The long-term goal of this work is the development of a pan-immunotherapy that works by stimulating cancer killing T cells to traffic to tumors and eradicate them. Despite the remarkable success of immune checkpoint therapies (ICTs) such as Keytruda® and Yervoy® that can elicit curative responses, most patients do not respond to ICTs and of those that do a significant fraction experience relapse due to acquired resistance. Cancers escape from the immune system in several ways such as producing immune cell inhibiting proteins, or by preventing lymphocytes (i.e., T cells) from migrating to the tumor which creates what is called an immune "excluded" or immune "desert". An immune "desert", or la...

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The long-term goal of this work is the development of a pan-immunotherapy that works by stimulating cancer killing T cells to traffic to tumors and eradicate them. Despite the remarkable success of immune checkpoint therapies (ICTs) such as Keytruda® and Yervoy® that can elicit curative responses, most patients do not respond to ICTs and of those that do a significant fraction experience relapse due to acquired resistance. Cancers escape from the immune system in several ways such as producing immune cell inhibiting proteins, or by preventing lymphocytes (i.e., T cells) from migrating to the tumor which creates what is called an immune "excluded" or immune "desert". An immune "desert", or lack of proximity between cytotoxic immune cells and tumors, results in profound resistance to cancer immunotherapy. Abnormal signaling by sphingosine-1-phosphate (S1P, a potent bioactive lipid) in tumors and tumor draining lymph nodes (TDLN) causes a form of immune "desertification" that keeps anti-tumor immune cells from leaving the TDLN. The TDLNs are critical lymphatic tissues where naïve T cells recognize tumor antigens and are activated to become tumor-specific cytotoxic killer T cells. Elevated S1P strongly and negatively correlates with survival of patients on ICT therapy and with reduced immune cells near the tumor. We have found that a prototype therapeutic enzyme that depletes S1P, dramatically increases the trafficking of lymphocytes out of TDLNs, increases tumor T cell infiltration and strongly or completely inhibits tumor growth when administered as a single agent. The work proposed in this HIHR project will: 1) examine S1P depletion for treating immune "desert", ICT resistant tumors, the effect upon tumor immune infiltration and how this may synergize in combination with ICT, and 2) engineer S1P degrading enzymes to produce a "lead" molecule with pharmacological properties suitable for advancement towards the clinic as a broad-spectrum immunotherapy.

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