SUBSET-OPTIMIZED CHIMERIC ANTIGEN RECEPTOR-CONTAINING T-CELLS

• US 20170209492A1
• Filed: 07/31/2015
• Published: 07/27/2017
• Est. Priority Date: 07/31/2014
• Status: Active Application

• Current Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Guedan Carrio, Sonia, Posey, Avery D., Scholler, John, June, Carl H.
• Application Number:
  US15/327,794
• Publication Number:
  US 20170209492A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/5156 expressing foreign proteins
• CPC Class Codes: A61K 2039/5158 Antigen-pulsed cells, e.g. T-cells
• CPC Class Codes: A61K 2039/572 cytotoxic response
• CPC Class Codes: A61K 2239/22 Intracellular domain
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2239/48 Blood cells, e.g. leukemia or lymphoma
• CPC Class Codes: A61K 2239/54 Pancreas
• CPC Class Codes: A61K 2239/55 Lung
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 35/17 Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes when activated by a specific antigen A61K39/00
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/001104 Epidermal growth factor receptors [EGFR]
• CPC Class Codes: A61K 39/00111 Hepatocyte growth factor receptor [HGFR or c-met]
• CPC Class Codes: A61K 39/001112 CD19 or B4
• CPC Class Codes: A61K 39/001113 CD22, BL-CAM, siglec-2 or sialic acid- binding Ig-related lectin 2
• CPC Class Codes: A61K 39/001119 Receptors for interleukins [IL]
• CPC Class Codes: A61K 39/001124 CD20
• CPC Class Codes: A61K 39/001168 : Mesothelin [MSLN]
• CPC Class Codes: A61K 39/001186 : MAGE
• CPC Class Codes: A61K 39/001188 : NY-ESO
• CPC Class Codes: A61K 39/001195 : Prostate specific membrane antigen [PSMA]
• CPC Class Codes: A61K 39/39558 : against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/4611 : T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4631 : Chimeric Antigen Receptors [CAR]
• CPC Class Codes: A61K 39/464402 : Receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: A61K 39/464411 : Immunoglobulin superfamily
• CPC Class Codes: A61K 39/464412 : CD19 or B4
• CPC Class Codes: A61K 39/464468 : Mesothelin [MSLN]
• CPC Class Codes: C07K 14/70503 : Immunoglobulin superfamily
• CPC Class Codes: C07K 14/7051 : T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 14/70521 : CD28, CD152
• CPC Class Codes: C07K 14/70578 : NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 NGF-receptor C07K14/71, TNF-receptor C07K14/7151
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/03 : containing a transmembrane segment
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C07K 2319/74 : containing a fusion for binding to a cell surface receptor
• CPC Class Codes: C12N 2501/51 : B7 molecules, e.g. CD80, CD86, CD28 (ligand), CD152 (ligand)
• CPC Class Codes: C12N 2510/00 : Genetically modified cells
• CPC Class Codes: C12N 5/0637 : Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg
• CPC Class Codes: C12N 5/0638 : Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]

Abstract

This disclosure provides, for instance subset-optimized CART cells and related methods. For instance, the disclosure describes methods and compositions of CD4′ and CD8′ T cells that express CARs containing specific combinations of intracellular signaling domains can be used to increase persistence and anti-tumor activity of the infused CAR-expressing T cells for treating a subject having a disease, e.g., a cancer.

Claims

1-13. -13. (canceled)

14. A composition or set of compositions comprising one or more of the following components:

1) a CD4+ T cell comprising a CAR (the CAR^CD4+) comprising;

an antigen binding domain;

a transmembrane domain; and

an intracellular signaling domain; and

2) a CD8+ T cell comprising a CAR (the CAR^CD8+) comprising;

an antigen binding domain;

a transmembrane domain; and

an intracellular signaling domain; and

,

wherein the intracellular signaling domain of CAR^CD4+ and the intracellular signaling domain of CAR^CD8+ differ from one another.

15. The composition, or set of compositions, of claim 14, wherein the CAR^CD4+ comprises an ICOS domain, and wherein the CAR^CD8+ does not comprise an ICOS domain.

17. The composition, or set of compositions, of claim 14, further comprising:

3) a second CD8+ T cell comprising a CAR (the second CAR^CD8+) comprising;

an antigen binding domain;

a transmembrane domain; and

an intracellular signaling domain,

wherein the second CAR^CD8+ differs from the CAR^CD4+ and the CAR^CD8+, and wherein the second CAR^CD8+ does not comprise an ICOS signaling domain and comprises an intracellular signaling domain not present on the CAR^CD8+.

19. The composition, or set of compositions, of claim 14, which is a pharmaceutically acceptable composition or pharmaceutically acceptable set of compositions.

20. The composition, or set of compositions, of claim 14, wherein the CAR^CD4+ does not include a 4-1BB domain or a CD28 domain.

22. The composition, or set of compositions, of claim 14, wherein the CAR^CD4+ does not include a costimulatory domain other than the ICOS domain.

23. The composition, or set of compositions, of claim 14, wherein the CAR^CD4+ comprises a primary intracellular signaling domain, which is optionally a primary signal domain from Table 4, which is optionally a CD3zeta domain.

24. The composition, or set of compositions, of claim 14, wherein the CAR^CD4+ comprises a second costimulatory signaling domain, which is optionally from Table 5.

25. The composition, or set of compositions, of claim 14, wherein the CAR^CD8+ comprises a primary intracellular signaling domain which is optionally a primary signal domain from Table 4 which is optionally a CD3zeta domain and a costimulatory signaling domain other than ICOS which is optionally from Table 5.

26. The composition, or set of compositions, of claim 14, wherein the CAR^CD8+ comprises a second costimulatory signaling domain which is optionally from Table 5.

27. The composition, or set of compositions, of claim 14, wherein the CAR^CD8+ comprises a CD3zeta domain.

28. The composition, or set of compositions, of claim 14, wherein the CAR^CD8+ comprises a costimulatory signaling domain selected from 4-1BB or CD28.

29. The composition, or set of compositions, of claim 14, wherein at least 10, 20, 30, 40, 50, 60, 70, or 80% of the T cells in the composition are CD4+ T cells comprising a CAR^CD4+.

30. The composition, or set of compositions, of claim 14, wherein at least 10, 20, 30, 40, 50, 60, 70, or 80% of the T cells in the composition are CD8+ T cells comprising a CAR^CD8+.

31. The composition, or set of compositions, of claim 14, wherein the CD4+ cell is a Th17 polarized cell.

32. The composition, or set of compositions, of claim 14, wherein the CAR^CD4+ and the CAR^CD8+ each comprises an antibody variable domain, an scFv, a nanobody, or an antigen binding fragment thereof.

33. The composition, or set of compositions, of claim 14, wherein the CAR^CD4+ and the CAR^CD8+ each comprises an antigen binding domain specific for a tumor antigen selected from CD19, CD20, CD22, ROR1, mesothelin, CD33/IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRv111, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, or an antigen listed in Table 2, and any combination thereof.

35. The composition, or set of compositions, of claim 14, wherein the CAR^CD4+ and the CAR^CD8+ each comprises an antigen binding domain selected from Table 2.

40. The composition or set of compositions of claim 15, wherein the ICOS domain comprises the sequence of SEQ ID NO:

46.

42. A kit comprising one or more components of the composition, or set of compositions, of claim 14.

45. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the composition, or set of compositions, of claim 14.

46. The method of claim 45, wherein the CAR^CD4+ is an autologous T cell or an allogeneic T cell.

47. The method of claim 45, wherein the CAR^CD8+ is an autologous T cell or an allogeneic T cell.

16. (canceled)

18. (canceled)

21. (canceled)

34. (canceled)

36-39. -39. (canceled)

41. A kit comprising one, or more, or all of the following components:

1) a nucleic acid comprising sequence encoding a CAR^CD4+ comprising;

an antigen binding domain;

a transmembrane domain; and

an intracellular signaling domain; and

2) a nucleic acid comprising sequence encoding a CAR^CD8+ comprising;

an antigen binding domain;

a transmembrane domain; and

an intracellular signaling domain; and

,

wherein the intracellular signaling domain of CAR^CD4+ and the intracellular signaling domain of CAR^CD8+ differ from one another.

43. A method of making a composition comprising a CD4+ T cell comprising a CAR (a CAR^CD4+) and a CD8+ T cell comprising a CAR (a CAR^CD8+), the method comprising:

providing a CD4+ T cell comprising a CAR^CD4+, optionally by introducing a nucleic acid sequence that encodes a CAR^CD4+ into a CD4+ T cell;

providing a CD8+ T cell comprising a CAR^CD8+, optionally by introducing a nucleic acid sequence that encodes a CAR^CD8+ into a CD8+ T cell;

wherein,

the CAR^CD4+ comprises;

an antigen binding domain;

a transmembrane domain; and

an intracellular signaling domain; and

the CAR^CD8+ comprises;

an antigen binding domain;

a transmembrane domain; and

an intracellular signaling domain,

wherein the intracellular signaling domain of CAR^CD4+ and the intracellular signaling domain of CAR^CD4+ are different.

44. The method of claim 43, comprising:

a) providing a CD4+ T cell;

b) introducing a nucleic acid sequence that encodes a CAR^CD4+ into the CD4+ T cell to provide a CD4+ T cell comprising a CAR^CD4+;

c) providing a CD8+ T cell;

d) introducing a nucleic acid sequence that encodes a CAR^CD8+ into the CD8+ T cell to provide a CD8+ T cell comprising a CARcD8+.