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. 2022 Jul 15;12(7):3141-3147.
eCollection 2022.

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

Christopher Larson  1 , Bryan Oronsky  1 , Tony Reid  1
Affiliations

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

Christopher Larson et al. Am J Cancer Res. .

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.

Keywords: BETA PRIME (NCT04673942); CTLA-4; Checkpoint inhibitor blockade; PD-L1; TGF-β; oncolytic adenovirus; oncolytic virotherapy.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Weight of mice in studies of combination therapy with anti-PD-L1 antibody. 129S4 mice with ADS-12 tumors were treated with intratumoral buffer or mouse-ADAPT-001 on days 0, 4, and 8 and intraperitoneal buffer or anti-PD-L1 antibody on days 1, 5, 9, and 13. Mean ± standard deviation of weight normalized to pre-treatment baseline is plotted for each group. n=10 mice in each group.
Figure 2
Figure 2
Tumor volumes in studies of combination therapy with anti-PD-L1 antibody. Mean ± SEM tumor volume for each group. n=10 mice per group.
Figure 3
Figure 3
AdAPT-001-treated, tumor-free mice rechallenged with ADS-12 tumor cells on the opposite flank from primary tumor confers long-term protective immunity.
Figure 4
Figure 4
Tumor antipredation strategies against the immune system.
Figure 5
Figure 5
Oncolytic viruses have the potential to convert uninflamed “cold” tumors, so called “immune deserts”, into “hot”/inflamed ones that respond well to checkpoint inhibition.
See this image and copyright information in PMC

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