Cancer immunotherapy include promising strategies based on immune checkpoint blockade (e.g. anti-PD-1/PD-L1, anti-CTLA-4). A limitation of such therapies for solid tumors stems from other immune-suppressive mechanisms mediated by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages. We hypothesize that molecules that target specific suppressive immune cells in the tumor microenvironment can reprogram the pro-tumor microenvironment towards anti-tumor immunity. Using our proteome-scale target/antitarget based lead optimization method (CANDESIGN) we designed and synthesized cell-specific non-toxic chemical libraries. Our target/anti-target network was iteratively identified using machine learning on experimental data for desired immune cell function ex vivo. Specifically, we altered suppressive function of MDSCs by targeting upregulated genes in activated monocytic MDSCs in the tumor microenvironment compared to cells in spleen. We identified a potent non-toxic lead that specifically modulates activated MDSC function and corresponding changes in CD4+ and CD8+ T-cells activity in a mouse bladder cancer model. We observed a significant reduction in tumor mass following treatment by oral gavage. Interestingly, the bladder cancer cells used in our mouse model are insensitive to our lead compound in vitro suggesting in vivo antitumor activity via immunomodulation. Our lead decreased frequencies of MDSC expressing suppressive functional markers (e.g. Arg1, iNOS, PD-L1) and increased IFN-g+CD8+ T-cells in the tumor microenvironment. A small clinical trial on pet dogs with bladder tumors treated with our compound for 4-5 weeks resulted in ~50% reduction in tumor volume. We conclude that designing immune cell-specific compounds perturbing the tumor microenvironment to combat immune suppression give a selective advantage to the immune system to combat solid tumors via single and combination drug/cell therapies.

Cell-specific chemical libraries targeting immune supression in the tumor microenvironment

255th National Meeting (2018)

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