Methods and compositions for the activation of gamma-delta T-cells
The present invention relates generally to methods and compositions for gene therapy and immunotherapy that activate gamma delta T-cells, and in particular, can be used in the treatment of various cancers and infectious diseases.
1. A method of treating a cancer in a subject using an immunotherapy-based composition, the method comprising administering a therapeutically-effective amount of the immunotherapy-based composition to the subject, wherein the immunotherapy-based composition comprises a lentiviral particle, the lentiviral particle comprising:
a. an envelope protein capable of infecting one or more cancer cells, and
b. at least one encoded shRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the at least one encoded shRNA comprises a sequence having at least 80% percent identity with:
i. GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCA GGACTTTTT (SEQ ID NO: 1);
ii. GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATC CTGCTTTTT (SEQ ID NO: 2);
iii. GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACA TGGCTTTTT (SEQ ID NO: 3); or
iv. GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCT TCTGCTTTTT (SEQ ID NO: 4);
or
c. at least one encoded microRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the at least one encoded microRNA comprises a sequence having at least 80% percent identity with:
(SEQ ID NO: 5)
i.
AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT
CCTTCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAA
GTGCTGCCTACTGCCTCGGACTTCAAGGGGCT;
(SEQ ID NO: 6)
ii.
AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCT
CCTTCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGT
GCTGCCTACTGCCTCGGACTTCAAGGGGCT;
(SEQ ID NO: 7)
iii.
TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTG
AAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTG
CCTCGGA;
(SEQ ID NO: 8)
iv.
CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCT
CCTTCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAA
GTCAGGACACAAGGCCTGTTACTAGCACTCA;
(SEQ ID NO: 9)
v.
CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCT
CCTTCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAG
TCTGACATTTTGGTATCTTTCATCTGACCA;
or
(SEQ ID NO: 10)
vi.
GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCT
CCTTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGT
CCTTCCCTCCCAATGACCGCGTCTTCGTCG.
2. The method of claim 1 , wherein the one or more cancer cells are present in a cancer selected from one or more of a carcinoma, a leukemia, a lymphoma, a sarcoma, a myeloma, a mesothelioma, a mixed type, or mixtures thereof.
3. The method of claim 1 , wherein the one or more cancer cells are present in a hepatocellular carcinoma.
4. The method of claim 2 , wherein the one or more cancer cells are present in a leukemia.
5. The method of claim 1 , wherein the one or more cancer cells are capable of activating a gamma delta T cell resident in the subject following infection of the one or more cancer cells with the immunotherapy-based composition.
6. The method of claim 5 , wherein activating the gamma delta T cell comprises increasing tumor necrosis factor (TNF)-α expression by the gamma delta T cell.
7. The method of claim 1 , wherein the enzyme of the mevalonate pathway is farnesyl diphosphate synthase (FDPS).
8. The method of claim 1 , further comprising administering an effective amount of an aminobisphosphonate drug to the subject.
9. The method of claim 8 , wherein the aminobisphosphonate drug comprises zoledronic acid.
10. The method of claim 8 , wherein the aminobisphosphonate drug is administered to the subject separately from the immunotherapy-based composition.
11. The method of claim 8 , wherein the aminobisphosphonate drug is administered to the subject together with the immunotherapy-based composition.