Prof Mark Smyth
Targeting the T cell immunoglobulin and ITIM domains (TIGIT) immune checkpoint has a future role in the management of multiple myeloma, early research at the QIMR Berghofer Medical Research Institute in Queensland suggests.
In a proof of concept study researchers at QIMR have demonstrated that TIGIT expression is upregulated in immune cells in both animal models challenged with multiple myeloma cells and in samples from newly diagnosed or relapsed MM patients.
“Compared with other inhibitory molecules, TIGIT was more frequently expressed on MM patient CD8+ T cells, suggesting that TIGIT represents a major immune checkpoint in MM,” the study authors write in the journal Blood.
They also found that TIGIT expression in CD8+ T cells was associated with a reduced production of cytokines TNFα and IFNγ.
“MM patients TIGIT+ CD8+ T cells also exhibited decreased CD107a expression, indicating poor killing capability as well as reduced proliferative capacity.”
The study showed that TIGIT deficiency or blocking TIGIT function with an anti-TGIT mAb significantly reduced tumour burden in an aggressive MM model and prolonged survival of MM-bearing animals.
“Moreover, mAbs blocking TIGIT function significantly improved cytokine production and degranulation of MM patients CD8+ T cells.”
“Our data demonstrate for the first time that blocking the TIGIT pathway prolongs survival in pre-clinical MM models and improves MM patient CD8+ T cell function, thereby providing a strong rationale for the evaluation of anti-TIGIT mAbs to treat MM,” the study said.
Professor Mark Smyth from QIMR’s Immunology in Cancer and Infection Laboratory told the limbic while it was very early days, proof of principle had been established.
“So far, the PD-1 therapies that have been so successful in so many other cancers have failed in multiple myeloma and it’s not entirely clear why that is. And so this is the first checkpoint blockage molecule of its type to show any pre-clinical efficacy in what we consider to be a very good model of the human disease.”
“We’ve looked at a few therapies in this model and this is a bit of a stand out for us. For single agent activity it’s quite impressive but whether the findings convert into clinical trials we’re not sure.”
He said anti-TIGIT antibodies were already being tested in early trials in Australia for other indications.
“The hope would be that a single agent could be successful but when the agent is brought into the clinical arena, it will be brought in in the context of conventional therapies such as bortezomib or immune modulators like lenalinomide.”
“There might also be some prospect of using these antibodies in the context of post- autologous stem cell transplants.”
Professor Smyth said further research was required to better understand the pathway, how blockade might work with conventional therapies, the ideal patient groups and biomarkers of response to therapy.