Methods and compositions for cells expressing a chimeric intracellular signaling molecule

Patent metadata

Field	Value
Publication number	US-11890301-B2
Application number	US-201615754227-A
Country	US
Kind code	B2
Filing date	Aug 26, 2016
Priority date	Aug 28, 2015
Publication date	Feb 6, 2024
Grant date	Feb 6, 2024

Abstract

The present invention relates to compositions and methods for enhancing T cell metabolism and activity for more effective adoptive T cell therapy. By expressing an chimeric antigen receptor and bispecific antibodies in T cells, the T cells are metabolically enhanced with improved cytotoxicity and resistance to immunosuppression imposed by tumor microenvironments. Certain aspects include modified T cells and pharmaceutical compositions comprising the modified cells for adoptive cell therapy and treating a disease or condition associated with enhanced immunity.

First claim

What is claimed:

1. A method of metabolically enhancing a tumor specific T cell, comprising:
introducing a first nucleic acid encoding a chimeric antigen receptor (CAR) into a T cell in vitro to obtain a CAR T cell, wherein the CAR comprises an antigen binding domain that binds to CD19, a transmembrane domain, and intracellular signaling domains of a 4-1BB molecule and a CD3zeta molecule;
arming the CAR T cell in vitro with a bispecific antibody, wherein arming the CAR T cell comprises introducing a second nucleic acid encoding the bispecific antibody into the CAR T cell, wherein the bispecific antibody binds CD3 on the CAR T cell, and wherein the bispecific antibody is capable of binding to an antigen on a tumor cell in vivo; and
administering the armed CAR T cell to a CD19+ subject wherein the intracellular signaling domain is activated, thereby metabolically enhancing the tumor specific T cell.

2. The method of claim 1 , wherein introducing the first nucleic acid comprises electroporating the first nucleic acid into the cell, wherein the first nucleic acid comprises an mRNA.

3. The method of claim 1 , wherein the antigen is HER2, epidermal growth factor receptor (EGFR), or CD20.

4. The method of claim 1 , wherein the bispecific antibody comprises an anti-CD3 antibody.

5. The method of claim 1 , wherein the bispecific antibody comprises a first antibody chemically heteroconjugated to a second antibody, wherein the first antibody is specific to the antigen, and wherein the second antibody is specific to the CD3.

6. The method of claim 1 , wherein introducing the second nucleic acid comprises electroporating the second nucleic acid into the cell, wherein the second nucleic acid comprises an mRNA.

7. The method of claim 1 further comprising irradiating the armed CAR T cell with up to 2500 rad, wherein said irradiation is sufficient to inhibit proliferation of the armed CAR T cell but is insufficient to inhibit cytokine secretion or cytotoxicity.

8. The method of claim 1 , wherein the CAR comprises the sequence of SEQ ID NO: 1.

Assignees

• Univ Pennsylvania
• Univ Wayne State

Inventors

• June Carl H
• Milone Michael
• Zhao Yangbing
• Lum Lawrence G
• Thakur Archana

Classifications

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/33

  Antibodies; T-cell engagers · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K2239/54

  Pancreas · CPC title