keywords: NanoString; TIS; Vigil; gene expression profile; immune response; immunotherapy; ovarian cancer.

Conflict of interest statement

R.R. reports consulting fees and sponsored research. Luciana Madeira da Silva reports sponsored research.

Figures

Figure 1
Figure 1
OS of Vigil-treated recurrent/refractory ovarian cancer patients from time of procurement.
Figure 2
Figure 2
Overall survival relationship of Vigil treatment recurrent/refractory ovarian cancer patients by γ-IFN-ELISPOT-positive vs. γ-IFN-ELISPOT-negative recurrent ovarian cancer patients from time of tissue procurement (A) and start of treatment (B).
Figure 3
Figure 3
Principal component analysis (PCA) was completed to detect intrinsic clusters between responders to Vigil treatment and γ-IFN-ELISPOT reactivity post-Vigil treatment as well as possible outliers. TISHIGH good responders (Tumor inflammation score (TIS)) > 6, OS > 12months) post-Vigil treatment = red; TISHIGH poor responders (TIS score > 6, OS < 12months) post-Vigil treatment = blue; TISLOW good responders (TIS score < 6, OS > 12months) post-Vigil treatment = green; TISLOW poor responders (TIS score < 6, OS < 12months) post-Vigil treatment = purple; γ-IFN-ELISPOT-negative = circles; γ-IFN-ELISPOT-positive = squares; post-Vigil; γ-IFN-ELISPOT not evaluable = triangle (A) Heatmap of immune pathways stratified by TIS status, response to Vigil therapy and γ-IFN-ELISPOT status. Blue scale indicates under-expressed genes and red scale upregulated genes (B).
Figure 4
Figure 4
γ-IFN-ELISPOT reactivity stratified by tumor inflammation scoreHIGH (TIS) vs. TISLOW. Whiskers represent minimum and maximum TIS scores. Statistical analyses of TIS scores were performed using unpaired T-tests with Welch correction. (A) Volcano plot of p-value versus log2 fold change in the differential expression between TISHIGH and TISLOW. The test for differential expression was done by fitting the log2 normalized count to the response with linear model. The p-values were adjusted by the Benjamini and Yekutieli (BY) adjustment. Dots corresponding to genes that are significant at p < 0.5 (dashed line) are labeled in red. Solid line represents p < 0.10 (B). Overall survival relationship of Vigil treatment stratified by TISHIGH vs. TISLOW (C).
Figure 5
Figure 5
Patient tumor inflammation score (TIS) scores and relationship with survival and immune pathways.
Figure 6
Figure 6
Baseline gene signatures correlate with overall survival after Vigil treatment.
Figure 7
Figure 7
Box plots displaying the distribution of signature scores within the low- and high-expression groups (cutoff = score median) and correlation with (A) ELISPOT reactivity post-Vigil treatment. ELISPOT-positive (green), -negative (red) or not tested (black) patients are displayed. (B) Signature scores within the low- and high-expression groups (cutoff = score median) and correlation with overall survival > 12 months (GR) or <12 months (PR) post-Vigil treatment. GR (green), PR (red) patients are displayed. Whiskers represent minimum and maximum TIS scores. Statistical analyses of TIS scores were performed using unpaired T-tests with Welch correction.

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