Why Resistance Happens: The Tumor Microenvironment
Checkpoint inhibitor resistance means that even if tumors are treated with a checkpoint inhibitor, they use other mechanisms to protect themselves from immune attack. One of these mechanisms is an immunosuppressive tumor microenvironment (TME). The TME is like a protective nest that surrounds tumors. It includes a collection of various cell types that have switched sides and now protect the cancer from immune system attacks. Various receptor tyrosine kinases (RTKs) have been implicated in creating and maintaining an immunosuppressive TME.
Sitravatinib Can Target RTKs to Assist Checkpoint Inhibitors
Uncovering the mechanisms behind checkpoint inhibitor-resistance has placed the drug development spotlight onto RTK-inhibitors. One such inhibitor is sitravatinib. Sitravatinib is a potent, spectrum-selective RTK inhibitor. It inhibits several closely related RTKs, including the TAM family (TYRO3, AXL and MER), VEGFR2 and KIT. This inhibition weakens the cancer’s defenses in the tumor microenvironment.
- Tyro3/Axl/MER – enhances immune responses through activation of key innate immune cell types including macrophages, dendritic cells and Natural Killer (NK) cells.
- VEGFR2 & KIT – suppresses immune cells that reduce the anti-tumor response including myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) leading to the increased activity of adaptive immune cells (CD4+ and CD8+ cells).
By targeting these specific RTK receptors with sitravatinib, the immunosuppressive TME is converted to an immune-supportive TME and cancers are more likely to respond to checkpoint inhibitor treatment.
Mirati researchers drew a connection: could sitravatinib be paired with a checkpoint inhibitor? The hypothesis was that sitravatinib and checkpoint inhibitors could work as a team, with the former targeting RTKs to reverse the immunosuppressive TME clearing the path for checkpoint inhibitors to take down cancer cells. Early clinical studies demonstrated encouraging data that support this hypothesis.