Transduced T cells expressing human SSTR2 and application thereof
The present invention is directed to transduced T cells expressing at least 100,000 molecules of human somatostatin receptor 2 (SSTR2), which improves PET/CT imaging sensitivity. The present invention is also directed to transduced T cells expressing SSTR2 and chimeric antigen receptor (CAR). In one embodiment, the CAR is specific to human ICAM-1 and the CAR comprises a binding domain that is scFv of anti-human ICAM-1, or an I domain of the αL subunit of human lymphocyte function-associated antigen-1. In another embodiment, the CAR is specific to human CD19, and the CAR comprises a binding domain that is scFv of anti-human CD19. The present invention is further directed to using the above transduced T cells for monitoring T cell distribution in a patient by PET/CT imaging and/or treating cancer.
1. Transduced T cells that express SSTR2 and a chimeric antigen receptor (CAR) specific to ICAM-1, wherein the CAR comprises a binding domain to human ICAM-1, wherein the binding domain is an I domain of the α L subunit human lymphocyte function-associated antigen-1, wherein the I domain is a mutant of the wild type I domain comprising the sequence of amino acids 130-310 of SE ID NO:1, and wherein the mutation is F292A, F292S, L289G, F292G, or F265S.
2. The transduced CART cells of claim 1 , wherein the CAR further comprises a transmembrane domain, at least one co-stimulating domain, and an activating domain.
3. The transduced CART cells according to claim 2 , wherein the co-stimulatory domain is selected from the group consisting of CD28, 4-1BB, ICOS-1, CD27, OX-40, GITR, and DAP10.
4. The transduced CAR T cells according to claim 2 , wherein the activating domain is CD3 zeta.
5. The transduced CART cells of Claim 1 , which expresses at least 100,000 molecules of SSTR2 per T cell.
6. A method for treating cancer and monitoring CAR T cell distribution in a patient, comprising the steps of:
incubating the transduced CART cells of claim 1 with a radioactive label that binds to SSTR2,
intravenously infusing the labelled CAR T cells into a patient in an amount of 10 6 -10 8 cells/kg patient, and
detecting the labelled CAR T cell distribution by PET/CT imaging,
whereby the labelled CAR T cells are infiltrated into cancer cells to kill the cancer cells.
7. The method according to claim 6 , wherein the cancer is thyroid cancer, gastric cancer, pancreatic cancer, or breast cancer.
8. The method according to claim 6 , wherein the radioactive label is 68 Ga-DOTATOC or 68 Ga-DODATATE.
9. A method for treating cancer and monitoring CAR T cell distribution in a patient, comprising the steps of:
intravenously infusing the transduced CAR T cells of claim 1 into a patient,
injecting to the patient a radioactive label that binds to SSTR2 at least one hour prior to PCT/CT imaging, and
detecting the labelled CAR T cell distribution by PET/CT imaging,
whereby the labelled CAR T cells are infiltrated into cancer cells to kill the cancer cells.
10. The method according to claim 9 , wherein the cancer is thyroid cancer, gastric cancer, pancreatic cancer, or breast cancer.
11. The method according to claim 9 , wherein the radioactive label is 68 Ga-DOTATOC or 68 Ga-DODATATE.
12. The transduced CAR T cells of claim 1 , wherein the mutation is F292A.