Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor
- PDF / 381,203 Bytes
- 10 Pages / 595.28 x 793.7 pts Page_size
- 95 Downloads / 180 Views
RESEARCH
Open Access
Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor Steven C Katz1*, Rachel A Burga1, Seema Naheed1, Lauren A Licata1, Mitchell Thorn1, Doreen Osgood1, Cang T Nguyen1, N Joseph Espat1, Jonathan A Fletcher3 and Richard P Junghans2
Abstract Background: Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells. Methods: Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions. Results: We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates. Conclusions: We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc. Keywords: GIST, Adoptive cell therapy, Immunotherapy, and Designer T cells
Background Gastrointestinal stromal tumor (GIST) is the most common GI mesenchymal neoplasm and nearly all GIST express KIT (CD117) [1]. Imatinib mesylate has been demonstrated to significantly prolong disease-free survival in the adjuvant setting and for patients with disseminated GIST [2,3]. Unfortunately, the majority of patients with metastatic GIST who are treated with imatinib develop resistance and subsequently progressive disease [4]. Therapeutic options are limited for patients who develop advanced GIST unresponsive to tyrosine
* Correspondence: [email protected] 1 Roger Williams Medical Center, Department of Surgery, Providence, RI/ Boston University School of Medicine, Boston, MA, USA Full list of author information is available at the end of the article
kinase inhibitor (TKI) therapy. In an effort to address this clinical need, we sought to develop a T cell-based therapy for the treatment of KIT+ tumor
Data Loading...
