Immunotherapy, which is designed to unleash the immune system to attack and kill cancer cells, holds enormouspromise for the treatment of cancer. Such promise was recognized by the 2018 Nobel Prize in Medicine orPhysiology awarded to Drs. James P. Allison (UT MD Anderson Cancer Center) and Tasuku Honjo (KyotoUniversity) for their discovery of cancer therapy by inhibition of negative immune regulation. Immune check pointinhibitors, such as monoclonal antibodies that target the negative immune regulators CTLA-4 and PD-1 havegained FDA approval for several types of cancer. Exemplifying their potential, the anti-CTLA-4 monoclonalantibody Ipilimumab (Yervoy, Bristol Myers Squibb) was approved in 2011 for the treatment of melanoma andsubsequently for other types of cancer. Likewise, anti-PD1 monoclonal antibodies Pembrolizumab (Keytruda,Merck) and Nivolumab (Opdivo, Bristol Myers Squibb) were also approved for melanoma and later for othertypes of cancers. Some results with these biologics have been very impressive. However, the promise ofimmunotherapy has been limited by the fact that in many patients there is no response.Potential pro-immune modulators with potential to boost response rate to immunotherapy have emerged fromour work on autoimmunity. This work has led us to discover that soluble interleukin-7 receptor (sIL7R) is a driverof autoimmunity, which is usually not a desirable outcome, but in the context of immuno-oncology it couldenhance anti-cancer immunity either alone or synergistically with immune checkpoint inhibitors. In this proposal,we test the hypothesis that increasing levels of sIL7R, a driver of autoimmunity, will lead to enhanced immune-reactivity and thus improved anti-cancer immunity. Given that sIL7R is produced by alternative splicing of thesixth exon of IL7R pre-mRNAs, specifically by exclusion of this exon, its expression can be controlled usingsplicing-modulating antisense oligonucleotides (ASOs). To increase sIL7R levels we generated two ASOs, IL7R-001 and IL7R-004, that increase exclusion of IL7R exon 6 and production of sIL7R (pro-sIL7R ASOs). IL7Rexpression is largely restricted to T cells, and thus this cell type is the main producer of sIL7R. We have optimizeddelivery of these ASOs into human primary T cells in vitro, which will facilitate in vitro testing in this proposal andis critical for subsequent in vivo efficacy studies. As proof-of-concept, here we will test in vitro whether pro-sIL7RASOs can modulate T cell function and enhance T cell-mediated killing of cancer cells.If pro-sIL7R ASOs enhance anti-cancer immunity in vitro, in Phase II we will test their anti-cancer therapeuticpotential in a highly relevant, genetically-induced hepatocellular carcinoma model in baboons (Papio anubis).This model developed by our collaborators at the Southwest National Primate Research Center (San Antonio,TX), is one of the first experimentally tractable models of cancer in nonhuman primates and an ideal model forin vivo testing of immunotherapy candidate drugs, such as pro-sIL7R ASOs. PROJECT NARRATIVE
Immunotherapies such as immune checkpoint inhibitors have shown tremendous potential for treatment of
previously intractable cancers but their promise is limited by low response rates between patients, thereby
creating a need for improved immunotherapies or additional drugs that can synergize with existing
immunotherapies to boost their activity. Addressing this need, our work on autoimmunity uncovered the soluble
interleukin 7 receptor (sIL7R) as a potent activator of self-reactive immune responses with the potential to
augment anti-cancer immunity. This proposal seeks to establish proof-of-concept by testing in vitro the potential
of antisense oligonucleotides that increase sIL7R expression to enhance T cell function and T cell-mediated
killing of cancer cells. 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