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Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors.

ABSTRACT: There is a growing interest in the antibody-based delivery of cytokines to the tumor environment as a means to boost the anti-cancer activity of tumor-resident T cells and NK cells. Here, we describe the expression and characterization of fusion proteins, featuring the L19 antibody (specific to the alternatively-spliced EDB domain of fibronectin) and an engineered cytokine with interleukin-2 and interleukin-15 properties. The cytokine moiety was fused either at the N-terminal or at the C-terminal extremity and both fusion proteins showed a selective tumor accumulation in a quantitative biodistribution experiment. The N-terminal fusion inhibited tumor growth in immunocompetent mice bearing F9 carcinomas or WEHI-164 sarcomas when used as single agent. The anticancer activity was compared to the one of the same cytokine payload used as recombinant protein or fused to an anti-hen egg lysozyme antibody, serving as negative control of irrelevant specificity in the mouse. These results indicate that the antibody-based delivery of engineered cytokines to the tumor neovasculature may mediate a potent anticancer activity.

SUBMITTER: Mortensen MR

PROVIDER: S-EPMC7646832 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors.

Mortensen Michael R MR Mock Jacqueline J Bertolini Marco M Stringhini Marco M Catalano Marco M Neri Dario D

Oncotarget 20201103 44

There is a growing interest in the antibody-based delivery of cytokines to the tumor environment as a means to boost the anti-cancer activity of tumor-resident T cells and NK cells. Here, we describe the expression and characterization of fusion proteins, featuring the L19 antibody (specific to the alternatively-spliced EDB domain of fibronectin) and an engineered cytokine with interleukin-2 and interleukin-15 properties. The cytokine moiety was fused either at the N-terminal or at the C-termina ...[more]

PMID: 33216834

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Project description:BACKGROUND:The anti-tumor immunity of natural killer (NK) cells can be paralyzed by the CD73-induced generation of immunosuppressive adenosine from precursor ATP within the hypoxic microenvironment of solid tumors. In an effort to redirect purinergic immunosuppression of NK cell anti-tumor function, we showed, for the first time, that immunometabolic combination treatment with NKG2D-engineered CAR-NK cells alongside blockade of CD73 ectonucleotidase activity can result in significant anti-tumor responses in vivo. METHODS:NK cells were engineered non-virally with NKG2D.CAR-presenting vectors based on the piggyBac transposon system with DAP10 and CD3? co-signaling domains. The anti-tumor immunity of NKG2D.CAR.NK cells in combination with CD73 targeting was evaluated against multiple solid tumor targets in vitro and humanized mouse xenografts in immunodeficient tumor-bearing mice in vivo. Intratumoral migration was evaluated via immunohistochemical staining, while degranulation capacity and IFN-? production of NK cells were measured in response to solid tumor targets. RESULTS:Our results showed that CD73 blockade can mediate effective purinergic reprogramming and enhance anti-tumor cytotoxicity both in vitro and in vivo by enhancing the killing ability of CAR-engineered NK cells against CD73+ solid tumor targets via mechanisms that might imply alleviation from adenosinergic immunometabolic suppression. CD73 blockade improved the intratumoral homing of CD56+ CAR-NK cells in vivo. These engineered NK cells showed synergistic therapeutic efficacy in combination with CD73 targeting against CD73+ human lung cancer xenograft models. Interestingly, CD73 blockade could inhibit tumor growth in vivo independently of adaptive immune cells, innate immunity or NK cell-mediated ADCC. CONCLUSIONS:Immunotherapies targeting the adenosinergic signaling cascade, which act by neutralizing CD73 ectoenzymatic activity, had thus far not been evaluated in humanized tumor models, nor had the implication of innate immunity been investigated. Taken together, our pre-clinical efficacy data demonstrate, for the first time, the potential of targeting CD73 to modulate purinergic signaling and enhance adoptive NK cell immunotherapy via mechanisms that could implicate autocrine tumor control as well as by mediating adenosinergic signaling.

Dataset Information

Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors.

Publications

Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors.

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