T-Sign Cancer Gene Therapy And Anti-Egfr Car-T Cells Synergize In Combination Therapy To Clear A549 Lung Tumor Xenografts And Lung Metastases In Nsg Mice.

Abstract Chimeric antigen receptor (CAR) T cell therapy is an effective treatment for hematologic malignancies but has demonstrated limited efficacy in solid tumors. This is largely attributed to the immunosuppressive tumor microenvironment (TME) that impairs the ability of CAR-T cells to infiltrate, become activated, and kill tumor cells. Virotherapy is another emerging cancer treatment that has so far shown only limited clinical efficacy as a monotherapy for solid tumors. Importantly, in addition to their ability to directly kill tumor cells, viral vectors can also be leveraged to deliver transgenes to “reprogram” the TME from an immunosuppressive to a pro-inflammatory environment. We hypothesized that IV-deliverable T-SIGn cancer gene therapy vectors based on the oncolytic adenovirus enadenotucirev, which carry a transgene cassette encoding human immunomodulatory molecules to aid recruitment and activation of T-cells, could enhance the anti-tumor activity of human anti-EGFR CAR T cells in vivo. To test this hypothesis, NSG mice implanted subcutaneously with human lung cancer A549 xenografts, were treated intravenously with the T-SIGn virus followed by treatment with human anti-EGFR CAR-T cells. This treatment regimen demonstrated clearance of the xenograft and pulmonary metastases, whereas either therapy alone showed either no efficacy or delayed disease progression. When xenograft transcript analysis was performed, robust expression of the virus-encoded transgenes, as well as an upregulation of transcripts involved in type I IFN responses (e.g. IRF1, SOCS1), antigen presentation (e.g. HLA.DRA, TAP1), T cell activation (IFNγ, GrB), and inflammation (e.g. CXCL9, TNFSF10) was measured in the xenografts of animals treated with combination therapy, indicating a reprogramming of the TME to more effectively recruit and/or enhance T-cell responses. In addition, the combination treatment also dramatically reduced the number of A549 tumor cell micrometastases detectable in the lungs. Since both agents were delivered systemically, this observation may reflect direct therapeutic activity at the metastatic sites. Taken together, these results indicate that combination therapy with a T-SIGn vector and CAR T cells holds great potential to be efficacious in humans with solid tumors. Citation Format: Olmo Sonzogni, Daniel Zak, Katy West, Rochelle Lear, Alice Muntzer, Brian R. Champion, James B. Rottman. T-SIGn cancer gene therapy and anti-EGFR CAR-T cells synergize in combination therapy to clear A549 lung tumor xenografts and lung metastases in NSG mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1582.