Genetically engineered macrophages persist in solid tumors and locally deliver therapeutic proteins to activate immune responses.

Autor:	Brempelis KJ; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Cowan CM; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Kreuser SA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Labadie KP; Department of Surgery, University of Washington, Seattle, Washington, USA., Prieskorn BM; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Lieberman NAP; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Ene CI; Department of Neurological Surgery, University of Washington, Seattle, Washington, USA.; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Moyes KW; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Chinn H; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., DeGolier KR; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Matsumoto LR; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Daniel SK; Department of Surgery, University of Washington, Seattle, Washington, USA., Yokoyama JK; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA.; Immunotherapy Integration Hub, Seattle Children's Research Institute, Seattle, Washington, USA., Davis AD; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Hoglund VJ; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Smythe KS; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Balcaitis SD; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA., Jensen MC; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA.; Immunotherapy Integration Hub, Seattle Children's Research Institute, Seattle, Washington, USA., Ellenbogen RG; Department of Neurological Surgery, University of Washington, Seattle, Washington, USA., Campbell JS; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Pierce RH; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Holland EC; Department of Neurological Surgery, University of Washington, Seattle, Washington, USA.; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA., Pillarisetty VG; Department of Surgery, University of Washington, Seattle, Washington, USA., Crane CA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA ccrane@mozart-tx.com.; Discovery and Translational Sciences, Mozart Therapeutics, Seattle, WA, 98119.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2020 Oct; Vol. 8 (2).
DOI:	10.1136/jitc-2020-001356
Abstrakt:	Background: Though currently approved immunotherapies, including chimeric antigen receptor T cells and checkpoint blockade antibodies, have been successfully used to treat hematological and some solid tumor cancers, many solid tumors remain resistant to these modes of treatment. In solid tumors, the development of effective antitumor immune responses is hampered by restricted immune cell infiltration and an immunosuppressive tumor microenvironment (TME). An immunotherapy that infiltrates and persists in the solid TME, while providing local, stable levels of therapeutic to activate or reinvigorate antitumor immunity could overcome these challenges faced by current immunotherapies. Methods: Using lentivirus-driven engineering, we programmed human and murine macrophages to express therapeutic payloads, including Interleukin (IL)-12. In vitro coculture studies were used to evaluate the effect of genetically engineered macrophages (GEMs) secreting IL-12 on T cells and on the GEMs themselves. The effects of IL-12 GEMs on gene expression profiles within the TME and tumor burden were evaluated in syngeneic mouse models of glioblastoma and melanoma and in human tumor slices isolated from patients with advanced gastrointestinal malignancies. Results: Here, we present a cellular immunotherapy platform using lentivirus-driven genetic engineering of human and mouse macrophages to constitutively express proteins, including secreted cytokines and full-length checkpoint antibodies, as well as cytoplasmic and surface proteins that overcomes these barriers. GEMs traffic to, persist in, and express lentiviral payloads in xenograft mouse models of glioblastoma, and express a non-signaling truncated CD19 surface protein for elimination. IL-12-secreting GEMs activated T cells and induced interferon-gamma (IFNγ) in vitro and slowed tumor growth resulting in extended survival in vivo. In a syngeneic glioblastoma model, IFNγ signaling cascades were also observed in mice treated with mouse bone-marrow-derived GEMs secreting murine IL-12. These findings were reproduced in ex vivo tumor slices comprised of intact MEs. In this setting, IL-12 GEMs induced tumor cell death, chemokines and IFNγ-stimulated genes and proteins. Conclusions: Our data demonstrate that GEMs can precisely deliver titratable doses of therapeutic proteins to the TME to improve safety, tissue penetrance, targeted delivery and pharmacokinetics. Competing Interests: Competing interests: The authors declare the following competing interests: CAC, KWM, NAPL and MCJ are inventors on 'Genetic Engineering of Macrophages for Immunotherapy,' Patent Number: US20170087185A1, which pertains to the development and use of GEMs as immunotherapy. CAC receives research support and is on the scientific advisory board for BlueRock Therapeutics. MCJ receives research support from Juno Therapeutics, A Bristol-Myers Squibb Company. (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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