10110640Mononuclear phagocyte-mediated particulate drug delivery for enhanced immunotherapy of advanced prostate cancerActiveCollaborative R&DInnovate UKCell Guidance Systems' mission is to improve the delivery of cancer immunotherapeutic drugs, focussing on late-stage prostate cancer, a disease which kills 12,000 men each year in the UK. The body's immune system can recognize and destroy cancerous cells. However, cancers gradually develop mechanisms to evade the immune system, ultimately undergoing uncontrolled growth. In the last three decades, major progress in cancer treatment has been made using immunotherapies that enable the immune system to control cancer. Cytotoxic T lymphocytes (CTL, a kind of white blood cell) are a major focus of immunotherapies. They are the front-line immune cells actively engaging with cancer cells. CTLs can recognize and bind to cancer cells, killing them with lytic enzymes. However, CTLs often become depleted and exhausted in tumours. Many cancer immunotherapies work by restoring functional CTLs. This immunotherapeutic strategy has allowed some late-stage cancer patients to achieve durable remission. However, only subsets of defined cancer types are responsive and, because the drugs also reach normal tissues, side effects are often severe. Improved targeting of drugs to improve the anti-cancer functionality of CTLs in tumours has the potential to increase drug efficacy whilst reducing side effects and is urgently needed. To improve drug delivery, we have been exploring the utility of mononuclear phagocytic immune cells (MPs) such as monocytes, macrophages and dendritic cells. MPs are found in the blood and ingest large particles. They also home towards, and then actively infiltrate cancer, accounting for as many as 50% of the cells present. This suggested to us the possibility of using MPs to actively, and more efficiently, deliver microscopic drug particles into the tumour to activate CTLs. We have developed microscopic, slow-release protein drug particles, called PODS, which are ingested by MPs. We have shown that cytokine protein drugs contained in the PODS are sustainably released from the MPs in a potent, bioactive form. We have also shown that when PODS are injected intravenously into a mouse with cancer, the cancer responds to the treatment. the number of CTLs increases and, consistent with low off-target toxicity, the drug is undetectable in the serum. This drug delivery strategy has enormous potential for improving cancer immunotherapeutic drug delivery and enabling new treatment options for all solid cancers. In the present project, we plan to use PODS-delivered chemokines to recruit CTLs and dendritic cells into prostate cancer and activate these using PODS-delivered cytokines and immune checkpoint inhibitors.