MIR-155 ENHANCEMENT OF CD8+ T CELL IMMUNITY
The present invention provides novel methods of enhancing CD8+ T cell mediated immunity (also referred to as “CD8+ T cell immunity”) in a patient having a diseased state. In particular, the present invention provides for the enhanced expression of miR-155 in a population of patient specific T cells through the introduction of a nucleic acid molecule encoding a miR-155 transcript or a nucleic acid molecule encoding a chimeric antigen receptor and a miR-155 transcript into those cells, followed by the reintroduction of the T cells into the patient. The present invention also provides methods of enhancing the expansion of these T cells relative to control cells. Increased expansion of CD8+ T cells following enhanced miR-155 expression is directly related to enhanced CD8+ T cell immunity. The present invention further provides methods of enhancing anti-cancer immunity in a patient through the increased expression of miR-155 in patient specific T cells.
1 . A method of increasing CD8+ T cell mediated immunity in a subject having a disease state comprising:
isolating a population of the subject's CD8+ T cells;
introducing a nucleic acid molecule encoding a miR-155 transcript into the isolated CD8+ T cells; and
reintroducing the CD8+ T cells into said subject.
2 . The method of claim 1 , wherein the nucleic acid molecule is introduced into the isolated CD8+ T cells by transduction or transfection.
3 . The method of claim 1 , wherein the nucleic acid molecule encoding the miR-155 transcript is the BIC gene or a portion thereof.
4 . The method of claim 1 , wherein the disease state is cancer.
5 . The method of claim 1 , wherein the disease state is a viral infection.
6 . The method of claim 1 , wherein the diseased state is a bacterial infection.
7 . The method of claim 1 , wherein the CD8+ T cells are isolated from the blood of the subject.
8 . The method of claim 1 , wherein the CD8+ T cells are isolated from a solid tumor from said subject.
9 . The method of claim 1 , wherein the nucleic acid molecule encoding a miR-155 transcript is encoded within an expression vector.
10 . A method of increasing T cell mediated immunity in a subject having a disease state comprising:
isolating a population of the subject's T cells;
introducing a nucleic acid molecule encoding a chimeric antigen receptor and a miR-155 transcript into the isolated T cells; and
reintroducing the T cells into said subject.
11 . The method of claim 10 , wherein the population of T cells comprises both CD4+ T cells and CD8+ T cells
12 . The method of claim 10 , wherein the population of T cells comprises either CD4+ T cells or CD8+ T cells.
14 . The method of claim 10 , wherein the nucleic acid molecule is introduced into the isolated T cells by transduction or transfection.
15 . The method of claim 10 , wherein the nucleic acid molecule encoding the miR-155 transcript is the BIC gene or a portion thereof.
16 . The method of claim 10 , wherein the disease state is cancer.
17 . The method of claim 10 , wherein the disease state is a viral infection.
18 . The method of claim 10 , wherein the diseased state is a bacterial infection.
19 . The method of claim 10 , wherein the T cells are isolated from the blood of the subject.
20 . The method of claim 10 , wherein the T cells are isolated from a solid tumor from said subject.
21 . The method of claim 10 , wherein the nucleic acid molecule encoding a chimeric antigen receptor and the miR-155 transcript is encoded within an expression vector.
22 . The method of claim 10 , wherein a nucleic acid molecule encoding miR-155 is located within the intracellular tail of the chimeric T cell receptor.
23 . The method of claim 22 , wherein a nucleic acid molecule encoding miR-155 alone is located within the intracellular tail of the chimeric T cell receptor.
24 . The method of claim 22 , wherein a nucleic acid molecule encoding miR-155 together with a costimulatory sequence is located within the intracellular tail of the chimeric T cell receptor.
25 . A method of increasing T cell mediated immunity in a subject having a disease state comprising:
isolating a population of the subject's T cells;
introducing a nucleic acid molecule encoding a chimeric antigen receptor into the T cells;
additionally introducing a nucleic acid molecule encoding a miR-155 transcript in the T cells; and
reintroducing the T cells into said subject.
26 . The method of claim 25 , wherein the population of T cells comprises both CD4+ T cells and CD8+ T cells.
27 . The method of claim 25 , wherein the population of T cells comprises either CD4+ T cells or CD8+ T cells.
28 . The method of claim 25 , wherein the nucleic acid molecule is introduced into the isolated T cells by transduction or transfection.
29 . The method of claim 25 , wherein the nucleic acid molecule encoding the miR-155 transcript is the BIC gene or a portion thereof.
30 . The method of claim 25 , wherein the disease state is cancer.
31 . The method of claim 25 , wherein the disease state is a viral infection.
32 . The method of claim 25 , wherein the diseased state is a bacterial infection.
33 . The method of claim 25 , wherein the T cells are isolated from the blood of the subject.
34 . The method of claim 25 , wherein the T cells are isolated from a solid tumor from said subject.
35 . The method of claim 25 , wherein the nucleic acid molecule encoding the chimeric antigen receptor and the nucleic acid molecule encoding the miR-155 transcript are encoded within expression vectors.