Methods for improving adoptive cell therapy

Patent metadata

Field	Value
Publication number	US-12350312-B2
Application number	US-201816645092-A
Country	US
Kind code	B2
Filing date	Sep 6, 2018
Priority date	Sep 6, 2017
Publication date	Jul 8, 2025
Grant date	Jul 8, 2025

Abstract

The present disclosure provides reagents and methods for treating disease using modified immune cells (e.g., T cell comprising CAR or TCR) in combination with an agent associated with induction of immunogenic cell death (ICD) and optionally further in combination with an agent that specifically binds to and/or inhibits an immune suppression component and/or an agonist of an immune stimulatory molecule.

First claim

What is claimed is:

1. A method for treating a solid tumor in a subject, the method comprising administering to the subject:
(a) an effective amount of a T cell comprising a heterologous polynucleotide that encodes a chimeric antigen receptor (CAR) that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells of the solid tumor; and
(b) an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to and is an inhibitor of PD-1 or PD-L1,
wherein prior to administering (a) and (b), the subject has been administered (c) oxaliplatin, or an active metabolite or derivative thereof, and (d) cyclophosphamide,
wherein the T cell is a CD4+ T cell, a CD8+ T cell, a stem cell memory T cell, or any combination thereof.

2. A method for treating a solid tumor in a subject, the method comprising administering to the subject an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to and is an inhibitor of PD-1 or PD-L1,
wherein prior to administering the effective amount of the antibody or antigen-binding fragment, the subject has been administered (1) a T cell comprising a heterologous polynucleotide that encodes a chimeric antigen receptor (CAR) that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells of the solid tumor, (2) oxaliplatin or an active metabolite or derivative thereof, and (3) cyclophosphamide,
wherein the T cell is a CD4+ T cell, a CD8+ T cell, a stem cell memory T cell, or any combination thereof.

3. A method for treating a solid tumor in a subject, the method comprising administering to the subject an effective amount of a T cell comprising a heterologous polynucleotide that encodes a chimeric antigen receptor (CAR) that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells of the solid tumor,
wherein the subject, prior to administering the effective amount of the T cell, has been administered (1) an antibody or antigen-binding fragment that specifically binds to and is an inhibitor of PD-1 or PD-L1, (2) oxaliplatin or an active metabolite or derivative thereof, and (3) cyclophosphamide, and
wherein the T cell comprises a CD4+ T cell, a CD8+ T cell, a stem cell memory T cell, or any combination thereof.

4. A method of treating a solid tumor in a subject, the method comprising administering to the subject (1) an effective amount of oxaliplatin or an active metabolite or derivative thereof, (2) an effective amount of a T cell comprising a heterologous polynucleotide that encodes a chimeric antigen receptor (CAR) that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells of the solid tumor, and (3) an effective amount of an antibody or antigen-binding fragment that specifically binds to and/or is an inhibitor of PD-1 or PD-L1,
wherein the subject has previously been administered cyclophosphamide, and
wherein the T cell comprises a CD4+ T cell, a CD8+ T cell, a stem cell memory T cell, or any combination thereof.

5. A method of treating a solid tumor in a subject, the method comprising administering to the subject (1) an effective amount of cyclophosphamide, (2) an effective amount of oxaliplatin or an active metabolite or derivative thereof, (3) an effective amount of a T cell comprising a heterologous polynucleotide that encodes a chimeric antigen receptor (CAR) that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells of the solid tumor, and (4) an effective amount of an antibody or antigen-binding fragment that specifically binds to and is an inhibitor of PD-1 or PD-L1, wherein (1) and (2) are administered prior to (3) and (4), and
wherein the T cell is a CD4+ T cell, a CD8+ T cell, a stem cell memory T cell, or any combination thereof.

6. The method of claim 1 , wherein prior to administering (a) and (b), the subject has further been administered (e) fludarabine.

7. The method of claim 2 , wherein prior to administering the effective amount of the antibody or antigen-binding fragment, the subject has further been administered (4) fludarabine.

8. The method of claim 3 , wherein prior to administering the effective amount of the T cell, the subject has further been administered (4) fludarabine.

9. The method of claim 4 , wherein the subject has previously further been administered fludarabine.

10. The method of claim 1 , whereupon following administration of
the T cell and the antibody or antigen binding fragment,
the subject achieves an immune response against the solid tumor that is elevated as compared to the immune response achieved by a reference subject that is not administered the oxaliplatin, or the active metabolite or derivative thereof, and the cyclophosphamide.

11. The method of claim 1 , further comprising administering to the subject a CTLA4-specific antibody or antigen-binding fragment thereof.

12. The method of claim 11 , wherein the CTLA4 specific antibody or antigen-binding fragment thereof comprises ipilimumab, tremelimumab, or any combination thereof.

13. The method of claim 1 , wherein the antibody that specifically binds to and is an inhibitor of PD-1 or PD-L1 comprises pidilizumab, nivolumab, pembrolizumab, MEDI0680, BMS-936559, durvalumab, atezolizumab, avelumab, or any combination thereof.

14. The method of claim 11 , wherein the CTLA4 specific antibody or antigen-binding fragment thereof is administered to the subject concurrently, simultaneously, or sequentially with: (i) the T cell; (ii) the antibody or antigen binding fragment; or (iii) both.

15. The method of claim 10 , wherein the elevated immune response comprises:
(1) an increased amount of immune cell localization to, and/or immune cell activity at, a site of the solid tumor;
(2) an increase in proliferation of immune cells in the subject;
(3) an increased amount of activated immune cells in the subject;
(4) an increased expression level in the subject, optionally in a sample of solid tumor tissue from the subject, of a gene associated with (a) a cytokine-cytokine receptor interaction, (b) a chemokine signaling pathway, (c) a cell adhesion molecule, or (d) any combination of (a)-(c);
(5) a reduction in the amount, growth, rate of growth, or spread, of solid tumor cells and/or tissue; or
(6) any combination of (1)-(5).

16. The method of claim 1 , wherein the CAR of the T cell comprises a transmembrane component disposed between an extracellular component comprising a binding domain and an intracellular component comprising an effector domain, wherein the transmembrane component of the CAR is from CD28 and the intracellular component effector domain comprises a 4-1BB signaling domain and a CD35 domain.

17. The method of claim 1 , wherein the T cell comprises a CD4+ T cell and a CD8+ T cell.

18. The method of claim 17 , wherein the subject is administered a unit dose comprising about a 1:1 ratio of CAR-encoding CD4+ T cells and CAR-encoding CD8+ T cells.

19. A kit, comprising:
(i) any one or more of (a)-(d):
(a) a T cell comprising a heterologous polynucleotide that encodes a chimeric antigen receptor (CAR) that specifically binds to a ROR1 cell-surface antigen expressed by or associated with a solid tumor;
(b) an antibody or antigen-binding fragment thereof that specifically binds to and is an inhibitor of PD-1 or PD-L1;
(c) oxaliplatin, or an active metabolite or derivative thereof; and
(d) cyclophosphamide, and

(ii) instructions for performing a method according to claim 1 .

20. The method of claim 5 , wherein, the method comprise

Assignees

• Fred Hutchinson Cancer Center

Inventors

• Riddell Stanley R
• Srivastava Shivani

Classifications

• A61K40/421

  Immunoglobulin superfamily · 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

• A61K2239/49

  Breast · CPC title

• A61K2239/48

  Blood cells, e.g. leukemia or lymphoma · CPC title