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AdAPT-001, an oncolytic adenovirus armed with a TGF-β trap, overcomes in vivo resistance to PD-L1-immunotherapy.

ABSTRACT: Monoclonal antibodies targeting the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) axes have permanently changed the therapeutic landscape for multiple tumor types previously associated with a dismal prognosis such as melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, MSI-high colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma. However, only a subset of patients initially benefits from these inhibitors, and increasing clinical experience indicates that in a substantial proportion of initial responders, lethal secondary resistance ultimately develops months or years later. In this paper we evaluated combination therapy with a Phase 1 oncolytic adenovirus called AdAPT-001, armed with a TGF-β "trap" that binds to and neutralizes the immunosuppressive cytokine, TGF-β, and a checkpoint inhibitor, anti-PD-L1, in PD-L1 resistant tumors. The study, which was performed in an immunocompetent syngeneic ADS-12 mouse model, demonstrated that the combination of AdAPT-001 with PD-L1 blockade reversed PD-L1 resistance, potentially representing a future paradigm shift for patients that are primarily or secondarily resistant to checkpoint inhibitors.

SUBMITTER: Larson C

PROVIDER: S-EPMC9360241 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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AdAPT-001, an oncolytic adenovirus armed with a TGF-β trap, overcomes <i>in vivo</i> resistance to PD-L1-immunotherapy.

Larson Christopher C Oronsky Bryan B Reid Tony T

American journal of cancer research 20220715 7

Monoclonal antibodies targeting the programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) axes have permanently changed the therapeutic landscape for multiple tumor types previously associated with a dismal prognosis such as melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma, MSI-high colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma. Howev ...[more]

PMID: 35968324

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Project description:BackgroundSecond-generation programmed cell death-protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, such as bintrafusp alfa (M7824), SHR-1701, and YM101, have been developed to simultaneously block PD-1/PD-L1 and transforming growth factor-beta/transforming growth factor-beta receptor (TGF-β/TGF-βR). Consequently, it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD-1/PD-L1 inhibitors but also sensitive to bifunctional drugs. The purpose of this study was to search for such predictors.MethodsMultivariable Cox regression was used to study the association between the clinical outcome of treatment with PD-1/PD-L1 inhibitors and lymphocyte recovery after lymphopenia in lung cancer patients. Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice. Bioluminescence imaging, flow cytometry, and immunohistochemistry were employed to determine response to immunotherapy and function of tumor-infiltrating immune cells.ResultsFor lung cancer patients treated with anti-PD-1/PD-L1 antibodies, poor lymphocyte recovery was associated with a shorter progression-free survival (PFS; P < 0.001), an accumulation of regulatory T cells (Tregs), and an elimination of CD8+ T cells in the peripheral blood. Levels of CD8+ T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy. Moreover, these mice failed to respond to anti-PD-1 antibodies but remained sensitive to the anti-PD-L1/TGF-βR fusion protein (SHR-1701). Consistently, SHR-1701 but not anti-PD-1 antibodies, markedly enhanced IFN-γ production and Ki-67 expression in peripheral CD8+ T cells from patients with impaired lymphocyte recovery.ConclusionsLung cancer patients with poor lymphocyte recovery and suffering from persistent lymphopenia after previous chemotherapy are resistant to anti-PD-1/PD-L1 antibodies but might be sensitive to second-generation agents such as SHR-1701.

Dataset Information

AdAPT-001, an oncolytic adenovirus armed with a TGF-β trap, overcomes in vivo resistance to PD-L1-immunotherapy.

Publications

AdAPT-001, an oncolytic adenovirus armed with a TGF-β trap, overcomes <i>in vivo</i> resistance to PD-L1-immunotherapy.

Similar Datasets

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