A new study published in the Journal of Biological Chemistry from UC Davis Comprehensive Cancer Center finds that TIGIT—an immune checkpoint receptor targeted by cancer immunotherapy drugs—triggers a different response in rhesus macaques compared with humans.
TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a “brake” on the immune system. It sits on certain immune cells, like T cells and natural killer (NK) cells, and prevents them from attacking too aggressively. Cancer cells take advantage of this “brake” to protect themselves from the immune system.
That’s why scientists are developing cancer immunotherapy drugs to block TIGIT so the immune system can fight tumors more effectively. However, multiple anti-TIGIT antibodies have failed in Phase III trials for solid tumors, raising questions about the underlying mechanism.
The study’s new findings show that rhesus macaques—but not humans—shed TIGIT from immune cell surfaces when exposed to plasmin. Plasmin is a natural enzyme involved in blood clot breakdown. The enzyme is highly upregulated in almost all solid cancers.
This shedding creates a soluble form of TIGIT that can still bind anti-TIGIT monoclonal antibodies, such as tiragolumab, an investigational cancer treatment. The result is that in macaques, antibodies may be soaked up by free-floating TIGIT instead of blocking immune suppression on the tumor-fighting cells. The problem is preclinical safety and dose estimation studies for cancer immunotherapy drugs targeting TIGIT are currently done in macaques.
“We know from our study of macaque response that the dilution of the drug away from T-cells is a problem. Tests in macaques will not predict proper safety and dose estimation data for human clinical trials,” said Jogender Tushir-Singh, an associate professor at UC Davis and senior author of the study. “It seems like TIGIT biology and mechanism are much more complex than expected.”
The researchers looked at TIGIT proteins from humans and monkeys. They made lab versions of these proteins and exposed them to plasmin to see what would happen. They found that in monkeys, a single difference in the protein’s amino acid compared with humans—at position 119—made it easy for plasmin to cut TIGIT.
When the team added plasmin to human and monkey immune cells, only the monkey cells shed TIGIT from their surfaces. They then checked whether the shed TIGIT in monkeys could still stick to cancer drugs—and it could.
The researchers say more studies are needed, but the findings raise questions for current and future TIGIT-targeted cancer trials. They note that testing TIGIT cancer drugs in macaques could have produced misleading safety and efficacy data. This may help explain why TIGIT therapies have underperformed in late-stage trials.
“The study underscores the need for improved models that better reflect human biology when developing next-generation immunotherapies,” Tushir-Singh said.
Information courtesy of UC Davis Comprehensive Cancer Center