Reducing side effects of immunotherapy using genetically modified hematopoietic cells

Patent metadata

Field	Value
Publication number	US-12318446-B2
Application number	US-202418732517-A
Country	US
Kind code	B2
Filing date	Jun 3, 2024
Priority date	Nov 26, 2014
Publication date	Jun 3, 2025
Grant date	Jun 3, 2025

Abstract

This disclosure provides a system for preventing or reducing side effects in a patent undergoing immunotherapy to remove diseased cells that express a target antigen: for example, by CAR T cell therapy. Side effects can ensue from concurrent depletion of hematopoietic cells bearing the same target antigen. A population of engineered hematopoietic cells is prepared by obtaining healthy hematopoietic cells from the patient or a third party donor, and using them to produce engineered hematopoietic cells. The engineered cells either do not express the target antigen, express it at a lower density, or express it in a modified form. The engineered hematopoietic cells are formulated for administration to the patient, whereupon they reconstitute hematopoietic cell function, thereby preventing or reducing the side effects.

First claim

The invention claimed is:

1. A method for reducing side effects of cancer treatment in a patient,
wherein the cancer treatment comprises administering to the patient immune effector cells that have been genetically modified to recognize a target antigen on malignant cells in the patient and thereby remove the malignant cells,
wherein the side effects are a consequence of the immune effector cells binding or removing from the patient non-malignant cells that also express the target antigen;
the method comprising:
(a) producing a population of engineered hematopoietic cells that are not recognized by the immune effector cells by:
(i) obtaining non-malignant hematopoietic cells from a donor;
(ii) genetically modifying the non-malignant hematopoietic cells to produce hematopoietic cells that do not express the target antigen, that express the target antigen at a lower density, or that express the target antigen in a modified form that is not recognized by the immune effector cells; and
(b) administering the engineered hematopoietic cells to the patient before, during, or after the cancer treatment;

wherein the engineered hematopoietic cells are resistant to the immune effector cells as a consequence of being genetically modified, and are thereby effective in reconstituting hematopoietic function and reducing the side effects of the cancer treatment in the patient.

2. The method of claim 1 , wherein the target antigen is a cluster of differentiation (CD) antigen.

3. The method of claim 1 , wherein the immune effector cells are cells with cytotoxic effector function.

4. The method of claim 1 , wherein the immune effector cells bear a receptor that is a T cell receptor (TCR) or a chimeric antigen receptor (CAR) that recognizes the target antigen.

5. The method of claim 1 , wherein the engineered hematopoietic cells do not express the target antigen.

6. The method of claim 1 , wherein the engineered hematopoietic cells express a truncated form of the target antigen that is not recognized by the immune effector cells.

7. The method of claim 1 , wherein the target antigen is expressed on the engineered hematopoietic cells at a lower density than it is expressed on the malignant cells.

8. The method of claim 1 , wherein the engineered hematopoietic cells express an altered form of the target antigen that comprises one or a plurality of amino acid substitutions or deletions, wherein the immune effector cells do not recognize the altered form of the target antigen.

9. The method of claim 8 , wherein the altered form of the target antigen expressed by the engineered hematopoietic cells is over 90% identical to the target antigen expressed on the malignant cells.

10. The method of claim 1 , wherein the immune effector cells have a binding affinity for the engineered hematopoietic cells that is one tenth or less of their binding activity for the malignant cells.

11. The method of claim 1 , wherein the donor of the non-malignant hematopoietic cells is the patient.

12. The method of claim 1 , wherein the donor of the non-malignant hematopoietic cells is an allogeneic donor.

13. The method of claim 1 , wherein the patient has a hematopoietic cell malignancy.

14. A method of reducing side effects of immunotherapy of a patient,
wherein the immunotherapy comprises removing diseased cells from the patient that express a target antigen,
wherein the side effects are a consequence of removing other cells from the patient that also express the target antigen;
the method comprising:
(a) producing a population of engineered hematopoietic cells that is resistant to the immunotherapy by:
(i) obtaining non-diseased hematopoietic cells from a donor;
(ii) genetically modifying the non-diseased hematopoietic cells to produce hematopoietic cells that do not express the target antigen, that express the target antigen at a lower density, or that express the target antigen in a modified form; and
(b) administering the engineered hematopoietic cells to the patient;

wherein the engineered hematopoietic cells are resistant to the immunotherapy as a consequence of being genetically modified, and are thereby effective in reducing the side effects of the immunotherapy in the patient.

15. The method of claim 14 , wherein the immunotherapy comprises administering to the patient CAR T or CAR NK cells that recognize the target antigen on the diseased cells, thereby removing the diseased cells.

16. The method of claim 14 , wherein the diseased cells are cancer cells.

17. The method of claim 14 , wherein the diseased cells are hematopoietic lineage cells.

18. The method of claim 14 , wherein the engineered hematopoietic cells are administered to the patient before the immunotherapy.

19. The method of claim 14 , wherein the patient has reduced hematopoietic cell function, and wherein the engineered hematopoietic cells are effective in reconstituting hematopoietic cell function in the patient.

Assignees

• Miltenyi Biotec Bv & Co Kg

Inventors

• Lutteropp Michael
• Richter Anne
• Kaiser Andrew
• Assenmacher Mario
• Miltenyi Stefan

Classifications

• A61K40/4221

  CD20 · 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

• A61K2039/5156

  expressing foreign proteins · CPC title

• A61K2035/124

  the cells being hematopoietic, bone marrow derived or blood cells · CPC title