Pre-clinical development of anti-KIT CAR-Ts for metastatic GIST

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract affecting approximately 5,000 individuals in the US each year. Up to 90% of GISTs arise from the interstitial cells of Cajal (ICC) of the stomach or small intestine via mutations in the KIT receptor causing constitutive oncogenic signaling. In many cases, patients with unresectable KIT+ GIST develop liver metastases (LM) and harbor additional mutations in KIT which confer resistance to treatment with tyrosine kinase inhibitors (TKIs) imatinib and sunitinib. To address this unmet clinical need, our team previously developed human anti-KIT chimeric antigen receptor T cells (CAR-Ts), which target KIT+ GIST tumors, and in particular TKI-resistant tumors. We demonstrated human anti-KIT CAR-Ts effectively kill KIT+ GIST cells in vitro and significantly reduce KIT+ GIST xenografts in immunodeficient mice. Presently, we are developing a murine anti-KIT CAR for pre-clinical testing in an immunocompetent model prior to phase I testing.