Inhibition of diacylglycerol kinase to augment adoptive T cell transfer

• US 9,937,205 B2
• Filed: 09/04/2013
• Issued: 04/10/2018
• Est. Priority Date: 09/04/2012
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Albelda, Steven M., Wang, Liang-Chuan, Koretzky, Gary, Riese, Matthew
• Primary Examiner(s): ANGELL, JON E
• Application Number:
  US14/425,452
• Publication Number:
  US 20150224142A1
• Time in Patent Office: 1,679 Days
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/55 Lung
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/45 Transferases (2)
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4631 Chimeric Antigen Receptors [CAR]
• CPC Class Codes: A61K 39/4644 Cancer antigens
• CPC Class Codes: A61K 39/464462 Kinases, e.g. Raf or Src
• CPC Class Codes: A61K 39/464468 Mesothelin [MSLN]
• CPC Class Codes: A61K 39/4648 Bacterial antigens
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C07K 2/00 Peptides of undefined number of amino acids; Derivatives thereof
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/531 Stem-loop; Hairpin
• CPC Class Codes: C12N 5/0638 Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]
• CPC Class Codes: C12N 9/16 : acting on ester bonds (3.1)
• CPC Class Codes: C12Y 207/01107 : Diacylglycerol kinase (2.7.1.107)

Abstract

The present invention provides compositions and methods for inhibiting one or more diacylglycerol kinase (DGK) isoform in a cell in order to enhance the cytolytic activity of the cell. In one embodiment, the cells may be used in adoptive T cell transfer. For example, in some embodiments, the cell is modified to express a chimeric antigen receptor (CAR). Inhibition of DGK in T cells used in adoptive T cell transfer increases cytolytic activity of the T cells and thus may be used in the treatment of a variety of conditions, including cancer, infection, and immune disorders.

Claims

1. A composition with enhanced cytolytic activity, said composition comprising an inhibitor of diacylglycerol kinase (DGK) or a downstream effector protein thereof and a T cell modified with a chimeric antigen receptor (CAR).

2. The composition of claim 1, wherein the inhibitor is selected from the group consisting of a small interfering RNA (siRNA), short hairpin RNA (shRNA), an antisense nucleic acid, a ribozyme, a dominant negative mutant, an antibody, a peptide, a zinc finger nuclease, and a small molecule.

3. The composition of claim 1, wherein the inhibitor enhances the T cell'"'"'s effector activity.

4. The composition of claim 1, wherein the inhibitor increases IFNγ

secretion by the T cell.

5. The composition of claim 1, wherein the composition inhibits the DGK isoform selected from the group consisting of DGKα

and DGKζ

.

6. The composition of claim 1, wherein the composition inhibits both DGKα

and DGKζ

.

13. The composition of claim 1, wherein the T cell is a human T cell.

7. An isolated T cell with enhanced cytolytic activity, wherein the T cell comprises an inhibitor of DGK or a downstream effector protein thereof and a chimeric antigen receptor (CAR).

8. The cell of claim 7, wherein the inhibitor is selected from the group consisting of a small interfering RNA (siRNA), short hairpin RNA (shRNA), an antisense nucleic acid, a ribozyme, a dominant negative mutant, an antibody, a peptide, a zinc finger nuclease, and a small molecule.

9. The cell of claim 7, wherein the inhibitor enhances the T cell'"'"'s effector activity.

10. The cell of claim 9, wherein the inhibitor increases IFNγ

secretion by the T cell.

11. The cell of claim 7, wherein the composition inhibits the DGK isoform selected from the group consisting of DGKα

and DGKζ

.

12. The cell of claim 7, wherein the cell comprises an inhibitor of DGKα

and DGKζ

.

14. The cell of claim 7, wherein the T cell is a human T cell.