Macaque Studies May Mislead Cancer Drug Progress, New Research Suggests
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New findings reveal critical differences in how a key immune system regulator, TIGIT, functions in monkeys versus humans, possibly explaining setbacks in cancer immunotherapy trials.
A groundbreaking study from the UC Davis Thorough Cancer Center reveals a significant discrepancy in the behavior of TIGIT, a crucial immune checkpoint protein targeted by emerging cancer therapies, between rhesus macaques and humans. The research, published this week, suggests that relying on macaque models for preclinical testing of anti-TIGIT therapies may be misleading, potentially explaining the disappointing results observed in recent clinical trials.
TIGIT, or T cell immunoreceptor with Ig and ITIM domains, is a protein that acts as a brake on the immune system, effectively applying the brakes to prevent overactive immune responses. Present on immune cells like T cells and natural killer (NK) cells, TIGIT prevents these cells from attacking healthy tissues. though,cancer cells cleverly exploit this mechanism,utilizing TIGIT to shield themselves from immune destruction.
Consequently, a new generation of cancer immunotherapy drugs aims to block TIGIT, unleashing the immune system to more effectively target and eliminate tumors. Despite this promising approach, multiple anti-TIGIT antibodies, including the investigational therapy tiragolumab, have failed to demonstrate efficacy in Phase III trials for solid tumors, prompting a reevaluation of current testing methodologies.
Macaques Shed TIGIT – Humans Do Not
The pivotal finding of the UC Davis study centers on a key difference in how TIGIT behaves in macaques compared to humans. Researchers discovered that macaques, when exposed to plasmin – a natural enzyme involved in blood clot breakdown and highly prevalent in solid cancers – shed TIGIT from the surface of their immune cells. Humans,though,do not exhibit this shedding behavior.
This shedding produces a soluble form of TIGIT that can still bind to anti-TIGIT monoclonal antibodies. “This means that in macaques, the drug may be absorbed by this free-floating TIGIT instead of effectively blocking immune suppression on the tumor-fighting cells,” explained a senior researcher involved in the study. “We know from our study of macaque response that the dilution of the drug away from T-cells is a problem.”
A Single Amino Acid Makes all the Difference
Delving deeper into the molecular mechanisms, the research team identified a single amino acid difference at position 119 in the TIGIT protein between monkeys and humans. This seemingly minor variation renders the macaque TIGIT protein more susceptible to cleavage by plasmin.
When plasmin was introduced to both human and macaque immune cells, only the macaque cells exhibited TIGIT shedding. Subsequent tests confirmed that the shed TIGIT in macaques could effectively bind to cancer drugs, further supporting the hypothesis that current preclinical models are flawed.
Implications for Future Cancer Drug development
These findings have significant implications for the future of cancer drug development. The study strongly suggests that relying on macaque models for assessing the safety and efficacy of TIGIT-targeted therapies may provide inaccurate data. This could explain the disappointing results observed in recent clinical trials.
“Tests in macaques will not predict proper safety and dose estimation data for human clinical trials,” stated a lead investigator. “It truly seems like TIGIT biology and mechanism are much more complex than expected.” The study underscores the urgent need for improved preclinical models that more accurately reflect human biology when developing next-generation immunotherapies.
This research reiterates the critical importance of carefully considering species differences in preclinical studies, especially for drugs targeting immune checkpoints like TIGIT, and may ultimately guide the development of more effective cancer treatments in the future.