Methods and compositions for dosing in adoptive cell therapy

Patent metadata

Field	Value
Publication number	US-10507219-B2
Application number	US-201514918451-A
Country	US
Kind code	B2
Filing date	Oct 20, 2015
Priority date	Oct 20, 2014
Publication date	Dec 17, 2019
Grant date	Dec 17, 2019

Abstract

Provided are methods for administering multiple doses of cells, such as T cells, to subjects for cell therapy. Also provided are compositions and articles of manufacture for use in the methods. The cells generally express recombinant receptors such as chimeric receptors, e.g., chimeric antigen receptors (CARs) or other transgenic receptors such as T cell receptors (TCRs). The methods generally involve administering a first and at least one consecutive dose of the cells. Timing of the doses relative to one another, and/or size of the doses, in some embodiments provide various advantages such as lower or reduced toxicity and improved efficacy, for example, due to increased exposure of the subject to the administered cells. In some embodiments, the first dose is a relatively low dose, such as one that reduces tumor or disease burden, thereby improving the efficacy of consecutive or subsequent doses, and the consecutive dose is a consolidating dose.

First claim

The invention claimed is:

1. A method of treatment, comprising:
administering a consecutive dose of T cells expressing a chimeric antigen receptor (CAR) that binds CD19 to a subject having a hematologic malignancy expressing CD19 and that has been previously administered a first dose of T cells expressing a CAR that binds CD19, said first dose comprising no more than about 1×10 6 of the CAR-expressing cells per kilogram body weight of the subject, no more than about 1×10 8 of the CAR-expressing cells, or no more than about 1×10 8 of the CAR-expressing cells/m 2 of the subject, wherein:
the CAR expressed by the cells in the first dose and the CAR expressed by the cells of the consecutive dose each, individually, comprises (i) an antigen binding domain that binds CD19; and (ii) an intracellular signaling region comprising an immunoreceptor tyrosine-based activation motif (ITAM) and a T cell co-stimulatory signaling domain; and
the consecutive dose of cells is administered at a point in time that is at least or more than about 14 days after and less than about 28 days after initiation of the administration of the first dose of cells.

2. The method of treatment of claim 1 , further comprising administering to the subject the first dose of cells.

3. The method of claim 1 , wherein, at the time of the administration of the consecutive dose:
(i) the serum level in the subject of a factor indicative of cytokine release syndrome (CRS) is no more than about 50 times that in the subject immediately prior to the administration of the first dose; and/or
(ii) the subject does not exhibit grade 3 or higher neurotoxicity; and/or
(iii) a CRS-related outcome or symptom of neurotoxicity in the subject has reached a peak level and begun to decline following the administration of the first dose; and/or
(iv) the subject does not exhibit a detectable humoral or cell-mediated immune response against the CAR expressed by the cells of said first dose.

4. The method of claim 1 , wherein prior to the administration of the first dose of cells, said subject had not received a dose of cells expressing the CAR expressed by the cells in the first dose.

5. The method of claim 1 , wherein the CAR expressed by the cells in the first dose and the CAR expressed by the cells in the consecutive dose contain the same antigen-binding domain.

6. The method of claim 1 , wherein:
the first and/or consecutive dose of cells comprises cells in an amount sufficient for reduction in burden of the hematologic malignancy in the subject; and/or
the administration of the consecutive dose leads to a reduction in burden of the hematologic malignancy in the subject.

7. The method of claim 1 , wherein:
if at a time just prior to initiation of administration of the consecutive dose of cells the subject exhibits morphologic disease, the consecutive dose comprises less than or about the same number of CAR-expressing cells as the number of CAR-expressing cells in the first dose; and
if at a time just prior to initiation of administration of the consecutive dose of cells the subject exhibits minimum residual disease, the consecutive dose comprises an increased number of CAR-expressing cells as compared to the first dose.

8. The method of claim 1 , wherein the consecutive dose comprises an increased number of CAR-expressing cells as compared to the first dose.

9. The method of claim 1 , wherein the number of CAR-expressing cells administered in the consecutive dose comprises between about 2×10 6 per kilogram (kg) body weight and about 6×10 6 /kg, inclusive.

10. The method of claim 9 , wherein the number of cells administered in the first dose is between about 0.5×10 6 cells/kg body weight of the subject and 3×10 6 cells/kg.

11. The method of claim 1 , further comprising administering a chemotherapeutic agent prior to the administration of the consecutive dose of cells.

12. The method of claim 1 , wherein the subject has been previously treated with a chemotherapeutic agent prior to administration of the first dose and/or prior to the administration of the consecutive dose.

13. The method of claim 11 , wherein the chemotherapeutic agent comprises an agent selected from the group consisting of cyclophosphamide and fludarabine.

14. The method of claim 11 , wherein the chemotherapeutic agent comprises a combination of cyclophosphamide and fludarabine.

15. The method of claim 12 , wherein the chemotherapeutic agent comprises an agent selected from the group consisting of cyclophosphamide and fludarabine.

16. The method of claim 12 , wherein the chemotherapeutic agent comprises a combination of cyclophosphamide and fludarabine.

17. The method of claim 1 , wherein:
the subject has been previously treated with a chemotherapeutic agent prior to the initiation of administration of the first dose; or
the subject has been previously treated with a chemotherapeutic agent subsequently to the initiation of the administration of the first dose, and prior to the initiation of administration of the consecutive dose.

18. The method of claim 2 , further comprising administering a chemotherapeutic agent prior to the administration of the first dose of cells.

19. The method of claim 1 , wherein the hematologic malignancy is a leukemia or lymphoma.

20. The method of claim 1 , wherein the hematologic malignancy is acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or non-Hodgkin lymphoma (NHL).

21. The method of claim 1 , wherein the number of CAR-expressing cells administered in the first dose is at or about or no more than at or about 1×10 6 per kilogram of the subject and/or the number of CAR-expressing cells administered in the consecutive dose is at or about 3×10 6 per kilogram of the subject.

22. The method of claim 1 , wherein the number of cells administered in the consecutive dose comprises 1×10 6 CAR-expressing cells or at least 1×10 6 CAR-expressing cells.

23. The method of claim 1 , wherein:
the number of cells administered in the first dose is between 1×10 6 and 1×10 8 CAR-expressing cells, inclusive.

24. The method of claim 1 , wherein the number of cells administered in the consecutive dose comprises 1×10 7 CAR-expressing cells or at least 1×10 7 CAR-expressing cells.

25. The method of claim 1 , wherein the number of cells administered in the consecutive dose comprises 1×10 8 CAR-expressing cells or at least 1×10 8 CAR-expressing cells.

26. The method of claim 8 , wherein:
the number of cells administered in the first dose is between 1×10 6 and 1×10 8 CAR-expressing cells.

27. The method of claim 26 , wherein the number of cells administered in the consecutive dose comprises 1×10 7 CAR-expressing cells or at least 1×10 7 CAR-expressing cells.

28. The method of claim 26 , wherein the number of cells administered in the consecutive dose comprises 1×10 8 CAR-expressing cells or at least 1×10 8 CAR-expressing cells.

29. The method of claim 1 , wherein the T cell co-stimulatory signaling domain is a signaling domain of 4-1BB or CD28.

30. The method of claim 1 , wherein the CAR expressed by the cells in the consecutive dose is identical to the CAR expressed by the cells in the first dose.

31. A method of treatment, comprising:
administering to a subject having a hematologic malignancy expressing CD19 a first dose o

Assignees

• Juno Therapeutics Inc

Inventors

• Gilbert Mark J

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2039/515

  Animal cells · CPC title

• C07K16/2803

  against the immunoglobulin superfamily · CPC title