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Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.

ABSTRACT: Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-?-induced killing while simultaneously blocking TNF-? growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-? signalling. Furthermore, our results implicate an important role for TNF-?-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.

SUBMITTER: Beug ST

PROVIDER: S-EPMC5330852 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.

Beug Shawn T ST Beauregard Caroline E CE Healy Cristin C Sanda Tarun T St-Jean Martine M Chabot Janelle J Walker Danielle E DE Mohan Aditya A Earl Nathalie N Lun Xueqing X Senger Donna L DL Robbins Stephen M SM Staeheli Peter P Forsyth Peter A PA Alain Tommy T LaCasse Eric C EC Korneluk Robert G RG

Nature communications 20170215

Small-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementat ...[more]

PMID: 28198370

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Project description:IntroductionImmune checkpoint inhibitors that boost cytotoxic T cell-based immune responses have emerged as one of the most promising approaches in cancer treatment. However, it is increasingly being realized that T cell activation needs to be rationally combined with molecularly targeted therapeutics for a maximal anti-tumor outcome. Currently, two oncogenic drivers, MAPK and PI3K-mTOR have emerged as the two main molecular targets for combining with immunotherapy. However, there are major challenges in enabling such combinations: first, such combinations can result in high rates of toxicity. Second, while, these molecular targets could be driving tumor progression, they are essential for activation of the immune cells. So, the kinase inhibitors and immunotherapy can antagonize each other.ObjectivesWe rationalized that the synergistic combination of kinase inhibitors and immunotherapy could be enabled by dual inhibitors-loaded supramolecular nanotherapeutics (DiLN) that can co-deliver PI3K- and MAPK-inhibitors to the cancer cells and activate immune response by T cell-modulating immunotherapy, resulting in greater anti-tumor efficacy while minimizing toxicity.MethodsWe engineered DiLNs by designing the amphiphilic building blocks (both drugs and co-lipids) that enables supramolecular nanoassembly. DiLNs were tested for their physiochemical properties including size, morphology, stability and drug release kinetics profiles. The efficacy of DiLNs was tested in drug-resistant cells such as BRAFV600E melanoma (D4M), Clear cell ovarian carcinoma (TOV21G) cells. The tumor inhibition efficiency of DiLNs in combination with immune checkpoint inhibitor antibody was studied in syngeneic D4M animal model.ResultsDiLNs were stable for over a month and released the drugs in a sustained manner. In vitro cytotoxicity studies in D4M and TOV21G cells showed that DiLNs were significantly more effective than free drugs. In vivo studies showed that the combination of DiLNs with anti PD-L1 antibody resulted in superior antitumor effect and survival.ConclusionThis study shows that the rational combination of DiLNs that target multiple oncogenic signaling pathways with immune checkpoint inhibitors could emerge as an effective strategy to improve immunotherapeutic response against drug resistant tumors.

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Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.

Publications

Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma.

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