IP Library › Granted Patent US 9,834,790
Granted Patent B1
US 9,834,790 · App. 15/706,481 · Granted Dec 5, 2017

Methods and compositions for the activation of gamma-delta T-cells

Inventors: Charles David Pauza (Baltimore, MD); Haishan Li (North Potomac, MD); Tyler Lahusen (Frederick, MD); Mei-Ling Liou (Germantown, MD)
C12N15/86A61K38/16C12N5/0636A61K48/00A61K2039/5158C12N5/00
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Quick Facts
Patent No.
US 9,834,790
App. No.
15/706,481
Granted
Dec 5, 2017
Kind
B1
Abstract

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.

Claims (178)

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 a cancer cell, and:

b. an encoded shRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the encoded shRNA comprises a sequence having at least 85% percent identity with:

(SEQ ID NO: 1)

  i. GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCAG

     GACTTTTT;

(SEQ ID NO: 2)

 ii. GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATCC

     TGCTTTTT;

(SEQ ID NO: 3)

iii. GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACAT

     GGCTTTTT;

     or

(SEQ ID NO: 4)

 iv. GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCTTC

     TGCTTTTT;

     or

c. an encoded microRNA capable of inhibiting production of an enzyme of the mevalonate pathway, wherein the encoded microRNA comprises a sequence having at least 85% percent identity with:

(SEQ ID NO: 5)

  i. AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCT

     TCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTGCTG

     CCTACTGCCTCGGACTTCAAGGGGCT;

(SEQ ID NO: 6)

 ii. AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCT

     TCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGTGCTGCC

     TACTGCCTCGGACTTCAAGGGGCT;

(SEQ ID NO: 7)

iii. TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTGAAG

     CCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTGCCTCGG

     A;

(SEQ ID NO: 8)

 iv. CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCTCCT

     TCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAAGTCAGG

     ACACAAGGCCTGTTACTAGCACTCA;

(SEQ ID NO: 9)

  v. CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCTCCT

     TCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAGTCTGAC

     ATTTTGGTATCTTTCATCTGACCA;

     or

(SEQ ID NO: 10)

 vi. GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCTCC

     TTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGTCCTT

     CCCTCCCAATGACCGCGTCTTCGTCG.

2. The method of claim 1 , wherein:

a. the encoded shRNA comprises a sequence having at least 90% percent identity with:

(SEQ ID NO: 1)

  i. GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCAG

     GACTTTTT;

(SEQ ID NO: 2)

 ii. GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATCC

     TGCTTTTT;

(SEQ ID NO: 3)

iii. GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACAT

     GGCTTTTT;

     or

(SEQ ID NO: 4)

 iv. GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCTTC

     TGCTTTTT;

     or

b. the encoded microRNA comprises a sequence having at least 90% percent identity with:

(SEQ ID NO: 5)

  i. AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCT

     TCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTGCTG

     CCTACTGCCTCGGACTTCAAGGGGCT;

(SEQ ID NO: 6)

 ii. AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCT

     TCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGTGCTGCC

     TACTGCCTCGGACTTCAAGGGGCT;

(SEQ ID NO: 7)

iii. TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTGAAG

     CCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTGCCTCGG

     A;

(SEQ ID NO: 8)

 iv. CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCTCCT

     TCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAAGTCAGG

     ACACAAGGCCTGTTACTAGCACTCA;

(SEQ ID NO: 9)

  v. CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCTCCT

     TCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAGTCTGAC

     ATTTTGGTATCTTTCATCTGACCA;

     or

(SEQ ID NO: 10)

 vi. GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCTCC

     TTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGTCCTT

     CCCTCCCAATGACCGCGTCTTCGTCG.

3. The method of claim 1 , wherein:

a. the encoded shRNA comprises a sequence having at least 95% percent identity with:

(SEQ ID NO: 1)

  i. GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCAG

     GACTTTTT;

(SEQ ID NO: 2)

 ii. GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATCC

     TGCTTTTT;

(SEQ ID NO: 3)

iii. GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACAT

     GGCTTTTT;

     or

(SEQ ID NO: 4)

 iv. GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCTTC

     TGCTTTTT;

     or

b. the encoded microRNA comprises a sequence having at least 95% percent identity with:

(SEQ ID NO: 5)

  i. AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCT

     TCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTGCTG

     CCTACTGCCTCGGACTTCAAGGGGCT;

(SEQ ID NO: 6)

 ii. AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCT

     TCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGTGCTGCC

     TACTGCCTCGGACTTCAAGGGGCT;

(SEQ ID NO: 7)

iii. TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTGAAG

     CCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTGCCTCGG

     A;

(SEQ ID NO: 8)

 iv. CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCTCCT

     TCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAAGTCAGG

     ACACAAGGCCTGTTACTAGCACTCA;

(SEQ ID NO: 9)

  v. CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCTCCT

     TCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAGTCTGAC

     ATTTTGGTATCTTTCATCTGACCA;

     or

(SEQ ID NO: 10)

 vi. GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCTCC

     TTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGTCCTT

     CCCTCCCAATGACCGCGTCTTCGTCG.

4. The method of claim 1 , wherein:

a. the encoded shRNA comprises:

(SEQ ID NO: 1)

  i. GTCCTGGAGTACAATGCCATTCTCGAGAATGGCATTGTACTCCAG

     GACTTTTT;

(SEQ ID NO: 2)

 ii. GCAGGATTTCGTTCAGCACTTCTCGAGAAGTGCTGAACGAAATCC

     TGCTTTTT;

(SEQ ID NO: 3)

iii. GCCATGTACATGGCAGGAATTCTCGAGAATTCCTGCCATGTACAT

     GGCTTTTT;

     or

(SEQ ID NO: 4)

 iv. GCAGAAGGAGGCTGAGAAAGTCTCGAGACTTTCTCAGCCTCCTTC

     TGCTTTTT;

     or

b. the encoded microRNA comprises:

(SEQ ID NO: 5)

  i. AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCT

     TCTGCGTGAAGCCACAGATGGCAGAAGGAGGCTGAGAAAGTGCTG

     CCTACTGCCTCGGACTTCAAGGGGCT;

(SEQ ID NO: 6)

 ii. AAGGTATATTGCTGTTGACAGTGAGCGACACTTTCTCAGCCTCCT

     TCTGCGTGAAGCCACAGATGGCAGAAGGGCTGAGAAAGTGCTGCC

     TACTGCCTCGGACTTCAAGGGGCT;

(SEQ ID NO: 7)

iii. TGCTGTTGACAGTGAGCGACTTTCTCAGCCTCCTTCTGCGTGAAG

     CCACAGATGGCAGAAGGAGGCTGAGAAAGTTGCCTACTGCCTCGG

     A;

(SEQ ID NO: 8)

 iv. CCTGGAGGCTTGCTGAAGGCTGTATGCTGACTTTCTCAGCCTCCT

     TCTGCTTTTGGCCACTGACTGAGCAGAAGGGCTGAGAAAGTCAGG

     ACACAAGGCCTGTTACTAGCACTCA;

(SEQ ID NO: 9)

  v. CATCTCCATGGCTGTACCACCTTGTCGGGACTTTCTCAGCCTCCT

     TCTGCCTGTTGAATCTCATGGCAGAAGGAGGCGAGAAAGTCTGAC

     ATTTTGGTATCTTTCATCTGACCA;

     or

(SEQ ID NO: 10)

 vi. GGGCCTGGCTCGAGCAGGGGGCGAGGGATACTTTCTCAGCCTCC

     TTCTGCTGGTCCCCTCCCCGCAGAAGGAGGCTGAGAAAGTCCTT

     CCCTCCCAATGACCGCGTCTTCGTCG.

5. The method of claim 1 , wherein the cancer is selected from one or more of a carcinoma, a leukemia, a lymphoma, a sarcoma, a myeloma, or a mesothelioma.

6. The method of claim 1 , wherein the cancer is a leukemia.

7. The method of claim 1 , wherein the cancer cell is capable of activating a gamma delta T cell resident in the subject following infection of the cancer cell with the immunotherapy-based composition.

8. The method of claim 7 , wherein activating the gamma delta T cell comprises increasing tumor necrosis factor (TNF)-α expression by the gamma delta T cell.

9. The method of claim 1 , wherein the enzyme of the mevalonate pathway is farnesyl diphosphate synthase (FDPS).

10. The method of claim 1 , further comprising administering an effective amount of an aminobisphosphonate drug to the subject.

11. The method of claim 10 , wherein the aminobisphosphonate drug comprises zoledronic acid.

12. The method of claim 10 , wherein the aminobisphosphonate drug is administered to the subject separately from the immunotherapy-based composition.

13. The method of claim 10 , wherein the aminobisphosphonate drug is administered to the subject together with the immunotherapy-based composition.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 31, 2026
From: PAUZA, CHARLES DAVID; LI, HAISHAN; LAHUSEN, TYLER; LIOU, MEI-LING
To: AMERICAN GENE TECHNOLOGIES INTERNATIONAL INC.
Reel/Frame 075486/0017 →
Continuity (3)
Continuation 15652080 · Jul 17, 2017
Continuation PCTUS2017013399 · Jan 13, 2017
Provisional Application 62279474 · Jan 15, 2016