Methods of conditioning patients for T cell therapy

Patent metadata

Field	Value
Publication number	US-12458654-B2
Application number	US-202217954070-A
Country	US
Kind code	B2
Filing date	Sep 27, 2022
Priority date	May 28, 2015
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

The invention provides methods of increasing the efficacy of a T cell therapy in a patient in need thereof. The invention includes a method of conditioning a patient prior to a T cell therapy, wherein the conditioning involves administering a combination of cyclophosphamide and fludarabine.

First claim

What is claimed is:

1 . A method of treating a patient having a tumor comprising (i) administering to the patient a single dose of cyclophosphamide at about 900 mg/m 2 /day and one or more doses of fludarabine at about 25 mg/m 2 /day; and (ii) administering to the patient a therapeutically effective amount of engineered chimeric antigen receptor (CAR) T cells, wherein the patient is determined to have an increase in the serum levels of IL-15 of at least 5-fold, IL-7 of at least 2-fold, and an increase in at least one of MCP-1 or CRP of at least 1.5 fold or IP-10 of at least 2-fold on the day of but prior to administration of the CAR-T cells, after the administration of cyclophosphamide and fludarabine; wherein the tumor is a leukemia and the engineered CAR-T cells are anti-CD19 CAR-T cells.

2 . The method of claim 1 , wherein the administration of cyclophosphamide and fludarabine (i) reduces endogenous lymphocytes, (ii) increases a serum level of a homeostatic cytokine, (iii) enhances an effector function of T cells administered after the conditioning, (iv) enhances antigen presenting cell activation and/or availability, or (v) any combination thereof.

3 . The method of claim 1 , wherein each dose of fludarabine is administered daily for three days.

4 . The method of claim 1 , wherein each dose of cyclophosphamide is administered before, after, or concurrently with the dose of fludarabine.

5 . The method of claim 4 , wherein the dose of cyclophosphamide is administered before the dose of fludarabine.

6 . The method of claim 1 , wherein the cyclophosphamide is administered once on day −2 and/or the fludarabine is administered on days −4, −3, and −2.

7 . The method of claim 1 , wherein the administration of cyclophosphamide and fludarabine induces an improved antitumor efficacy of the CAR-T cell administration compared to the antitumor efficacy of the CAR-T cell administration without the administration of cyclophosphamide and fludarabine.

8 . The method of 1 , wherein the patient after the administration of cyclophosphamide and fludarabine and/or the T cell therapy further exhibits an increased serum concentration of a cytokine or a pro-inflammatory factor selected from the group consisting of IL-10, IL-5, IL-8, PLGF, SICAM-1, sVCAM-1, IL-1, IL-2, IL-3, IL-4, IL-6, IL-9, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-20, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor D (VEGF-D), macrophage inflammatory protein 1β (MIP-1β), leukemia inhibitory factor (LIF), oncostatin M (OSM), interferon (IFN) alpha, IFN-beta, IFN-gamma, tumor necrosis factor (TNF) alpha, TNF-beta, CD154, lymphotoxin (LT) beta, 4-1BB ligand (4-1BBL), a proliferation-inducing ligand (APRIL), CD70, CD153, CD178, glucocorticoid-induced TNFR-related ligand (GITRL), tumor necrosis factor superfamily member 14 (TNFSF14), OX40L, TNF-αnd ApoL-related leukocyte-expressed ligand 1 (TALL-1), TNF-related apoptosis-inducing ligand (TRAIL), chemokine (C-C motif) ligand (CCL) 1, macrophage inflammatory protein 1 alpha (MIP-1a or CCL3), CCL5, monocyte-specific chemokine 3 (MCP3 or CCL7), monocyte chemoattractant protein 2 (MCP-2 or CCL8), CCL13, thymus and activation regulated chemokine (TARC or CCL17), CCL22, and any combination thereof.

9 . The method of claim 1 , wherein a therapeutically effective amount of the engineered CAR T cells is about 1×10 6 cells/kg or 2×10 6 cells.

10 . The method of claim 1 , wherein the leukemia is acute lymphoblastic leukemia (ALL).

11 . The method of claim 1 , wherein the leukemia is selected from the group consisting of B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, hairy cell leukemia, Burkitt leukemia, T-cell prolymphocytic leukemia, T-cell large granular lymphocyte leukemia, aggressive NK cell leukemia, adult T-cell leukemia, B-lymphoblastic leukemia, B-lymphoblastic leukemia with recurrent genetic abnormalities, and T-lymphoblastic leukemia.

12 . The method of claim 1 , wherein the leukemia is a lymphoblastic leukemia.

Assignees

• Kite Pharma Inc
• Us Secretary Department Of Health And Human Services

Inventors

• Bot Adrian
• Wiezorek Jeffrey
• GO William
• JAIN Rajul
• Kochenderfer James N
• Rosenberg Steven A

Classifications

• A61K40/4211

  CD19 or B4 · CPC title

• A61K2239/31

  characterized by the route of administration · CPC title

• A61K2239/38

  characterised by the dose, timing or administration schedule · 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