clinical topic updates
Immunotherapy and Gastrointestinal Stromal Tumors
Tyrosine kinase inhibitors (TKIs) for gastrointestinal stromal tumors (GIST) are effective; however, resistance typically develops. In addition to the development of novel biochemically designed TKIs, research focused on immunotherapy for GIST has shown promise, and this treatment is being investigated with and without concurrent TKI therapy.
“This is a rich area of ongoing research, both in the laboratory and in the clinic. There may be a role for immunotherapy in GIST, and we hope to have more definitive data in the coming years.”
GIST has traditionally been thought of as a disease that is driven by the tyrosine kinase receptors KIT and PDGFRA. For the most part, that pathophysiology is very sound, but there have always been indicators of more happening in the pathobiology. GIST cells arise in the context of a tumor microenvironment consisting of blood vessels, supporting cells, and immune cells. The immune cells include tumor-associated macrophages, T cells, and natural killer cells. While, certainly, there is a rich interplay going on, we do not fully understand all of the interactions that are occurring.
An increased understanding of the tumor microenvironment, together with preclinical findings in a mutant mouse model, have spurred the investigation of immunomodulating drugs or drug combinations in patients with GIST. DeMatteo and colleagues developed a GIST mutant mouse model. In these models, TKIs are very effective, but the effect is augmented with the addition of immunotherapy. In a trial investigating the CTLA-4–blocking drug ipilimumab plus a TKI, it was speculated that this combination would have synergistic or additive properties; however, the results of the study were disappointing. Another trial conducted by researchers in France examined the effects of cyclophosphamide used in combination with the PD-1 inhibitor pembrolizumab in 10 patients with GIST, but the combination showed only modest activity. Cyclophosphamide is an immunosuppressive drug, and it may have inhibited the activity of pembrolizumab in this study. There is also evidence suggesting that interferon gamma might be associated with a more sustained response to imatinib. The addition of interferon may help recruit effector cells into the tumor microenvironment, where they eradicate tumors.
In our own work here at the University of California, Los Angeles, we have used checkpoint blockers, including the PD-1 blocker nivolumab, in combination with ipilimumab in patients with GIST. We have shown that some patients with GIST experienced sustained benefits with either single-agent nivolumab or the combination. We have not seen much tumor shrinkage, but we have observed the inhibition of disease progression with this combination.
Thus, this is a rich area of ongoing research, both in the laboratory and in the clinic. There may be a role for immunotherapy in GIST, and we hope to have more definitive data in the coming years.
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