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OX40-targeted immune agonist antibodies induce potent antitumor immune responses without inducing liver damage in mice.

ABSTRACT: Despite promising preclinical and clinical data demonstrating that immune agonist antibody immunotherapies (IAAs) such as αOX40 induce strong antitumor immune responses, clinical translation has been significantly hampered by the propensity of some IAAs to induce dose-limiting and sometimes life-threatening immunotoxicities such as cytokine release syndrome and hepatotoxicity. For example, in a recent study αOX40 was shown to induce significant liver damage in mice by inducing the pyroptosis of liver natural killer T cells (NKT) cells. Surprisingly; however, given these previous reports, αOX40 treatment in our hands did not induce NKT cell pyroptosis or liver damage. We investigated numerous potential confounding factors including age, sex, tumor burden, dosing strategy, and the gut microbiota, which could have explained this discrepancy with the previous study. In none of these experiments did we find that αOX40 induced any more than very mild inflammation in the liver. Our study therefore suggests that, preclinically, αOX40 is a safe and effective immunotherapy and further studies into the clinical benefit of αOX40 are warranted.

SUBMITTER: Tee YC

PROVIDER: S-EPMC8493970 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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OX40-targeted immune agonist antibodies induce potent antitumor immune responses without inducing liver damage in mice.

Tee Yee C YC Blake Stephen J SJ Lynn David J DJ

FASEB bioAdvances 20210716 10

Despite promising preclinical and clinical data demonstrating that immune agonist antibody immunotherapies (IAAs) such as αOX40 induce strong antitumor immune responses, clinical translation has been significantly hampered by the propensity of some IAAs to induce dose-limiting and sometimes life-threatening immunotoxicities such as cytokine release syndrome and hepatotoxicity. For example, in a recent study αOX40 was shown to induce significant liver damage in mice by inducing the pyroptosis of ...[more]

PMID: 34632317

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Project description:Viral immunotherapies are being recognized in cancer treatment, with several currently approved or undergoing clinical testing. While contemporary approaches have focused on oncolytic viral therapies, our efforts center on the development of plant virus-based cancer immunotherapies. In a previous work, we demonstrated the potent efficacy of the cowpea mosaic virus (CPMV), a plant virus that does not replicate in animals, applied as an in situ vaccine. CPMV is an immunostimulatory drug candidate, and intratumoral administration remodels the tumor microenvironment leading to activation of local and systemic antitumor immunity. Efficacy has been demonstrated in multiple tumor mouse models and canine cancer patients. As wild-type CPMV is infectious toward various legumes and because shedding of infectious virus from patients may be an agricultural concern, we developed UV-inactivated CPMV (termed inCPMV) which is not infectious toward plants. We report that as a monotherapy, wild-type CPMV outperforms inCPMV in mouse models of dermal melanoma or disseminated colon cancer. Efficacy of inCPMV is less than that of CPMV and similar to that of RNA-free CPMV. Immunological investigation using knockout mice shows that inCPMV does not signal through TLR7 (toll-like receptor); structure-function studies indicate that the RNA is highly cross-linked and therefore unable to activate TLR7. Wild-type CPMV signals through TLR2, -4, and -7, whereas inCPMV more closely resembles RNA-free CPMV which signals through TLR2 and -4 only. The structural features of inCPMV explain the increased potency of wild-type CPMV through the triple pronged TLR activation. Strikingly, when inCPMV is used in combination with an anti-OX40 agonist antibody (administered systemically), exceptional efficacy was demonstrated in a bilateral B16F10 dermal melanoma model. Combination therapy, with in situ vaccination applied only into the primary tumor, controlled the progression of the secondary, untreated tumors, with 10 out of 14 animals surviving for at least 100 days post tumor challenge without development of recurrence or metastatic disease. This study highlights the potential of inCPMV as an in situ vaccine candidate and demonstrates the power of combined immunotherapy approaches. Strategic immunocombination therapies are the formula for success, and the combination of in situ vaccination strategies along with therapeutic antibodies targeting the cancer immunity cycle is a particularly powerful approach.

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OX40-targeted immune agonist antibodies induce potent antitumor immune responses without inducing liver damage in mice.

Publications

OX40-targeted immune agonist antibodies induce potent antitumor immune responses without inducing liver damage in mice.

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