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Sarcoma

E416: Ripretinib is more potent than imatinib and increases intratumoral T cells in gastrointestinal stromal tumor

Introduction:

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, and 85% of cases are caused by a mutated receptor tyrosine kinase. Ripretinib is a fourth-line tyrosine kinase inhibitor with multiple targets. We sought to compare the efficacy of ripretinib to imatinib in a genetically engineered mouse model of GIST and to characterize its effect on the immune response.

Methods:

KitV558Δ/+ mice, which spontaneously develop an intestinal GIST, were treated with vehicle, imatinib, or ripretinib for 2 weeks. Tumors were sectioned for histology and immunohistochemistry. RNA and protein were extracted, and RT-PCR and western blot were performed. Tumors were processed for flow cytometry with and without T cell stimulation with PMA/ionomyocin/Golgi plug to analyze immune populations.

Results:

Ripretinib and imatinib each decreased tumor weight by 66% (n=4-5 per group, p< 0.0001 vs. vehicle). However, compared to imatinib, ripretinib also decreased gross vascularity and tumor cellularity on H&E and increased tumor fibrosis by trichrome staining. By western blot analysis, ripretinib decreased Kit signaling compared to both control and imatinib-treated tumors with less phosphorylated (i.e. activated) forms of Kit, AKT serine/threonine kinase, ribosomal protein S6, and the transcription factor STAT3. Flow cytometry revealed a 50% increase in intratumoral CD3 T cells in the ripretinib group compared to control (p< 0.05) and a 20% increase compared to imatinib. Of the CD3 T cell subpopulations, ripretinib decreased CD8 T cells by 40% (p< 0.0005) and concomitantly increased CD4 T cells by 15% compared to control. Compared to imatinib, there was no difference in CD8 T cells, but there was a 10% increase in CD4 T cells with ripretinib. After T cell stimulation, CD8 T cells produced 50% more IFNg in the ripretinib group compared to both control and imatinib (p< 0.05). Ripretinib decreased tumor-associated macrophages (TAMs) by 70% compared to control (p< 0.0005), similar to imatinib. By PCR, there were decreases in the expression of the TAM-recruiting cytokine CCL2, by 60% with ripretinib treatment compared to control (p< 0.01) and imatinib (p< 0.05). The decrease in TAMs and increase in CD3 T cells were confirmed by immunohistochemistry.

Conclusions:

Ripretinib is more potent than imatinib and is associated with increased intratumoral T cell infiltration.

Learning Objectives:

  • Upon completion, participants will be able to specify different antitumoral effects caused by ripretinib.
  • Upon completion, participants will be able to determine the effects on the number of T cells, T cell subpopulations, and T cell cytokine production after ripretinib treatment.
  • Upon completion, participants will be able to specify the effect on the number of macrophages and the underlying mechanism after ripretinib treatment.