Editors' ChoiceCancer

Designer platelets pump up PD-1 blockade

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Science Translational Medicine  15 Aug 2018:
Vol. 10, Issue 454, eaau7389
DOI: 10.1126/scitranslmed.aau7389

Abstract

Genetically engineered platelets promote eradication of residual tumor by immune cells after surgery in mice.

The majority (~60%) of cancer patients undergo surgery as part of treatment, and incomplete removal of tumor cells often leads to local and distant tumor recurrences. Cancer patients have cytotoxic T cells capable of eradicating the residual tumor cells. However, these T cells are usually inhibited by multiple immunosuppressive mechanisms exploited by tumor cells. Here, Zhang et al. developed genetically engineered platelets to overcome immunosuppression in post-surgery tumors, promote immune attack on cancer cells, and prevent tumor relapses.

The strategy contains three key aspects: a vehicle that spontaneously accumulates at the surgery site, blocking immunosuppression by cancer cells, and a drug to eliminate immunosuppressive regulatory T cells. To achieve these aspects, the researchers genetically engineered murine platelet-producing cells, megakaryocytes, to express a receptor named programmed cell death 1 (PD-1) that can bind to its ligand, PD-L1, commonly expressed on tumor cells. This pathway is currently targeted in the clinic with antibodies. Upon stimulation, megakaryocyte cells generate platelets that carry PD-1 on their surfaces. The authors confirmed that, although both PD-1–free and PD-1–expressing platelets can aggregate in response to the blood coagulation factor thrombin, only the PD-1–expressing platelets can effectively bind to and trigger internalization by cancer cells, blocking and/or removing PD-L1 on cancer cells. To evaluate the in vivo efficacy of the engineered platelets, the researchers partially removed tumors in a melanoma model before injecting platelets into the mice. The engineered platelets were shown to aggregate at the residual tumors, similar to the regular, PD-1–free platelets through the same mechanism. Importantly, after incomplete tumor removal, the PD-1–expressing platelets significantly delayed tumor growth and promoted survival of the treated mice. To further counter immunosuppression, the authors loaded a drug (cyclophosphamide) in the platelets, which can selectively deplete regulatory T cells. They showed that the combination of PD-1 expression and co-delivered drug by platelets significantly suppressed tumor progression and improved survival of the treated mice. Lastly, the researchers confirmed that the regulatory T cells were indeed depleted by the drug treatment, while the PD-1–expressing platelets increased the tumor-infiltrating cytotoxic T cells. Although additional studies are needed to elucidate the necessity of carrying the drug within the platelets and to improve the treatment regimen for better post-surgery survival, this strategy has great potential in reducing the cost and improving the efficacy of the existing antibody-based cancer immunotherapy of PD-1/PD-L1 checkpoint blockade.

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