Reversing immune checkpoint inhibitor resistance with adenoviral IL-24 and p53 tumor suppressor immune gene therapy.

Chada, Sunil; Wiederhold, Dora; Menander, Kerstin B.; Ahn, Hyomin; Oh, Eonju; Yun, Chae‐Ok; Sobol, Robert E.

doi:10.1200/jco.2018.36.5_suppl.64

Cited by 7 publications

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“…[ 10 ] For example, by delivering p53 mRNA or adenoviral vector encoding p53 combined with a PD‐1 antibody can increase the number of infiltrating CD8 + T cells and mature NK cells. [ 11 ] Furthermore, combination of a p53 agonist with programmed cell death protein 1 (PD‐1) or programmed cell death 1 ligand 1 (PD‐L1) antibodies has resulted in complete tumor regression and a significant increase in survival. [ 12 ] This combination therapy strategy has markedly improved the treatment efficacy, but the optimal dose and order of administration of different agents remain elusive, which often causes an increase in immune‐related adverse events (irAEs).…”

Section: Introductionmentioning

confidence: 99%

A Totipotent “All‐In‐One” Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment

et al. 2022

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Immune checkpoint blockade combined with reversal of the immunosuppressive tumor microenvironment (TME) can dramatically enhance anti‐tumor immunity, which can be achieved by using multiple‐agent therapy. However, the optimal dose and order of administration of different agents remain elusive. To address this dilemma, multiple agents are often grafted together to construct “all‐in‐one” totipotent drugs, but this usually comes at the cost of a lack of synergy between the agents. Herein, by comprehensively analyzing the conserved sites of the immune checkpoint and TME drug targets, peptide secondary structures, assembly properties, and other physicochemical properties, a high‐content peptide library is designed. By using the “3D‐molecular‐evolution” screening strategy, an efficient and totipotent “all‐in‐one” peptide (TAP) is obtained, which possesses the abilities of self‐assembling, blocking the PD‐1/PD‐L1 axis, inhibiting Rbm38‐eIF4E complex formation, and activating p53. It is shown that in mice treated with TAP, with either subcutaneous tumors or patient‐derived xenografts, PD‐L1 is blocked, with increased activation of both T and NK cells whilst reversing the immunosuppressive TME. Moreover, TAP can mitigate tumor activity and suppress tumor growth, showing superior therapeutic effect over antibody‐based drugs.

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Section: Introductionmentioning

confidence: 99%

A Totipotent “All‐In‐One” Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment

et al. 2022

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“…In this regard, pre-clinical data has demonstrated the ability of Ad-p53 to reverse resistance to anti-PD-1/anti-PD-L1 therapy in cancer models (13,14) and these findings led to the initiation of a Phase 2 clinical trial of combined Ad-p53 and anti-PD-1 therapy in recurrent HNSCC and other cancers (https:// clinicaltrials.gov/ct2/show/NCT03544723). To identify potential mechanisms of Ad-p53 action contributing to enhanced anti-tumor immunity, pre and post treatment biopsies were evaluated by nanostring gene expression assays.…”

Section: Discussionmentioning

confidence: 99%

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

Sobol¹,

Menander²,

Chada³

et al. 2021

Front. Oncol.

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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.

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“…In this regard, pre-clinical data has demonstrated the ability of Ad-p53 to reverse resistance to anti-PD-1/anti-PD-L1 therapy in cancer models (13) and these findings led to the initiation of a Phase 2 clinical trial of combined Ad-p53 and anti-PD-1 therapy in recurrent HNSCC and other cancers (https://clinicaltrials.gov/ct2/show/NCT03544723). To identify potential mechanisms of Ad-p53 action contributing to enhanced anti-tumor immunity, pre and post treatment biopsies were evaluated by nanostring gene expression assays.…”

Section: Discussionmentioning

confidence: 99%

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

Sobol¹,

Menander²,

Chada³

et al. 2021

Preprint

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BackgroundWe conducted a meta-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 meta-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 Type I 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.

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Reversing immune checkpoint inhibitor resistance with adenoviral IL-24 and p53 tumor suppressor immune gene therapy.

Cited by 7 publications

References 0 publications

A Totipotent “All‐In‐One” Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment

A Totipotent “All‐In‐One” Peptide Sequentially Blocks Immune Checkpoint and Reverses the Immunosuppressive Tumor Microenvironment

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

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

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