BIOMARKERS PREDICTIVE OF CYTOKINE RELEASE SYNDROME

• US 20180252727A1
• Filed: 09/02/2016
• Published: 09/06/2018
• Est. Priority Date: 09/03/2015
• Status: Active Grant

• Current Assignee: Novartis Ag, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Inventors: Garfall, Alfred, Ganetsky, Alex, Gill, Saar, Lacey, Simon, Melenhorst, Jan J., Teachey, David
• Granted Patent: US 11,747,346 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 2239/48 Blood cells, e.g. leukemia or lymphoma
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• 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 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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 39/464412 CD19 or B4
• CPC Class Codes: A61K 39/464417 Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/7051 T-cell receptor (TcR)-CD3 complex
• 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 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2319/02 containing a signal sequence
• CPC Class Codes: C07K 2319/03 containing a transmembrane segment
• CPC Class Codes: C12Q 1/6876 Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/158 : Expression markers
• CPC Class Codes: G01N 2800/24 : Immunology or allergic disorders
• CPC Class Codes: G01N 2800/50 : Determining the risk of developing a disease
• CPC Class Codes: G01N 2800/52 : Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/7095 : Inflammation
• CPC Class Codes: G01N 33/5047 : Cells of the immune system
• CPC Class Codes: G01N 33/6863 : Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: G01N 33/6866 : Interferon
• CPC Class Codes: G01N 33/6869 : Interleukin
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere

Abstract

The present disclosure relates to the identification and use of biomarkers (e.g., analytes, analyte profiles, or markers (e.g., gene expression and/or protein expression profiles)) with clinical relevance to cytokine release syndrome (CRS).

Claims

1. A method of evaluating, e.g., predicting, a subject'"'"'s risk of developing cytokine release syndrome (CRS), e.g., severe CRS, comprising:

acquiring a CRS risk status for the subject, e.g., in response to a CAR-expressing cell therapy (e.g., a CAR19-expressing cell therapy), wherein said CRS risk status comprises a measure of one, two, three, four, five, six, seven, eight, nine, ten, or more (all) of the following;

(i) the level or activity of soluble gp130 (sgp130) or interferon-gamma (IFN-g), or a combination thereof, in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or pediatric subject;

(ii) the level or activity of sgp130, IFN-gamma, or IL1Ra, or a combination thereof (e.g., a combination of any two or all three of sgp130, IFN-gamma, and IL1Ra), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or pediatric subject;

(iii) the level or activity of sgp130 or IFN-gamma or a combination thereof, in a sample (e.g., a blood sample), and the level of bone marrow disease in the subject, e.g., wherein the subject is a pediatric subject;

(iv) the level or activity of sgp130, IFN-gamma, or MIP1-alpha, or a combination thereof (e.g., a combination of any two or all three of sgp130, IFN-gamma, and MIP1-alpha), in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(v) the level or activity of sgp130, MCP1, or eotaxin, or a combination thereof (e.g., a combination of any two or all three of sgp130, MCP1, or eotaxin), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or a pediatric subject;

(vi) the level or activity of IL2, eotaxin, or sgp130, or a combination thereof (e.g., a combination of any two or all three of IL2, eotaxin, or sgp130), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or a pediatric subject;

(vii) the level or activity of IFN-gamma, IL2, or eotaxin, or a combination thereof (e.g., a combination of any two or all three of IFN-gamma, IL2, or eotaxin), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(viii) the level or activity of IL10 and the level of disease burden in the subject, or a combination thereof in a subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(ix) the level or activity of IFN-gamma or IL-13, or a combination thereof, in the subject, e.g., wherein the subject is a pediatric subject;

(x) the level or activity of IFN-gamma, IL-13, or MIP1-alpha, or a combination thereof (e.g., a combination of any two or all three of IFN-gamma, IL-13, and MIP1-alpha), in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

or

(xi) the level or activity of IFN-gamma or MIP1-alpha, or a combination thereof, in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject

wherein the CRS risk status is indicative of the subject'"'"'s risk for developing CRS, e.g., severe CRS.

3. The method of claim 1 or 2, which further comprises, responsive to a determination of the CRS risk status, performing one, two, or more (all) of:

identifying the subject as being at high risk of developing severe CRS or at low risk of developing severe CRS;

administering an altered dosing of the CAR-expressing cell therapy;

altering the schedule or time course of the CAR-expressing cell therapy;

administering a therapy to treat CRS, e.g., a therapy chosen from one or more of;

an IL-6 inhibitor (e.g., tocilizumab), a vasoactive medication, an immunosuppressive agent, a corticosteroid, or mechanical ventilation;

or

administering an alternative therapy, e.g., for a subject at high risk of developing severe CRS, e.g., a standard of care for a particular cancer type.

6. The method or composition for use of any of the preceding claims, wherein the CRS risk status is indicative of whether the subject is at high risk or low risk of developing severe CRS.

7. The method or composition for use of any of the preceding claims, wherein the CRS is of clinical grade 1-3, or the severe CRS is of clinical grade 4-5.

8. The method of any of claim 1-3, 6, or 7, which is performed on a subject that does not have a symptom (e.g., a clinical symptom) of CRS, e.g., one or more of low blood pressure or a fever.

9. The method of any of claim 1-3, 6, or 7, which is performed on a subject that does not have a symptom (e.g., a clinical symptom) of severe CRS, e.g., one or more of grade 4 organ toxicity or need for mechanical ventilation.

10. The method or composition for use of any of the preceding claims, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of sgp130 or IFN-gamma or a combination thereof (e.g., in a sample, e.g., a blood sample) relative to a reference, e.g., compared to a subject at low risk of severe CRS or compared to a control level or activity.

11. The method or composition for use of claim 10, wherein the subject is an adult or pediatric subject.

12. The method or composition for use of any of the preceding claims, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of sgp130, a greater level or activity of IFN-gamma, or a lower level or activity of IL1Ra, or a combination thereof (e.g., in a sample, e.g., a blood sample) relative to a reference, e.g., compared to a subject at low risk of severe CRS or compared to a control level or activity.

13. The method or composition for use of claim 12, wherein the subject is an adult or pediatric subject.

14. The method or composition for use of claim 12 or 13, wherein the subject at high risk of severe CRS is identified as having:

a greater level or activity of sgp130 and a greater level or activity of IFN-gamma;

a greater level or activity of sgp130 and a lower level or activity of IL1Ra;

a greater level or activity of IFN-gamma and a lower level or activity of IL1Ra;

or

a greater level or activity of sgp130, a greater level or activity of IFN-gamma, and a lower level or activity of IL1Ra,

compared to a reference, e.g., a subject at low risk of severe CRS or a control level or activity.

15. The method or composition for use of any of claims 1-10, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of sgp130 or a greater level or activity of IFN-gamma or a combination thereof, and a greater level of bone marrow disease, in the subject (e.g., in a sample, e.g., a blood sample) relative to a reference, e.g., compared to a subject at low risk of severe CRS or compared to a control level or activity.

16. The method or composition for use of claim 15, wherein the subject is a pediatric subject.

17. The method or composition for use of claim 15 or 16, wherein the subject is identified as having a greater level of:

sgp130 and IFN-gamma;

sgp130 and bone marrow disease;

IFN-gamma and bone marrow disease;

or

sgp130, IFN-gamma bone, and marrow disease,

compared to a reference, e.g., a subject at low risk of severe CRS or a control level or activity.

18. The method or composition for use of any of claims 1-10, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of sgp130, a greater level or activity of IFN-gamma, or a lower level or activity of MIP1-alpha, or a combination thereof (e.g., in a sample, e.g., a blood sample) compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

19. The method or composition for use of claim 18, wherein the subject is a pediatric subject.

20. The method or composition for use of claim 18 or 19, wherein a subject at high risk of severe CRS is identified as having:

a greater level or activity of sgp130 and a greater level or activity of IFN-gamma;

a greater level or activity of sgp130 and a lower level or activity of MIP1-alpha;

a greater level or activity of IFN-gamma and a lower level or activity of MIP1-alpha;

or

a greater level or activity of sgp130, a greater level or activity of IFN-gamma, and a lower level or activity of MIP1-alpha;

compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

21. The method or composition for use of any of claims 1-10, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of sgp130, a greater level or activity of MCP1, or a lower level or activity of eotaxin, or a combination thereof (e.g., in a sample, e.g., a blood sample) compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

22. The method or composition for use of claim 21, wherein a subject at high risk of severe CRS is identified as having:

a greater level or activity of sgp130 and a greater level or activity of MCP1;

a greater level or activity of sgp130 and a lower level or activity of eotaxin;

a greater level or activity of MCP1 and a lower level or activity of eotaxin;

or

a greater level or activity of sgp130, a greater level or activity of MCP1, and a lower level or activity of eotaxin;

compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

23. The method or composition for use of any of claims 1-10, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of IL-2, a lower level or activity of eotaxin, or a greater level or activity of sgp130, or a combination thereof (e.g., in a sample, e.g., a blood sample) compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

24. The method or composition for use of claim 23, wherein a subject at high risk of severe CRS is identified as having:

a greater level or activity of IL-2 and a lower level or activity of eotaxin;

a greater level or activity of IL-2 and a greater level or activity of sgp130;

a lower level or activity of eotaxin and a greater level or activity of sgp130;

or

a greater level or activity of IL-2, a lower level or activity of eotaxin, and a greater level or activity of sgp130;

compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

25. The method or composition for use of any of claims 1-10, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of IFN-gamma, a greater level or activity of IL-2, or a lower level or activity of eotaxin, or a combination thereof (e.g., in a sample, e.g., a blood sample) compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

26. The method of claim 25, wherein the subject is a pediatric subject.

27. The method of claim 25 or 26, wherein a subject at high risk of severe CRS is identified as having:

a greater level or activity of IFN-gamma and a greater level or activity of IL-2;

a greater level or activity of IFN-gamma and a lower level or activity of eotaxin;

a greater level or activity of IL-2 and a lower level or activity of eotaxin;

or

a greater level or activity of IFN-gamma, a greater level or activity of IL-2, and a lower level or activity of eotaxin;

compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

28. The method or composition for use of any of claims 1-10, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of IL10 or a greater level of disease burden, or a combination thereof (e.g., in a sample, e.g., a blood sample) compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

29. The method or composition for use of claim 28, wherein the subject is a pediatric subject.

30. The method or composition for use of any of claims 1-10, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of IFN-gamma or a lower level of IL-13, or a combination thereof (e.g., in a sample, e.g., a blood sample) compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

31. The method or composition for use of claim 30, wherein the subject is a pediatric subject.

32. The method or composition for use of any of claims 1-10, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of IFN-gamma, a lower level or activity of IL-13, a lower level or activity of MIP1-alpha, or a combination thereof (e.g., in a sample, e.g., a blood sample) compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

33. The method or composition for use of claim 32, wherein the subject is a pediatric subject.

34. The method or composition for use of claim 32 or 33, wherein a subject at high risk of severe CRS is identified as having:

a greater level or activity of IFN-gamma and a lower level or activity of IL-13;

a greater level or activity of IFN-gamma and a lower level or activity of MIP1-alpha;

a lower level or activity of IL-13 and a lower level or activity of MIP1-alpha;

a greater level or activity of IFN-gamma, a lower level or activity of IL-13, and a lower level or activity of MIP1-alpha;

or

compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

35. The method or composition for use of any of the preceding claims, wherein the measure of one or more of (i)-(xi) evaluates one or more of mRNA levels or protein levels.

36. The method or composition for use of any of the preceding claims, further comprising acquiring a measure of the level or activity of one, two, three, four, five, ten, twenty or more of a cytokine or cytokine receptor chosen from sTNFR2, IP10, sIL1R2, sTNFR1, M1G, VEGF, sILR1, TNFα

, IFNα

, GCSF, sRAGE, IL4, IL10, IL1R1, IFN-γ

, IL6, IL8, sIL2Rα

, sgp130, sIL6R, MCP1, MIP1α

, MIP1β

, or GM-CSF, or a combination thereof, in the subject, e.g., in a sample (e.g., a blood sample) from the subject.

37. The method or composition for use of any of the preceding claims, wherein a subject at high risk of severe CRS is identified as having a greater level or activity of one or more (e.g., two, three, four, five, ten, fifteen, twenty, or all) of a cytokine or cytokine receptor chosen from sTNFR2, IP10, sIL1R2, sTNFR1, M1G, VEGF, sILR1, TNFα

, IFNα

, GCSF, sRAGE, IL4, IL10, IL1R1, IFN-γ

, IL6, IL8, sIL2Rα

, sgp130, sIL6R, MCP1, MIP1α

, MIP1β

, or GM-CSF or a combination thereof, compared to a reference, e.g., a subject at low risk of severe CRS or compared to a control level or activity.

38. The method of any of the preceding claims, further comprising determining the level of C-reactive protein (CRP) in a sample (e.g., a blood sample) from the subject.

39. The method of claim 38, wherein a subject at low risk of severe CRS is identified as having a CRP level of less than 7 mg/dL (e.g., 7, 6.8, 6, 5, 4, 3, 2, 1 mg/dL or less).

40. The method or composition for use of any of the preceding claims, wherein a subject at high risk of severe CRS is identified as having a greater level of CRP in a sample (e.g., a blood sample) compared to a subject at low risk of severe CRS or compared to a control level or activity.

41. The method or composition for use of any of claims 37-40, wherein the greater level or activity is at least 2-fold greater (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 100, 500, 1000-fold or more greater) compared to a subject at low risk of severe CRS or compared to a control level or activity.

42. The method of any of the preceding claims, further comprising the step of selecting a CAR-expressing cell therapy for the subject, based on the CRS risk status acquired.

43. The method of claim 42, wherein the CRS risk status acquired is that the subject is at high risk of severe CRS, and the therapy suggested is a subsequent (e.g., second, third, or fourth) dose of CAR-expressing cells that is at a lower dose than the previous dose of CAR-expressing cell therapy administered to the subject.

44. The method of claim 42, wherein the CRS risk status acquired is that the subject is at high risk of severe CRS, and the therapy suggested is a subsequent (e.g., second, third, or fourth) dose of CAR-expressing cells that comprises a different CAR or different cell type than the previous CAR-expressing cell therapy administered to the subject.

45. The method or composition for use of any of the preceding claims, wherein the CAR-expressing cell therapy comprises a plurality of CAR-expressing immune effector cells, e.g., a CAR19 therapy (e.g., CTL019 therapy).

46. The method or composition for use of any of the preceding claims, wherein the cancer or hematological cancer is associated with CD19 expression.

47. The method or composition for use of any of the preceding claims, wherein the cancer or hematological cancer is selected from the group consisting of B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), B cell promyelocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt'"'"'s lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin'"'"'s lymphoma, Hodgkin'"'"'s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, and Waldenstrom macroglobulinemia.

48. The method or composition for use of any of the preceding claims, wherein the subject, e.g., a sample from the subject, is evaluated while receiving the CAR-expressing cell therapy or wherein the subject, e.g., a sample from the subject, is evaluating after receiving the CAR-expressing cell therapy.

49. The method or composition for use of any of the preceding claims, wherein the subject, e.g., a sample from the subject, is evaluated 10 days or less (e.g., 1-10 days, 1-9 days, 1-8 days, 1-7 days, 1-6 days, 1-5 days, 1-4 days, 1-3 days, or 1-2 days, 5 days, 3 days, 2 days, 1 day or less) after infusion with the CAR-expressing cell therapy.

50. The method or composition for use of any of the preceding claims, wherein the subject is a human.

51. The method or composition for use of any of the preceding claims, wherein the subject is an adult subject or a pediatric subject.

53. The method, or composition for use, or kit of any of the preceding claims, wherein the CAR-expressing cell is a T cell or an NK cell.

54. The method, or composition for use, or kit of any of the preceding claims, wherein if the subject is identified a being at risk for severe CRS and is identified as being sensitive to an IL6 receptor inhibitor, said subject is treated with an IL6 receptor inhibitor such as tocilizumab.

55. The method, or composition for use, or kit of any of the preceding claims, wherein if the subject is identified a being at risk for severe CRS and is identified as having reduced sensitivity to an IL6 receptor inhibitor, said subject is treated with a CRS therapy other than an IL6 receptor inhibitor, e.g., other than tocilizumab.

2. A method for treating a subject having a cancer, e.g., a hematological cancer, comprising:

administering to the subject a therapeutically effective dose of a CAR-expressing cell therapy, e.g., a CAR19 therapy; and

acquiring a CRS risk status for the subject, wherein said CRS risk status comprises a measure of one, two, three, four, five, six, seven, eight, nine, ten, or more (all) of the following;

(i) the level or activity of sgp130 or IFN-gamma or a combination thereof, in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or pediatric subject;

(ii) the level or activity of sgp130, IFN-gamma, or IL1Ra, or a combination thereof (e.g., a combination of any two or all three of sgp130, IFN-gamma, and IL1Ra), in the subject, e.g., a sample (e.g., a blood sample), e.g., wherein the subject is an adult or pediatric subject;

(iii) the level or activity of sgp130 or IFN-gamma or a combination thereof, in the subject, e.g., in a sample (e.g., a blood sample), and the level of bone marrow disease in the subject, e.g., wherein the subject is a pediatric subject;

(iv) the level or activity of sgp130, IFN-gamma, or MIP1-alpha, or a combination thereof (e.g., a combination of any two or all three of sgp130, IFN-gamma, and MIP1-alpha), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(v) the level or activity of sgp130, MCP1, or eotaxin, or a combination thereof (e.g., a combination of any two or all three of sgp130, MCP1, or eotaxin), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or a pediatric subject;

(vi) the level or activity of IL2, eotaxin, or sgp130, or a combination thereof (e.g., a combination of any two or all three of IL2, eotaxin, or sgp130), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or a pediatric subject;

(vii) the level or activity of IFN-gamma, IL2, or eotaxin, or a combination thereof (e.g., a combination of any two or all three of IFN-gamma, IL2, or eotaxin), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(viii) the level or activity of IL10 and the level of disease burden in the subject, or a combination thereof in a subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(ix) the level or activity of IFN-gamma or IL-13, or a combination thereof, in the subject, e.g., wherein the subject is a pediatric subject;

(x) the level or activity of IFN-gamma, IL-13, or MIP1-alpha, or a combination thereof (e.g., a combination of any two or all three of IFN-gamma, IL-13, and MIP1-alpha), in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

or

(xi) the level or activity of IFN-gamma or MIP1-alpha, or a combination thereof, in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

wherein the CRS risk status is indicative of the subject'"'"'s risk for developing CRS, e.g., severe CRS.

4. A CAR-expressing cell therapy, e.g., a CAR19 therapy, for use in a subject having a cancer, e.g., a hematological cancer, wherein the subject is identified as having a CRS risk status indicative of the subject'"'"'s risk for developing CRS, e.g., severe CRS, wherein said CRS risk status comprises a measure of one, two, three, four, five, six, seven, eight, nine, ten, or more (all) of the following:

(i) the level or activity of sgp130 or IFN-gamma or a combination thereof, in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or pediatric subject;

(ii) the level or activity of sgp130, IFN-gamma, or IL1Ra, or a combination thereof (e.g., a combination of any two or all three of sgp130, IFN-gamma, and IL1Ra), in the subject, e.g., a sample (e.g., a blood sample), e.g., wherein the subject is an adult or pediatric subject;

(iii) the level or activity of sgp130 or IFN-gamma or a combination thereof, in the subject, e.g., in a sample (e.g., a blood sample), and the level of bone marrow disease in the subject, e.g., wherein the subject is a pediatric subject;

(iv) the level or activity of sgp130, IFN-gamma, or MIP1-alpha, or a combination thereof (e.g., a combination of any two or all three of sgp130, IFN-gamma, and MIP1-alpha), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(v) the level or activity of sgp130, MCP1, or eotaxin, or a combination thereof (e.g., a combination of any two or all three of sgp130, MCP1, or eotaxin), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or a pediatric subject;

(vi) the level or activity of IL2, eotaxin, or sgp130, or a combination thereof (e.g., a combination of any two or all three of IL2, eotaxin, or sgp130), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is an adult or a pediatric subject;

(vii) the level or activity of IFN-gamma, IL2, or eotaxin, or a combination thereof (e.g., a combination of any two or all three of IFN-gamma, IL2, or eotaxin), in the subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(viii) the level or activity of IL10 and the level of disease burden in the subject, or a combination thereof in a subject, e.g., in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

(ix) the level or activity of IFN-gamma or IL-13, or a combination thereof, in the subject, e.g., wherein the subject is a pediatric subject;

(x) the level or activity of IFN-gamma, IL-13, or MIP1-alpha, or a combination thereof (e.g., a combination of any two or all three of IFN-gamma, IL-13, and MIP1-alpha), in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject;

or

(xi) the level or activity of IFN-gamma or MIP1-alpha, or a combination thereof, in a sample (e.g., a blood sample), e.g., wherein the subject is a pediatric subject.

5. The composition for use of claim 4, wherein one, two, or more (all) of:

responsive to a determination of the CRS risk status, the subject is identified as being at high risk of developing severe CRS or at low risk of developing severe CRS;

responsive to a determination of the CRS risk status, the subject is administered an altered dosing of the CAR-expressing cell therapy;

responsive to a determination of the CRS risk status, the schedule or time course of the CAR-expressing cell therapy is altered;

responsive to a determination of the CRS risk status, the subject is administered a therapy to treat CRS, e.g., a therapy chosen from one or more of;

an IL-6 inhibitor (e.g., tocilizumab), a vasoactive medication, an immunosuppressive agent, a corticosteroid, or mechanical ventilation;

or

responsive to a determination of the CRS risk status, the subject is administered an alternative therapy, e.g., for a subject at high risk of developing severe CRS, e.g., a standard of care for a particular cancer type.

52. A kit for evaluating, e.g., predicting, a subject'"'"'s risk of developing cytokine release syndrome (CRS), e.g., severe CRS, comprising:

a set of reagents that specifically detects the level or activity of one or more genes or proteins chosen from;

sgp130 and IFN-gamma;

sgp130, IFN-gamma, and IL1Ra;

sgp130, IFN-gamma, and MIP1-alpha;

sgp130, MCP1, and eotaxin;

IL2, eotaxin, and sgp130;

IFN-gamma, IL2, and eotaxin;

IFN-gamma and IL-13;

or

IFN-gamma, IL-13, and MIP1-alpha;

or a combination thereof; and

instructions for using said kit;

wherein said instructions for use provide that if one or more of the detected level or activity of IFN-gamma, sgp130, or MCP1 is greater than a reference value, and/or if one or more of the detected level or activity of IL-13, IL1Ra, MIP1alpha, or eoxtaxin is less than a reference value, the subject is more likely to develop CRS (e.g., severe CRS) than a subject having a detected level or activity at the reference value.

56. A method of distinguishing between CRS and sepsis in a subject, comprising acquiring a measure of one or more of the following:

(i) the level or activity of one or more of (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of) GM-CSF, HGF, IFN-γ

, IFN-α

, IL-10, IL-15, IL-5, IL-6, IL-8, IP-10, MCP1, MIG, MIP-1β

, sIL-2Rα

, sTNFRI, and sTNFRII, wherein a level or activity that is higher than a reference is indicative of CRS;

or

(ii) the level or activity of one or more of (e.g., 2, 3, 4, 5, 6, or all of) CD163, IL-1β

, sCD30, sIL-4R, sRAGE, sVEGFR-1, and sVEGFR-2, wherein a level or activity that is higher than a reference is indicative of sepsis.

57. A method of treating one or more of a neurological toxicity, CRS, or posterior reversible encephalopathy syndrome (PRES), comprising administering to a subject in need thereof a therapeutically effective amount of cyclophosphamide,

wherein the administration of cyclophosphamide is subsequent to a cell-based therapy for cancer, a CD19-inhibiting therapy, or a CD19-depleting therapy, or

wherein the subject has been previously treated with cell-based therapy for cancer, a CD19-inhibiting therapy, or a CD19-depleting therapy.

58. A method of evaluating, e.g., predicting, a subject'"'"'s responsiveness to an IL6 receptor inhibitor (e.g., tocilizumab), comprising evaluating the subject'"'"'s IL-6R genotype, wherein a genotype associated with low sIL-6R levels is indicative of sensitivity to the IL6 receptor inhibitor (e.g., tocilizumab).

59. A method of evaluating, e.g., predicting, a subject'"'"'s responsiveness to an IL6 receptor inhibitor (e.g., tocilizumab), comprising evaluating the subject'"'"'s sIL-6R level, wherein a sIL-6R level that is lower than a reference level is indicative of sensitivity to the IL6 receptor inhibitor (e.g., tocilizumab).

60. The method of claim 59, wherein evaluating the subject'"'"'s IL-6R genotype comprises determining the subject'"'"'s genotype at rs2228145.

61. The method of claim 59 or 60, wherein the subject (e.g., a subject identified as being sensitive to an IL6 receptor inhibitor such as tocilizumab) is treated with an IL6 receptor inhibitor such as tocilizumab, or the subject (e.g., a subject identified as having reduced sensitivity to an IL6 receptor inhibitor such as tocilizumab) is treated with a CRS therapy other than an IL6 receptor inhibitor, e.g., other than tocilizumab.