Methods related to toxicity and response associated with cell therapy for treating b cell malignancies

A method of selecting a subject for treatment with a cell therapy, wherein the method comprises:

• assessing one or more parameters of disease burden selected from among lymph node tumor burden, blood tumor burden and the ratio of blood tumor burden to lymph node tumor burden, in a subject having a chronic lymphoblastic leukemia (CLL) or a small lymphocytic lymphoma (SLL) that is a candidate for treatment with a cell therapy, said cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), wherein the parameter is assessed from the subject prior to administering the cell therapy;
• and
• comparing, individually, the value of the one or more parameters to a threshold level for the respective parameter, wherein:
• (1) if (a) the lymph node tumor burden is at or above the threshold level for lymph node tumor burden;
• (b) the blood tumor burden is below the threshold level for blood tumor burden;
• and/or (c) the ratio of blood tumor burden to lymph node tumor burden is below the threshold level for the ratio, selecting the subject for:
• (i) administration of the cell therapy at a reduced dose;
• (ii) administration of an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of the neurotoxicity;
• (iii) administration of the cell therapy that is carried out or is specified to be carried out in an in-patient setting and/or with admission to a hospital for one or more days;
• and/or
• (iv) administration of an alternative treatment other than the cell therapy for treating the CLL or SLL;
• or
• (2) if (a) the lymph node tumor burden is below the threshold level for tumor burden;
• (b) the blood tumor burden is at or above the threshold level for blood tumor burden;
• and/or (c) the ratio of blood tumor burden to lymph node tumor burden is above the threshold level for the ratio, selecting the subject for:
• (i) administration of the cell therapy, optionally wherein:
• (a) the subject is not administered an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of a toxicity unless or until the subjects exhibits a sign or symptom of a toxicity, optionally at or after the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic;
• and/or
• (b) the administration of the cell therapy and any follow-up is carried out on an outpatient basis and/or without admitting the subject to a hospital and/or without an overnight stay at a hospital and/or without requiring admission to or an overnight stay at a hospital, optionally unless or until the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic.

A method of determining the risk of developing a toxicity after administration of a cell therapy, the method comprising:

• assaying a biological sample for the level, amount or concentration of tumor necrosis factor (TNF) and/or interleukin-16 (IL-16), wherein the biological sample is from a subject having a chronic lymphoblastic leukemia (CLL) or a small lymphocytic lymphoma (SLL) that is a candidate for treatment with a cell therapy, said cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), wherein the biological sample is obtained from the subject prior to administering the cell therapy or prior to peak CAR+ T cell expansion and/or within at or about 11 days after the initiation of administration of the cell therapy;
• and
• comparing, individually, the level, amount or concentration of TNF and/or IL-16 to a threshold level for each, wherein:
• the threshold level for TNF is a value between at or about 7 pg/mL and at or about 25 pg/mL;
• and/or
• the threshold level for IL-16 is a value between at or about 400 pg/mL and at or about 1000 pg/mL;
• and
• (1) if the level, amount or concentration of TNF and/or IL-16 is at or above the respective threshold level, identifying the subject as at risk for developing a neurotoxicity following administration of the cell therapy;
• or
• (2) if the level, amount or concentration of TNF and/or IL-16 is below the respective threshold level, identifying the subject as not at risk for developing a neurotoxicity following administration of the cell therapy.

A method of assessing likelihood of a response to a cell therapy, the method comprising:

• assessing the level, amount or concentration of vascular endothelial growth factor C (VEGFC) and/or vascular endothelial growth factor receptor 1 (VEGFR1) in a biological sample, wherein the biological sample is from a subject having a chronic lymphoblastic leukemia (CLL) or a small lymphocytic lymphoma (SLL) that is a candidate for treatment with a cell therapy, said cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), wherein the biological sample is obtained from the subject prior to administering the cell therapy;
• and
• comparing, individually, the level, amount or concentration of the VEGFC and/or VEGFR1 in the sample to a threshold level;
• wherein:
• (1) if the level, amount or concentration of VEGFC and/or VEGFR1 is below the respective threshold level, identifying the subject as having a high likelihood of achieving a response to the cell therapy;
• or
• (2) if the level, amount or concentration of VEGFC and/or VEGFR1 is at or above the respective threshold level, identifying the subject as having a low likelihood of achieving a response to the cell therapy.

A method of selecting a subject for treatment with a cell therapy, wherein the method comprises:

• assessing the level, amount or concentration of vascular endothelial growth factor C (VEGFC) and/or vascular endothelial growth factor receptor 1 (VEGFR1) in a biological sample, wherein the biological sample is from a subject having a chronic lymphoblastic leukemia (CLL) or a small lymphocytic lymphoma (SLL) that is a candidate for treatment with a cell therapy, said cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), wherein the biological sample is obtained from the subject prior to administering the cell therapy;
• and
• selecting a subject who is likely to respond to treatment based on the results of determining a likelihood that a subject will achieve a response to the cell therapy by comparing, individually, the level, amount or concentration of the VEGFC and/or VEGFR1 in the sample to a threshold level for each;
• wherein:
• (1) if the level, amount or concentration of VEGFC and/or VEGFR1 is below the respective threshold level, identifying the subject as having a high likelihood of achieving a response to the cell therapy;
• or
• (2) if the level, amount or concentration of VEGFC and/or VEGFR1 is at or above the respective threshold level, identifying the subject as having a low likelihood of achieving a response to the cell therapy.

A method for treatment, wherein the method comprises:

• (a) selecting a subject who is likely to respond to treatment based on the results of determining a likelihood that a subject will achieve a response to the cell therapy by comparing, individually, the level, amount or concentration of vascular endothelial growth factor C (VEGFC) and/or vascular endothelial growth factor receptor 1 (VEGFR1) in a biological sample, to a threshold level for each, wherein:
• (1) if the level, amount or concentration of VEGFC and/or VEGFR1 is below the respective threshold level, identifying the subject as having a high likelihood of achieving a response to the cell therapy;
• or
• (2) if the level, amount or concentration of VEGFC and/or VEGFR1 is at or above the respective threshold level, identifying the subject as having a low likelihood of achieving a response to the cell therapy;
• wherein the biological sample is from a subject having a CLL or a SLL that is a candidate for treatment with a cell therapy, said cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), wherein the biological sample is obtained from the subject prior to administering the cell therapy and/or the subject does not comprise the T cells expressing the CAR;
• and
• (b) administering the cell therapy to a subject selected for treatment.