METHODS AND COMPOSITIONS FOR TREATING GASTROINTESTINAL STROMAL TUMOR (GIST)
The invention features nucleic acid constructs encoding chimeric immunoreceptors (CIRs) that are useful for treating a KIT+ associated disease in patients. In general, the CIRs contain an extracellular domain (e.g., a KIT-ligand (KL) or stem cell factor (SCF)) which interacts with and destroys KIT+ tumor cells, a transmembrane domain, and a cytoplasmic domain for mediating T cell activation (e.g., CD3 zeta and/or the domain of CD28). The invention also features the use of the nucleic acid constructs and/or host cells expressing CIRs in the treatment of a KIT+ associated disease, in particular gastrointestinal stromal tumor (GIST).
1 . A nucleic acid construct encoding a chimeric immune receptor (CIR) protein comprising
a. an extracellular domain of KIT-ligand (KL), or a fragment thereof,
b. a transmembrane domain, and
c. a cytoplasmic domain,
wherein said transmembrane domain comprises a domain of the CD3 zeta chain, or a fragment thereof, and said cytoplasmic domain comprises a domain of the CD3 zeta chain, or a fragment thereof.
2 . A nucleic acid construct encoding a CIR protein comprising
a. an extracellular domain of KIT-ligand, or a fragment thereof,
b. a transmembrane domain, and
c. a cytoplasmic domain,
wherein said transmembrane domain comprises a domain of CD28, or a fragment thereof, and said cytoplasmic domain comprises a domain of the CD3 zeta chain and a domain of CD28, or fragments thereof.
3 . The nucleic acid construct of claim 2 , wherein said extracellular domain further comprises a domain of CD28, or a fragment thereof.
4 . The nucleic acid construct of claim 1 , wherein said CIR protein, when expressed in a T cell, is capable of activating said T cell in the presence of a tyrosine-protein kinase KIT+ (KIT+) tumor cell.
5 . The nucleic acid construct of claim 1 , wherein said extracellular domain of said CIR protein is capable of interacting with KIT on the surface of a tumor cell when expressed in a T cell.
6 . A vector comprising the nucleic acid construct of claim 1 .
7 . A host cell comprising the nucleic acid construct of claim 1 .
8 . The host cell of claim 7 , wherein said host cell is selected from the group consisting of a T cell, a hematopoietic stem cell, a natural killer cell, a natural killer T cell, a B cell, and a cell of monocytic lineage.
9 . A method of destroying a KIT+ cell, said method comprising administering a composition comprising the nucleic acid construct of claim 1 .
10 . A method of destroying a KIT+ cell, said method comprising contacting said KIT+ cell with a composition comprising the host cell of claim 7 .
11 . The method of claim 10 , further comprising administering to said KIT+ cell a second agent.
12 . The method of claim 11 , wherein said second agent is a tyrosine-kinase inhibitor.
13 . A method of treating a subject with a KIT+ associated disease, said method comprising administering a composition comprising the nucleic acid construct of claim 1 .
14 . A method of treating a subject with a KIT+ associated disease, said method comprising administering a composition comprising the host cell of claim 7 .
15 . The method of claim 14 , wherein said KIT+ associated disease is characterized by the presence of KIT+ tumor cells.
16 . The method of claim 15 , wherein said KIT+ associated disease is selected from the group consisting of: gastrointestinal stromal tumor, acute myelogenous leukemia, small-cell lung carcinoma, ovarian carcinoma, breast carcinoma, melanoma, neuroblastoma, and soft-tissue sarcomas of neuroectodermal origin.
17 . The method of claim 16 , wherein said KIT+ associated disease is gastrointestinal stromal tumor (GIST).
18 . The method of claim 17 , wherein said GIST is resistant to imatinib mesylate.
19 . The method of claim 14 , wherein said host cell is autologous to said subject.
20 . The method of claim 14 , wherein said host cell is not autologous to said subject.
21 . The method of claim 14 , further comprising administering a second agent.
22 .- 23 . (canceled)