Activation of the immune system against cancer has major advantages over conventional therapies, including greater specificity, stronger potency, and longer term efficacy. Progress made recent years focuses on overcoming T-cell immunological checkpoints with blocking monoclonal antibodies (mAbs) to CTLA-4 and PD-1/PD-L1. Despite targeting PD-1/PD-L1 in cancer has shown beneficial responses in some cancer types, it is not effective in colorectal cancer liver metastasis and pancreatic cancer, two most deadly malignant human diseases. We address the challenges by developing affinity molecules based on protein domains (called traps) that potently and specifically bind and disrupt the biological functions of signaling molecules that play pivotal roles in the immunosuppression of tumor microenvironment (TME). To deliver traps to the diseased tissues, we have used targeted nanoparticles encapsulating a plasmid encoding the trap protein and delivered it to TME. Local and transient expression of the traps in TME profoundly remodeled and revoked its immunosuppression, resulting in activation of CD8 T-cells to inhibit tumor growth and metastasis. Using an orthotopic, syngeneic CT26 mouse model, we demonstrated that the liver metastasis of colorectal cancer was drastically blocked by delivering a CXCL12 trap (Science Translational Medicine, 2016 Nov 9; 8(364):364ra153). Using an orthotopic, syngeneic KPC mouse model, we demonstrated that the local and transient expression of a combination of a CXCL12 trap and an innovative trimeric PD-L1 trap potently shrunk pancreatic cancer and significantly prolonged the host survival (ACS Nano, 2017 Sep 26; 11(9):8690-8706). Combo trap therapy also significantly reduced metastasis of pancreatic cancer to other organs. Significantly, our mechanistic studies showed that the CXCL12 trap allowed the penetration of T-cells into the tumor, while the PD-L1 trap allowed the activation of infiltrated T-cells to kill cancer cells. This novel cancer immunotherapy has distinctive advantages over conventional mAbs in that the gene therapy approach allows local and highly effective reversal of the immunosuppression of TME, as well as tunable combination of more than two traps targeting signaling pathways with synergistic therapeutic effect, making it possible to avoid the immunodeficiency and other side toxicities resulted from the systemic use of immunotherapeutics with long half-lives.

Revoke immunosuppression of tumor microenvironment using engineered molecular traps

255th National Meeting (2018)

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