Analysis of Adenoviral p53 Gene Therapy Clinical Trials in Recurrent Head and Neck Squamous Cell Carcinoma

Abstract

BackgroundWe conducted an analysis of previous adenoviral p53 (Ad-p53) treatment data in recurrent head and neck squamous cell carcinoma (HNSCC) patients to identify optimal Ad-p53 treatment methods for future clinical trials.MethodsThe analysis involved recurrent HNSCC patients treated with Ad-p53 for whom p53 genotyping and immunohistochemistry tumor biomarker studies had been performed (n = 70). Ad-p53 tumor treatment responses defined by RECIST 1.1 criteria were correlated with Ad-p53 dose and tumor p53 biomarkers. Gene expression profiles induced by Ad-p53 treatment were evaluated using the Nanostring IO 360 panel.ResultsAd-p53 dose based upon the injected tumor volume had a critical effect on tumor responses. All responders had received Ad-p53 doses greater than 7 × 1010 viral particles/cm3 of tumor volume. There was a statistically significant difference in tumor responses between patients treated with greater than 7 × 1010 viral particles/cm3 compared to patients treated at lower Ad-p53 doses (Tumor Response 31% (9/29) for Ad-p53 > 7 × 1010 viral particles/cm3 versus 0% (0/25) for Ad-p53 < 7 × 1010 viral particles/cm3; p = 0.0023). All responders were found to have favorable p53 biomarker profiles defined by less than 20% p53 positive tumor cells by immunohistochemistry (IHC), wild type p53 gene sequence or p53 deletions, truncations, or frame-shift mutations without functional p53 tetramerization domains. Preliminary gene expression profiling results revealed that Ad-p53 treatment increased interferon signaling, decreased TGF-beta and beta-catenin signaling resulting in an increased CD8+ T cell signature which are associated with increased responses to immune checkpoint blockade.ConclusionsOur findings have important implications for future p53 targeted cancer treatments and identify fundamental principles to guide Ad-p53 gene therapy. We discovered that previous Ad-p53 clinical trials were negatively impacted by the inclusion of patients with unfavorable p53 biomarker profiles and by under dosing of Ad-p53 treatment. Future Ad-p53 clinical trials should have favorable p53 biomarker profiles inclusion criteria and Ad-p53 dosing above 7 × 1010 viral particles/cm3 of injected tumor volume. Preliminary gene expression profiling identified p53 mechanisms of action associated with responses to immune checkpoint blockade supporting evaluation of Ad-p53 in combination with immune checkpoint inhibitors.

Trial watch: intratumoral immunotherapy

“… 250 In preclinical studies, a p53 -armed adenoviral vector (Ad-p53), alone or combined with PD1 blockade, showed an enhanced control of local treated and distant untreated tumors compared with anti-PD1 alone, suggesting that Ad-p53 immunotherapy mediates abscopal effects and can reverse resistance to ICI. 249 , 251 , 252 These results encouraged the clinical evaluation of Ad-p53 in combination with PD1 blockade. Along this line, the Phase I–II investigation NCT02842125 aimed at evaluating the safety and efficacy of i.t .…”

Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers

“…A Phase 2 trial [NCT03544723] is ongoing to investigate the combination of gendicine with clinicians’ choice of ICIs. Preliminary gene expression analysis comparing pre- and post- gendicine-treated HNC tumor revealed upregulation of IFNγ-signaling genes, decreased TGF-β and β-catenin signaling ( 74 ) and increased CD8+ T cells signature, which is associated with increased clinical responses to ICIs ( 74 ).…”

Current and Emerging Molecular Therapies for Head and Neck Squamous Cell Carcinoma

“…A Phase III clinical trial for use of Advexin (adenovirus containing TP53) (INGN 201, Ad5CMV-p53) versus methotrexate in treating advanced recurrent HNSCC showed that patients with wild-type p53 had better response to Advexin, whereas patients carrying mutant p53 were more responsive to methotrexate chemotherapy which indicates the potential of p53 as a biomarker to design a targeted therapy [141]. This approach has subsequently been used in a Phase II trial (NCT03544723) investigating safety and efficacy of p53 gene therapy combined with immune checkpoint inhibitors in solid tumours including HNSCC [142]. Previous Ad-p53 clinical trials appear to have been negatively impacted by the inclusion of patients with unfavourable p53 biomarker profiles and by under dosing of Ad-p53 treatment [142].…”

“…This approach has subsequently been used in a Phase II trial (NCT03544723) investigating safety and efficacy of p53 gene therapy combined with immune checkpoint inhibitors in solid tumours including HNSCC [142]. Previous Ad-p53 clinical trials appear to have been negatively impacted by the inclusion of patients with unfavourable p53 biomarker profiles and by under dosing of Ad-p53 treatment [142]. This has important implications for Ad-p53 gene therapy and future p53-targeted therapy.…”