Cell based anti-cancer compositions with reduced toxicity and methods of making the same

Patent metadata

Field	Value
Publication number	US-11286308-B2
Application number	US-201816236249-A
Country	US
Kind code	B2
Filing date	Dec 28, 2018
Priority date	Mar 15, 2013
Publication date	Mar 29, 2022
Grant date	Mar 29, 2022

Abstract

Isolated pluralities of T cells which recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen and pharmaceutical compositions comprising the same are disclosed. Methods of making a plurality of T cells that recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen are also disclosed. Methods of treating an individual who has been diagnosed with cancer of a mucosal tissue or preventing such cancer in an individual at elevated risk are disclosed as are nucleic acid molecules that comprise a nucleotide sequence that encode proteins that recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen and T cells comprising such nucleic acid molecules.

First claim

The invention claimed is:

1. A plurality of T cells which recognize at least one epitope of guanylyl cyclase C and which are modified to inhibit expression or activity of α 4 β 7 integrin, wherein said T cells are derived from clonal expansion of T cells that are isolated from an individual and transformed with a nucleic acid molecule which encodes a chimeric antigen receptor which binds to guanylyl cyclase C.

2. The plurality of T cells of claim 1 wherein the chimeric antigen receptor that binds to guanylyl cyclase C comprises:
a guanylyl cyclase C specific scFv linked to a truncated CD28 extracellular domain to the intracellular part of the FcRIγ chain;
a guanylyl cyclase C specific scFv linked to a truncated CD28 extracellular domain to the intracellular part of the CD3zeta signaling chain;
a guanylyl cyclase C specific scFv linked to the intracellular part of the FcRIγ chain; or
a guanylyl cyclase C specific scFv linked to the intracellular part of the CD3zeta signaling chain.

3. The plurality of T cells of claim 1 , wherein the plurality of T cells are modified to inhibit expression of α 4 β 7 integrin by providing the plurality of T cells with nucleic acid sequences selected from the group consisting of: nucleic acid sequences that express siRNA which inhibits expression of α 4 β 7 integrin, nucleic acid sequences that express microRNA which inhibits expression of α 4 β 7 integrin, and nucleic acid sequences that express antisense sequences which inhibit expression of α 4 β 7 integrin.

4. The plurality of T cells of claim 1 , wherein the plurality of T cells are modified to inhibit activity of α 4 β 7 integrin by providing the plurality of T cells with nucleic acid sequences selected from the group consisting of: nucleic acid sequences that encode decoy molecules which bind to α 4 β 7 integrin at the site α 4 β 7 integrin binds to MAdCAM-1, nucleic acid sequences that encode anti-α 4 β 7 integrin antibodies, nucleic acid sequences that express negative mutant form of α 4 of α 4 β 7 integrin that binds to β 7 to produce an inactive integrin; nucleic acid sequences that express negative mutant form of β 7 of α 4 β 7 integrin that binds to α 4 to produce an inactive integrin; nucleic acid sequences that encode a protein that competitive forms heterodimers with α 4 of α 4 β 7 integrin to dimerize with β 7 and produce non-α 4 β 7 integrin heterodimers; nucleic acid sequences that encode a protein that competitive forms heterodimers with β 7 of α 4 β 7 integrin to dimerize with α 4 and produce non-α 4 β 7 integrin heterodimers; and nucleic acid sequences that encode MAdCAM-1 which binds to α 4 β 7 integrin.

5. A pharmaceutical composition comprising a plurality of T cells of claim 1 and a pharmaceutically acceptable carrier or diluent.

6. A method of treating an individual who has been diagnosed with cancer that expresses guanylyl cyclase C comprising the step of administering to the individual an effective amount of a plurality of T cells of claim 1 .

7. The plurality of T cells of claim 2 , wherein the plurality of T cells are modified to inhibit expression of α 4 β 7 integrin by providing the plurality of T cells with nucleic acid sequences selected from the group consisting of: nucleic acid sequences that express siRNA which inhibits expression of α 4 β 7 integrin, nucleic acid sequences that express microRNA which inhibits expression of α 4 β 7 integrin, and nucleic acid sequences that express antisense sequences which inhibit expression of α 4 β 7 integrin.

8. The plurality of T cells of claim 2 , wherein the plurality of T cells are modified to inhibit activity of α 4 β 7 integrin by providing the plurality of T cells with nucleic acid sequences selected from the group consisting of: nucleic acid sequences that encode decoy molecules which bind to α 4 β 7 integrin at the site α 4 β 7 integrin binds to MAdCAM-1, nucleic acid sequences that encode anti-α 4 β 7 integrin antibodies, nucleic acid sequences that express negative mutant form of α 4 of α 4 β 7 integrin that binds to β 7 to produce an inactive integrin; nucleic acid sequences that express negative mutant form of β 7 of α 4 β 7 integrin that binds to α 4 to produce an inactive integrin; nucleic acid sequences that encode a protein that competitive forms heterodimers with α 4 of α 4 β 7 integrin to dimerize with β 7 and produce non-α 4 β 7 integrin heterodimers; nucleic acid sequences that encode a protein that competitive forms heterodimers with β 7 of α 4 β 7 integrin to dimerize with α 4 and produce non-α 4 β 7 integrin heterodimers; and nucleic acid sequences that encode MAdCAM-1 which binds to α 4 β 7 integrin.

9. A method of treating an individual who has been diagnosed with cancer that expresses guanylyl cyclase C comprising the step of administering to the individual an effective amount of a plurality of T cells of claim 2 .

Assignees

• Univ Jefferson

Inventors

• Waldman Scott A
• Snook Adam E
• Magee Michael S

Classifications

• A61K40/4254

  Adhesion molecules, e.g. NRCAM, EpCAM or cadherins · CPC title

• A61K40/4244

  Enzymes · CPC title

• A61K40/4219

  Receptors for chemokines · 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