Search

Microsatellite-stable colorectal cancer (CRC) is known to be resistant to immunotherapy. The combination of quercetin (Q) and alantolactone (A) was found to induce synergistic immunogenic cell death (ICD) at a molar ratio of 1:4 (Q:A). To achieve ratiometric loading and delivery, the micellar delivery of Q and A (QA-M) was developed with high entrapment efficiency and drug loading at an optimal ratio. QA-M achieved prolonged blood circulation and increased tumor accumulation for both drugs. More importantly, QA-M retained the desired drug ratio (molar ratio of Q to A = 1:4) in tumors at 2 and 4 h after intravenous injection for synergistic immunotherapy. Tumor growth was significantly inhibited in murine orthotopic CRC by the treatment of QA-M compared to PBS and the combination of free drugs ( p < 0.005). The combination of nanotherapy stimulated the host immune response to induce long-term tumor destruction and induced memory tumor surveillance with a 1.3-fold increase in survival median time compared to PBS ( p < 0.0001) and a combination of free drugs ( p < 0.0005). The synergistic therapeutic effect induced by codelivery of Q and A is capable of reactivating antitumor immunity by inducing ICD, causing cell toxicity and modulating the immune-suppressive tumor microenvironment. Such a combination of Q and A with synergistic effects entrapped in a simple and safe nanodelivery system may provide the potential for scale-up manufacturing and clinical applications as immunotherapeutic agents for CRC.

The development and progression of colorectal cancer (CRC) is closely related to gut microbiome. Here, the impact of lipopolysaccharide (LPS), one of the most prevalent products in the gut microbiome, on CRC immunotherapy is investigated. It is found that LPS is abundant in orthotopic CRC tissue and is associated with low responses to anti-PD-L1 mAb therapy, and clearance of Gram-negative bacteria from the gut using polymyxin B (PmB) or blockade of Toll-like receptor 4 using TAK-242 will both relieve the immunosuppressive microenvironment and boost T-cell infiltration into the CRC tumor. Further, an engineered LPS-targeting fusion protein is designed and its coding sequence is loaded into a lipid-protamine-DNA (LPD) nanoparticle system for selective expression of LPS trap protein and blocking LPS inside the tumor, and this nanotrapping system significantly relieves the immunosuppressive microenvironment and boosts anti-PD-L1 mAb therapy against CRC tumors. This LPS trap system even attenuates CRC liver metastasis when applied, suggesting the importance of blocking LPS in the gut-liver axis. The strategy applied here may provide a useful new way for treating CRC as well as other epithelial cancers that interact with mucosa microbiome., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although great success has been obtained in the clinic, the current immune checkpoint inhibitors still face two challenging problems: low response rate and immune-related adverse effects (irAEs). Here we report the combination of immunogenic chemotherapy and locally expressed PD-L1 trap fusion protein for efficacious and safe cancer immunotherapy. We demonstrate that oxaliplatin (OxP) boosts anti-PD-L1 mAb therapy against murine colorectal cancer. By design of a PD-L1 trap and loading its coding plasmid DNA into a lipid-protamine-DNA nanoparticle, PD-L1 trap is produced transiently and locally in the tumor microenvironment, and synergizes with OxP for tumor inhibition. Significantly, unlike the combination of OxP and anti-PD-L1 mAb, the combination of OxP and PD-L1 trap does not induce obvious Th17 cells accumulation in the spleen, indicating better tolerance and lower tendency to irAEs. The reports here may highlight the potential of applying PD-L1 inhibitor, especially locally expressed PD-L1 trap, in cancer therapy following OxP-based chemotherapy.

The ability to generate potent immunotherapies locally and transiently for the treatment of cancers is a promising strategy to improve efficacy and decrease off-target toxicities. Here, we explored an alternative approach for the delivery of immunotherapeutic agents, in which we deliver the pDNA of an engineered PD-L1 trap and/or CXCL12 trap to the nucleus of liver hepatocytes via a lipid calcium phosphate nanoparticle. This strategy greatly increased the concentrations of immunotherapeutic agents in the local tissue, allowing the therapy to inhibit the accumulation of immune suppressive cells and liver metastasis. Furthermore, we find that the lipid calcium phosphate nanoparticles containing the pCXCL12 trap resolved the formation of immune suppressive ectopic lymphoid structures, while the pPD-L1 trap promoted T-cell survival and migration into the liver following vaccination against tumor antigens (>180% increase in survival). This approach showed superior efficacy in the treatment of the liver metastasis compared to free protein immunotherapies. This strategy should be considered as an approach to support liver metastasis therapies as well as for future research interested in manipulating the chemokine/cytokine immune factors within the liver., Significance: Our approach results in transient liver specific expression of gene immunotherapies with improved efficacy and reduced off-target toxicities over traditional systemically administered immunotherapies. This approach would allow clinicians to manipulate the liver and immune microenvironment to resist cancer invasion, improve organ health, and prolong patient survival., (Copyright © 2017 Elsevier Ltd. All rights reserved.)