Methods relating to toxicity and response associated with cell therapy for treating B-cell malignancies

Abstract

Methods are provided for determining the risk of toxicity (e.g., neurotoxicity) and / or likelihood of success of cell therapy. In some aspects, the methods generally involve assessing a parameter or biomarker (e.g., a blood analyte) associated with toxicity and / or success. In some aspects, the methods relate to adoptive cell therapy, which involves administering a dose of cells to treat a subject with a particular B-cell malignancy, e.g., chronic lymphocytic leukemia (CLL), such as relapsed or refractory CLL, or small lymphocytic lymphoma (SLL). Cells for adoptive cell therapy generally express a recombinant receptor, such as a chimeric antigen receptor (CAR). In some aspects, the methods can be used, for example, to identify or select subjects for treatment with cell therapy. TIFF2023504737000038.tif94128

Description

[Technical Field]

[0001] Cross - reference to related applications This application claims priority to U.S. Provisional Application No. 62 / 945,105, filed December 6, 2019, entitled "METHODS RELATED TO TOXICITY AND RESPONSE ASSOCIATED WITH CELL THERAPY FOR TREATING B CELL MALIGNANCIES," the contents of which are incorporated herein by reference for all purposes.

[0002] Incorporation by reference of the Sequence Listing This application is filed with an electronic Sequence Listing. The Sequence Listing is provided as a file named 735042022840SeqList.TXT, created on December 3, 2020, and is 36,864 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

[0003] Field In some aspects, the present disclosure relates to methods for determining the risk of toxicity (e.g., neurotoxicity) and / or likelihood of success of cell therapy. In some aspects, the methods generally involve assessing parameters or biomarkers (e.g., blood analytes) associated with toxicity and / or success. In some aspects, the methods relate to adoptive cell therapy, which involves administering multiple doses of cells to treat subjects with certain B-cell malignancies, e.g., chronic lymphocytic leukemia (CLL) such as relapsed or refractory CLL or small lymphocytic lymphoma (SLL). Cells for adoptive cell therapy generally express a recombinant receptor, such as a chimeric antigen receptor (CAR). In some aspects, the methods can be used, for example, to identify or select subjects for treatment with cell therapy. [Background technology]

[0004] Background Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are indolent cancers in which immature lymphocytes are found in the blood and bone marrow and / or lymph nodes. CLL and SLL are considered incurable, and patients eventually relapse or become refractory to available treatments. Certain methods are available for adoptive cell therapy using engineered cells expressing recombinant receptors, such as chimeric antigen receptors (CARs). Improved methods are needed, for example, to reduce the risk of toxicity and / or improve the efficacy of treatment. Methods, uses, and articles of manufacture that meet such needs are provided. Summary of the Invention

[0005] Summary Provided herein are methods for determining the risk of developing toxicity and the likelihood of success after administering a cell therapy. In some embodiments, the methods involve comparing the value of a parameter or the level, concentration, or amount of a biomarker or analyte to a threshold value for that particular parameter, biomarker, or analyte. In some embodiments, the comparison can be used to determine the risk of toxicity and / or the likelihood of success of the cell therapy. In some embodiments, the comparison can be used to determine the risk of toxicity. In some embodiments, the comparison can be used to determine the likelihood of success of the cell therapy. In some embodiments, the cell therapy includes a dose of engineered cells, including T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19). In some embodiments, the parameter, biomarker, or analyte is assessed from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL), or is assessed in a sample obtained from such a subject. In some embodiments, the subject has chronic lymphoblastic leukemia (CLL). In some embodiments, the subject has small lymphocytic lymphoma (SLL). In some of any of the embodiments, the subject is a candidate for and / or has been treated with cell therapy. In some of any of the embodiments, the subject is a candidate for and / or has been treated with cell therapy. In some of the embodiments, the subject is a candidate for and / or has been treated with cell therapy. In some of the embodiments, the subject is a candidate for and / or has been treated with cell therapy. In some of the embodiments, the provided methods can be used to identify or select subjects at risk of developing toxicity and / or likely to benefit from cell therapy, and / or to select subjects for treatment with a particular treatment, e.g., an additional therapeutic agent. In some of the embodiments, the provided methods can be used to identify or select subjects at risk of developing toxicity. In some of the embodiments, the provided methods can be used to identify or select subjects likely to benefit from cell therapy.In some optional embodiments, the methods provided can be used to select subjects for a particular treatment, eg, treatment with an additional therapeutic agent.

[0006] Provided herein is a method for determining the risk of developing toxicity following administration of a cell therapy, the method comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and the ratio of blood tumor burden to lymph node tumor burden in a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and wherein the parameters are assessed in the subject prior to administering the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually, identifying the subject as at risk of developing neurotoxicity after administration of the cell therapy if the lymph node tumor burden is equal to or greater than the threshold level for lymph node tumor burden, the blood tumor burden is less than the threshold level for blood tumor burden, and / or the ratio of blood tumor burden to lymph node tumor burden is less than the threshold level for that ratio, or identifying the subject as not at risk of developing neurotoxicity after administration of the cell therapy if the lymph node tumor burden is less than the threshold level for tumor burden, the blood tumor burden is equal to or greater than the threshold level for blood tumor burden, and / or the ratio of blood tumor burden to lymph node tumor burden is greater than the threshold level for that ratio.

[0007] In some embodiments, if the subject is identified as being at risk of developing neurotoxicity, the method further comprises administering to the subject a cell therapy, optionally at a reduced dose, wherein the method optionally further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of developing neurotoxicity, and / or the administration of the cell therapy to the subject is performed or is designated to be performed in an inpatient setting and / or involves one or more days of hospitalization; or the method further comprises administering to the subject an alternative treatment other than cell therapy for treating CLL or SLL. In some embodiments, if the subject is identified as being at risk of developing neurotoxicity, the method further comprises administering to the subject a cell therapy at a reduced dose. In some embodiments, if the subject is identified as being at risk of developing neurotoxicity, the method further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of developing neurotoxicity. In some embodiments, if a subject is identified as being at risk of developing neurotoxicity, the administration of cell therapy to the subject is performed or is designated to be performed in an inpatient setting and / or with one or more days of hospitalization. In some embodiments, if a subject is identified as being at risk of developing neurotoxicity, the method comprises administering to the subject an alternative treatment other than cell therapy for treating CLL or SLL.

[0008] In some of any of the embodiments, if the subject is identified as not at risk for developing neurotoxicity, the method further comprises administering a cell therapy to the subject, optionally wherein: Optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or Optionally, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject exhibits a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with an antipyretic. In some of any of the embodiments, if the subject is identified as not at risk for developing neurotoxicity, the method further comprises administering the cell therapy to the subject. In some of any of the embodiments, if the subject is identified as not at risk for developing neurotoxicity, the subject is not administered an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity unless or until the subject exhibits signs or symptoms of toxicity. In some of the embodiments, if a subject is identified as not at risk for developing neurotoxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the development of toxicity or the risk of developing toxicity unless or until the subject exhibits a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with antipyretics. In some embodiments, if a subject is identified as not at risk for developing neurotoxicity, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital. In some embodiments, if the subject is identified as not at risk for developing neurotoxicity, administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with antipyretic medication.

[0009] Provided herein is a method for selecting a subject for treatment with cell therapy, the method comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and the ratio of blood tumor burden to lymph node tumor burden in a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and wherein the parameters are assessed in the subject prior to administering the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually, and if the lymph node tumor burden is equal to or greater than the threshold level for lymph node tumor burden, the blood tumor burden is less than the threshold level for blood tumor burden, and / or the ratio of blood tumor burden to lymph node tumor burden is less than the threshold level for that ratio, then selecting the subject for administration of a cell therapy at a reduced dose; administration of an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of the onset of neurotoxicity; administration of a cell therapy that is performed or designated to be performed in an inpatient setting and / or with one or more days of hospitalization; and / or administration of an alternative treatment other than a cell therapy for treating CLL or SLL; or if the lymph node tumor burden is less than the threshold level for tumor burden, the blood tumor burden is equal to or greater than the threshold level for blood tumor burden, and / or the ratio of blood tumor burden to lymph node tumor burden is above the threshold level for that ratio, then selecting the subject for administration of a cell therapy, optionally wherein Optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or Optionally, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretic medication.

[0010] Also provided herein is a method of selecting a subject for treatment with cell therapy, comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and the ratio of blood tumor burden to lymph node tumor burden in a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and wherein the parameters are assessed in the subject prior to administering the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually, and if the lymph node tumor burden is equal to or greater than the threshold level for lymph node tumor burden, the blood tumor burden is less than the threshold level for blood tumor burden, and / or the ratio of blood tumor burden to lymph node tumor burden is less than the threshold level for that ratio, selecting the subject for administration of a cell therapy at a reduced dose; administration of an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of the onset of neurotoxicity; administration of a cell therapy that is performed or designated to be performed in an inpatient setting and / or with one or more days of hospitalization; and / or administration of an alternative treatment other than a cell therapy for treating CLL or SLL; or if the lymph node tumor burden is less than the threshold level for tumor burden, the blood tumor burden is equal to or greater than the threshold level for blood tumor burden, and / or the ratio of blood tumor burden to lymph node tumor burden is above the threshold level for that ratio, selecting the subject for administration of a cell therapy. In some embodiments, a subject is not administered an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of onset of toxicity unless or until the subject exhibits signs or symptoms of toxicity. In some embodiments, a subject is not administered an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of onset of toxicity unless or until the subject exhibits signs or symptoms of toxicity, for example, until the subject exhibits a persistent fever or a fever that does not subside or does not subside after treatment with antipyretics or a fever that does not subside by more than 1°C after treatment with antipyretics. In some embodiments, the administration of cell therapy and any follow-up is performed on an outpatient basis. In some embodiments, the administration of cell therapy and any follow-up is performed without the subject being hospitalized. In some embodiments, the administration of cell therapy and any follow-up is performed without the subject being hospitalized.In some embodiments, the administration of the cell therapy and any follow-up is carried out without requiring hospitalization or an overnight stay in the hospital. In some embodiments, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or without requiring hospitalization or an overnight stay in the hospital unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with an antipyretic.

[0011] In some embodiments, the method further comprises administering to the subject a cell therapy, an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of toxicity or the risk of the onset of toxicity, and / or an alternative treatment. In some embodiments, the method further comprises administering to the subject a cell therapy. In some embodiments, the method further comprises administering to the subject the agent. In some embodiments, the method further comprises administering to the subject another treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of toxicity or the risk of the onset of toxicity. In some embodiments, the method further comprises administering to the subject an alternative treatment.

[0012] In some embodiments, assessing blood tumor burden comprises determining the lymphocyte concentration in the subject's blood. In some embodiments, the concentration is lymphocytes per microliter (μL) of blood. In some embodiments, the threshold level for blood tumor burden is a value between 800 or about 800 lymphocytes / μL and 3000 or about 3000 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL, or 3000 lymphocytes / μL. / μL, or a value of about 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL, or 3000 lymphocytes / μL, or any value therebetween. In some of any of the embodiments, the threshold level for blood tumor burden is a value of 800 or about 800 lymphocytes / μL. In some of any of the embodiments, the threshold level for blood tumor burden is a value of 900 or about 900 lymphocytes / μL. In some of any of the embodiments, the threshold level for blood tumor burden is a value of 1000 or about 1000 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 1250 or about 1250 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 1500 or about 1500 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 1750 or about 1750 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 2000 or about 2000 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 2250 or about 2250 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 2500 or about 2500 lymphocytes / μL.In some of the embodiments, the threshold level for blood tumor burden is at or about 2750 lymphocytes / μL. In some of the embodiments, the threshold level for blood tumor burden is at or about 3000 lymphocytes / μL.

[0013] In some embodiments, assessing lymph node burden includes determining maximum lymph node diameter. In some embodiments, maximum lymph node diameter is measured in centimeters (cm). In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value between or about 4 cm and 7 or about 7 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is 4 cm, 4.25 cm, 4.5 cm, 4.75 cm, 5 cm, 5.25 cm, 5.5 cm, 5.75 cm, 6 cm, 6.25 cm, 6.5 cm, 6.75 cm, or 7 cm, or a value between or about 4 cm, 4.25 cm, 4.5 cm, 4.75 cm, 5 cm, 5.25 cm, 5.5 cm, 5.75 cm, 6 cm, 6.25 cm, 6.5 cm, 6.75 cm, or 7 cm, or any value therebetween. In some of any of the embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 4 or about 4 cm. In some of any of the embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 4.25 or about 4.25 cm. In some of any of the embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 4.5 or about 4.5 cm. In some of any of the embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 4.75 or about 4.75 cm. In some of any of the embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 5 or about 5 cm. In some of any of the embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 5.25 or about 5.25 cm. In some of any of the embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 5.5 or about 5.5 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 5.75 or about 5.75 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 6.0 or about 6.0 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 6.25 or about 6.25 cm.In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 6.5 or about 6.5 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 6.75 or about 6.75 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 7.0 or about 7.0 cm.

[0014] In some embodiments, assessing the ratio of blood tumor burden to lymph node tumor burden comprises determining the ratio of lymphocytes per microliter (μL) of blood to largest lymph node diameter in centimeters (cm). In some embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as the ratio of blood tumor burden to lymph node tumor burden is a value from at or about 300 to at or about 1000. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is at or about a value of 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000, or any value therebetween. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is at or about a value of 300. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 350 or about 350. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 400 or about 400. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 450 or about 450.In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 500 or about 500. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 550 or about 550. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 600 or about 600. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 650 or about 650. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 700 or about 700. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 750 or about 750. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 800 or about 800. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 850 or about 850.In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 900 or about 900. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 950 or about 950. In some of any of the embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 1000 or about 1000.

[0015] In some of the embodiments, assessing lymph node burden includes determining the sum of the products of diameters (SPD). In some of the embodiments, SPD is measured in square centimeters (cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is 10 or about 10 cm 2 ~40 or about 40cm 2 In some of the optional embodiments, the threshold level for SPD as lymph node burden is 10 cm 2 , 12.5cm 2 , 15cm 2 , 17.5cm 2 , 20cm 2 , 22.5cm 2 , 25cm 2 , 27.5cm 2 , 30cm 2 , 32.5cm 2 , 35cm 2 , 37.5cm 2 Or 40cm 2 , or about 10 cm 2 , 12.5cm 2 , 15cm 2 , 17.5cm 2, 20cm 2 , 22.5cm 2 , 25cm 2 , 27.5cm 2 , 30cm 2 , 32.5cm 2 , 35cm 2 , 37.5cm 2 Or 40cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 10 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 12.5 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 15 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 17.5 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 20 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 22.5 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 25 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 27.5 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 30 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 32.5 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 35 cm 2In some of the embodiments, the threshold level for SPD as lymph node burden is 37.5 or about 37.5 cm 2 In some of the embodiments, the threshold level for SPD as lymph node burden is at or about 40 cm 2 is the value.

[0016] In some of the embodiments, assessing the ratio of blood tumor burden to lymph node tumor burden is measured in square centimeters (cm 2In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value from at or about 25 to at or about 500. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is at or about 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500, or a value of at or about 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500, or any value between the foregoing. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 25 or about 25. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 50 or about 50. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 75 or about 75. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 100 or about 100. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 150 or about 150. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 200 or about 200.In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 250 or about 250. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 300 or about 300. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 350 or about 350. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 400 or about 400. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 450 or about 450. In some of any of the embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 500 or about 500.

[0017] Provided herein is a method for determining the risk of developing toxicity following administration of a cell therapy, the method comprising the steps of: assaying a biological sample for a level, amount, or concentration of tumor necrosis factor (TNF) and / or interleukin-16 (IL-16), wherein the biological sample is derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and 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 11 days or about 11 days after initiating administration of the cell therapy; and comparing the level, amount or concentration of TNF and / or IL-16 to a threshold level for each, respectively, wherein the threshold level for TNF is a value between at or about 7 pg / mL and 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value between at or about 400 pg / mL and 900 or about 900 pg / mL, and if the level, amount or concentration of TNF and / or IL-16 is equal to or greater than the respective threshold level, the subject is identified as being at risk of developing neurotoxicity after administration of the cell therapy, or if the level, amount or concentration of TNF and / or IL-16 is less than the respective threshold level, the subject is identified as not being at risk of developing neurotoxicity after administration of the cell therapy.

[0018] Provided herein is a method for determining the risk of developing toxicity following administration of a cell therapy, the method comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and comparing the level, amount or concentration of TNF and / or IL-16 to a threshold level for each, respectively, wherein the threshold level for TNF is a value between at or about 7 pg / mL and 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value between at or about 400 pg / mL and 900 or about 900 pg / mL, and if the level, amount or concentration of TNF and / or IL-16 is equal to or greater than the respective threshold level, the subject is identified as being at risk of developing neurotoxicity after administration of the cell therapy, or if the level, amount or concentration of TNF and / or IL-16 is less than the respective threshold level, the subject is identified as not being at risk of developing neurotoxicity after administration of the cell therapy.

[0019] In some embodiments, if the subject is identified as being at risk of developing neurotoxicity, the method further comprises administering to the subject a cell therapy, optionally at a reduced dose, wherein the method optionally further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of developing neurotoxicity, and / or the administration of the cell therapy to the subject is performed or is designated to be performed in an inpatient setting and / or involves one or more days of hospitalization; or the method further comprises administering to the subject an alternative treatment other than cell therapy for treating CLL or SLL. In some embodiments, if the subject is identified as being at risk of developing neurotoxicity, the method further comprises administering to the subject a cell therapy. In some embodiments, if the subject is identified as being at risk of developing neurotoxicity, the method further comprises administering to the subject a reduced dose of cell therapy. In some embodiments, if a subject is identified as being at risk for developing neurotoxicity, the method further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of developing neurotoxicity. In some embodiments, if a subject is identified as being at risk for developing neurotoxicity, the administration of cell therapy to the subject is performed or designated to be performed in an inpatient setting and / or with one or more days of hospitalization. In some embodiments, if a subject is identified as being at risk for developing neurotoxicity, the method further comprises administering to the subject an alternative treatment other than cell therapy for treating CLL or SLL.

[0020] In some of any of the embodiments, if the subject is identified as not at risk for developing neurotoxicity, the method further comprises administering a cell therapy to the subject, optionally wherein: Optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or Optionally, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject exhibits a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with an antipyretic. In some of the embodiments, if the subject is identified as not at risk of developing neurotoxicity, the method further comprises administering the cell therapy to the subject. In some embodiments, if the subject is identified as not at risk of developing neurotoxicity, the subject is not administered an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity unless or until the subject exhibits signs or symptoms of toxicity. In some embodiments, if a subject is identified as not at risk of developing neurotoxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of developing toxicity unless or until the subject exhibits a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with antipyretics. In some embodiments, if a subject is identified as not at risk of developing neurotoxicity, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital. In some embodiments, if the subject is identified as not at risk for developing neurotoxicity, administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretics.

[0021] Provided herein is a method for selecting a subject for treatment with cell therapy, the method comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and comparing the level, amount or concentration of TNF and / or IL-16 to a threshold level for each, individually, wherein the threshold level for TNF is a value of 7 or about 7 pg / mL to 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value of 400 or about 400 pg / mL to 900 or about 900 pg / mL, and if the level, amount or concentration of TNF and / or IL-16 is at or above the respective threshold level, the subject is treated with a reduced dose of cell therapy; administration of an agent or other treatment that can treat, prevent, delay, reduce or attenuate the risk of the development of neurotoxicity; administration of a cell therapy that is performed or designated to be performed in an inpatient setting and / or with one or more days of hospitalization; and / or select for administration of an alternative treatment other than a cell therapy to treat CLL or SLL; or if the level, amount or concentration of TNF and / or IL-16 is below the respective threshold level, the subject is selected for administration of a cell therapy, optionally wherein Optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or Optionally, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretic medication.

[0022] In some embodiments, the method further comprises administering to the subject a cell therapy, an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of toxicity or the risk of the onset of toxicity, and / or an alternative treatment. In some embodiments, the method further comprises administering to the subject a cell therapy. In some embodiments, the method further comprises administering to the subject the agent. In some embodiments, the method further comprises administering to the subject another treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of toxicity or the risk of the onset of toxicity. In some embodiments, the method further comprises administering to the subject an alternative treatment.

[0023] Provided herein is a method for determining the risk of developing toxicity following administration of a cell therapy, the method comprising the steps of: Assaying a biological sample from a subject who has received a cell therapy comprising a dose of engineered cells comprising T cells expressing a CAR for treating CLL or SLL for the level, amount, or concentration of TNF and / or IL-16, wherein the biological sample is obtained from the subject prior to peak CAR+ T cell expansion and / or within 11 days or about 11 days after initiation of administration of the cell therapy; and comparing the level, amount or concentration of TNF and / or IL-16 with a threshold level for each, wherein the threshold level for TNF is a value between 7 or about 7 pg / mL and 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value between 400 or about 400 pg / mL and 900 or about 900 pg / mL, and if the level, amount or concentration of TNF and / or IL-16 is equal to or greater than the respective threshold level, identifying the subject as being at risk of developing neurotoxicity; or if the level, amount or concentration of TNF and / or IL-16 is less than the respective threshold level, identifying the subject as not at risk of developing neurotoxicity.

[0024] In some embodiments, if the subject is identified as being at risk for developing neurotoxicity, the method further includes administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of the onset of neurotoxicity, optionally prior to peak CAR+ T cell expansion and / or within at or about 11 days of administering the cell therapy to the subject; and / or follow-up is carried out in an inpatient setting and / or with one or more days of hospitalization. In some embodiments, if the subject is identified as not being at risk for developing neurotoxicity, follow-up is optionally carried out on an outpatient basis and / or without hospitalization of the subject and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretics. In some embodiments, if a subject is identified as being at risk for developing neurotoxicity, the method further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of developing neurotoxicity. In some embodiments, if a subject is identified as being at risk for developing neurotoxicity, the method further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of developing neurotoxicity prior to peak CAR+ T-cell expansion. In some embodiments, if a subject is identified as being at risk for developing neurotoxicity, the method further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of developing neurotoxicity within 11 or about 11 days of administering the cell therapy to the subject. In some of any of the embodiments, if a subject is identified as being at risk for developing neurotoxicity, follow-up is performed in an inpatient setting and / or involves one or more days of hospitalization.In some of the embodiments, if a subject is identified as not at risk for developing neurotoxicity, follow-up is performed on an outpatient basis, and / or without admitting the subject to the hospital, and / or without requiring an overnight stay in the hospital, and / or without requiring hospitalization or an overnight stay in the hospital. In some of the embodiments, if a subject is identified as not at risk for developing neurotoxicity, follow-up is performed on an outpatient basis, and / or without admitting the subject to the hospital, and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretics.

[0025] Provided herein is a method of treatment involving the steps of: Administering an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the onset of toxicity or the risk of the onset of toxicity to a subject identified as being at risk for developing neurotoxicity, wherein the subject has previously received a cell therapy for treating CLL or SLL, and the subject is selected or identified as being at risk for developing neurotoxicity if, at the time of administration of the agent or immediately prior to administration of the agent, the level or amount or concentration of TNF and / or IL-16 in a biological sample obtained from the subject prior to peak CAR+ T cell expansion and / or within 11 days or about 11 days of initiating administration of the cell therapy, is above a threshold level for each, wherein the threshold level for TNF is a value of 7 at or about 7 pg / mL to 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value of 400 at or about 400 pg / mL to 900 or about 900 pg / mL. In some embodiments, the threshold level for TNF is a value of 7 or about 7 pg / mL to 25 or about 25 pg / mL, hi some embodiments, the threshold level for IL-16 is a value of 400 or about 400 pg / mL to 900 or about 900 pg / mL.

[0026] Provided herein are methods for selecting a subject for treatment with an agent, the methods involving: Assaying a biological sample from a subject who has received a cell therapy comprising a dose of engineered cells comprising T cells expressing a CAR that binds to CD19 for treating CLL or SLL for the level, amount, or concentration of TNF and / or IL-16, wherein the biological sample is obtained from the subject prior to peak CAR+ T cell expansion and / or within 11 days or about 11 days after initiation of administration of the cell therapy; and comparing the level, amount or concentration of TNF and / or IL-16 to a threshold level for each individually, wherein the threshold level for TNF is a value of 7 or about 7 pg / mL to 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value of 400 or about 400 pg / mL to 900 or about 900 pg / mL, and if the level, amount or concentration of TNF and / or IL-16 is at or above the respective threshold level, selecting the subject for administration of an agent or other treatment that can treat, prevent, delay, reduce or attenuate the manifestation of neurotoxicity or the risk of the manifestation of neurotoxicity.

[0027] In some embodiments, the method further includes administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity. In some embodiments, the administering of the agent or other treatment is performed when the subject presents with a persistent fever or a fever that does not subside or does not subside after treatment with an antipyretic, or a fever that does not subside by more than 1° C. after treatment with an antipyretic. In some embodiments, the administering of the cell therapy to the subject is performed on an outpatient basis, and if the level, amount, or concentration of TNF and / or IL-16 is above a threshold level, the method involves hospitalizing the patient for one or more days.

[0028] In some embodiments, the threshold level for TNF is 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, or 25 pg / mL, or a value of about 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, or 25 pg / mL, or any value therebetween. In some embodiments, the threshold level for TNF is a value of 8 or about 8 pg / mL to 10 or about 10 pg / mL. In some embodiments, the threshold level for TNF is a value of 7 or about 7 pg / mL. In some embodiments, the threshold level for TNF is a value of 8 or about 8 pg / mL. In some embodiments, the threshold level for TNF is a value of 9 or about 9 pg / mL. In some embodiments, the threshold level for TNF is at or about 10 pg / mL. In some embodiments, the threshold level for TNF is at or about 15 pg / mL. In some embodiments, the threshold level for TNF is at or about 20 pg / mL. In some embodiments, the threshold level for TNF is at or about 25 pg / mL.

[0029] In some embodiments, the threshold level for IL-16 is 400 pg / mL, 500 pg / mL, 600 pg / mL, 700 pg / mL, 800 pg / mL, 900 pg / mL, or 1000 pg / mL, or a value of about 400 pg / mL, 500 pg / mL, 600 pg / mL, 700 pg / mL, 800 pg / mL, 900 pg / mL, or 1000 pg / mL, or any value therebetween. In some embodiments, the threshold level for IL-16 is a value of 500 or about 500 pg / mL to 700 or about 700 pg / mL. In some embodiments, the threshold level for IL-16 is 400 or about 400 pg / mL. In some embodiments, the threshold level for IL-16 is a value of 500 or about 500 pg / mL. In some embodiments, the threshold level for IL-16 is at a value of 600 or about 600 pg / mL. In some embodiments, the threshold level for IL-16 is at a value of 700 or about 700 pg / mL. In some embodiments, the threshold level for IL-16 is at a value of 800 or about 800 pg / mL. In some embodiments, the threshold level for IL-16 is at a value of 900 or about 900 pg / mL. In some embodiments, the threshold level for IL-16 is at a value of 1000 or about 1000 pg / mL.

[0030] In some of any of the embodiments, the levels, amounts, or concentrations of both TNF and IL-16 are assessed, and the threshold level for TNF is 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, or 25 pg / mL, or a value of about 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, or 25 pg / mL, or any of the foregoing. and the threshold level for IL-16 is 400pg / mL, 500pg / mL, 600pg / mL, 700pg / mL, 800pg / mL, 900pg / mL or 1000pg / mL, or a value of about 400pg / mL, 500pg / mL, 600pg / mL, 700pg / mL, 800pg / mL, 900pg / mL or 1000pg / mL, or any value between the foregoing.

[0031] In some of any of the embodiments, the levels, amounts, or concentrations of both TNF and IL-16 are assessed, with the threshold level for TNF being a value of 8 or about 8 pg / mL to 10 or about 10 pg / mL, and the threshold level for IL-16 being a value of 500 or about 500 pg / mL to 700 or about 700 pg / mL.

[0032] In some embodiments, the biological sample is a blood, plasma, or serum sample, or is obtained from a blood, plasma, or serum sample. In some embodiments, the evaluating step comprises contacting the biological sample with one or more reagents capable of detecting TNF and / or IL-16 or specific for TNF and / or IL-16, optionally wherein the one or more reagents comprise an antibody that specifically recognizes TNF and / or IL-16; and detecting the presence or absence of a complex comprising the one or more reagents and TNF and / or IL-16. In some embodiments, the evaluating step comprises contacting the biological sample with one or more reagents capable of detecting TNF or specific for TNF, and detecting the presence or absence of a complex comprising the one or more reagents and TNF. In some embodiments, the one or more reagents comprise an antibody that specifically recognizes TNF. In some embodiments, the evaluating step includes contacting the biological sample with one or more reagents capable of detecting IL-16 or specific for IL-16, and detecting the presence or absence of a complex comprising the one or more reagents and IL-16. In some embodiments, the one or more reagents include an antibody that specifically recognizes IL-16. In some embodiments, the evaluating step includes an immunoassay. In some embodiments, the evaluating step includes an enzyme-linked immunosorbent assay (ELISA), immunoblotting, immunoprecipitation, radioimmunoassay (RIA), immunostaining, flow cytometry assay, surface plasmon resonance (SPR), chemiluminescence assay, lateral flow immunoassay, inhibition assay, or avidity assay. In some embodiments, the evaluating step includes an enzyme-linked immunosorbent assay (ELISA). In some embodiments, the evaluating step includes a sandwich enzyme-linked immunosorbent assay (ELISA). In some embodiments, the ELISA is a bead-based ELISA.

[0033] In some embodiments, the agent or other treatment is or comprises an anti-IL-6 antibody, an anti-IL-6R antibody, or a steroid. In some embodiments, the agent or other treatment is or comprises an anti-IL-6 antibody. In some embodiments, the agent or other treatment is or comprises an anti-IL-6 antibody. In some embodiments, the agent or other treatment is or comprises an anti-IL-6R antibody. In some embodiments, the agent or other treatment is or comprises a steroid. In some embodiments, the agent is or comprises tocilizumab, siltuximab, or dexamethasone. In some embodiments, the agent is or comprises tocilizumab, siltuximab, or dexamethasone. In some embodiments, the agent is or comprises tocilizumab. In some embodiments, the agent is or comprises siltuximab. In some embodiments, the agent is or comprises dexamethasone. In some embodiments, the neurotoxicity is severe neurotoxicity. In some embodiments, the neurotoxicity is Grade 3 or higher neurotoxicity. In some embodiments, the neurotoxicity is Grade 3 neurotoxicity. In some embodiments, the neurotoxicity is Grade 4 neurotoxicity. In some embodiments, the neurotoxicity is Grade 5 neurotoxicity.

[0034] Provided herein is a method for assessing the likelihood of success of a cell therapy, the method comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and A step of individually comparing the level, amount or concentration of VEGFC and / or VEGFR1 in the sample with a threshold level, and 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 if the level, amount or concentration of VEGFC and / or VEGFR1 is equal to or greater than the respective threshold level, identifying the subject as having a low likelihood of achieving a response to the cell therapy.

[0035] Provided herein is a method for selecting a subject for treatment with cell therapy, the method comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and Selecting subjects likely to respond to treatment based on the results of determining the likelihood of the subject achieving a response to cell therapy by individually comparing the level, amount, or concentration of VEGFC and / or VEGFR1 in the sample with a respective threshold level, wherein if the level, amount, or concentration of VEGFC and / or VEGFR1 is below the respective threshold level, the subject is identified as likely to achieve a response to cell therapy, or if the level, amount, or concentration of VEGFC and / or VEGFR1 is equal to or greater than the respective threshold level, the subject is identified as unlikely to achieve a response to cell therapy. In some embodiments, the method further comprises administering cell therapy to the subjects selected for treatment.

[0036] Provided herein is a method for treatment, which involves the steps of: selecting a subject likely to respond to treatment based on determining the likelihood of the subject achieving a response to cell therapy by individually comparing the level, amount, or concentration of vascular endothelial growth factor C (VEGFC) and / or vascular endothelial growth factor receptor 1 (VEGFR1) in the biological sample with a respective threshold level, wherein the subject is identified as likely to achieve a response to the cell therapy if the level, amount, or concentration of VEGFC and / or VEGFR1 is below the respective threshold level, or the subject is identified as unlikely to achieve a response to the cell therapy if the level, amount, or concentration of VEGFC and / or VEGFR1 is equal to or greater than the respective threshold level, wherein the biological sample is derived from a subject with CLL or SLL who is a candidate for cell therapy treatment, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the subject does not comprise CAR-expressing T cells; and Administering the cell therapy to the subject selected for treatment.

[0037] In some of any of the embodiments, the threshold level is within 25%, within 20%, within 15%, within 10%, or within 5%, and / or within one standard deviation of, about, or above the median or mean level, amount, or concentration of VEGFC and / or VEGFR1 in biological samples obtained from a group of subjects prior to receiving cell therapy, wherein each of the subjects in the group achieves a response after administration of a dose of engineered cells expressing a CAR to treat CLL or SLL; the threshold level is within 25%, 20%, 15%, 10%, or 5%, and / or within one standard deviation of, about, or above the median or mean level, amount, or concentration of VEGFC and / or VEGFR1 in biological samples obtained from the group of subjects prior to receiving cell therapy, wherein each of the subjects in the group achieves a response after administration of a dose of engineered cells expressing a CAR to treat CLL or SLL; The threshold level is 1.25-fold or more, 1.3-fold or more, 1.4-fold or more, or 1.5-fold or more higher than the median or mean level, amount, or concentration of VEGFC and / or VEGFR1, wherein each of the subjects in the group achieves a response after administration of a dose of engineered cells expressing a CAR for treating CLL or SLL; the threshold level is 1.25-fold or more, 1.3-fold or more, 1.4-fold or more, or 1.5-fold or more higher than the level, amount, or concentration of VEGFC and / or VEGFR1 in a biological sample obtained from a group of normal or healthy subjects who are not candidates for cell therapy treatment. In some embodiments, the threshold level for VEGFC is a value of 60 or about 60 pg / mL to 70 or about 70 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 80 or about 80 pg / mL to 120 or about 120 pg / mL. In some embodiments, the levels, amounts, or concentrations of both VEGFC and VEGFR1 are assessed, and the threshold level for VEGFC is between 60 or about 60 pg / mL and 70 or about 70 pg / mL, and the threshold level for VEGFR1 is between 80 or about 80 pg / mL and 120 or about 120 pg / mL. In some embodiments, the threshold level for VEGFC is between 60 or about 60 pg / mL. In some embodiments, the threshold level for VEGFC is between 65 or about 65 pg / mL. In some embodiments, the threshold level for VEGFC is between 70 or about 70 pg / mL. In some embodiments, the threshold level for VEGFR1 is between 80 or about 80 pg / mL.In some embodiments, the threshold level for VEGFR1 is a value of 90 or about 90 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 100 or about 100 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 11 or about 11 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 120 or about 120 pg / mL.

[0038] In some embodiments, the biological sample is a blood, plasma, or serum sample, or is obtained from a blood, plasma, or serum sample. In some embodiments, the evaluating step includes contacting the biological sample with one or more reagents capable of detecting VEGFC and / or VEGFR1 or specific to VEGFC and / or VEGFR1, optionally wherein the one or more reagents comprise an antibody that specifically recognizes VEGFC and / or VEGFR1; and detecting the presence or absence of a complex comprising the one or more reagents and VEGFC and / or VEGFR1. In some embodiments, the evaluating step includes contacting the biological sample with one or more reagents capable of detecting VEGFC or specific to VEGFC, and detecting the presence or absence of a complex comprising the one or more reagents and VEGFC. In some embodiments, the one or more reagents comprise an antibody that specifically recognizes VEGFC. In some embodiments, the evaluating step comprises contacting the biological sample with one or more reagents capable of detecting VEGFR1 or specific to VEGFR1, and detecting the presence or absence of a complex comprising the one or more reagents and VEGFR1. In some embodiments, the one or more reagents comprise an antibody that specifically recognizes VEGFR1. In some embodiments, the evaluating step comprises an immunoassay. In some embodiments, the response comprises an objective response.In some of any of the embodiments, an objective response includes a complete response (CR; sometimes known as complete remission), a complete remission with incomplete blood count recovery (CRi), a complete remission (CR), a CR with incomplete marrow recovery (CRi), a nodular partial remission (nPR), or a partial response (PR). In some of any of the embodiments, the response is assessed 1, 2, or 3 months or about 1, 2, or 3 months or more after initiation of administration of the cell therapy.

[0039] In some embodiments, the response is evaluated at or about 1 month after initiation of administration of cell therapy. In some embodiments, the response is evaluated at or about 2 months after initiation of administration of cell therapy. In some embodiments, the response is evaluated at or about 3 months after initiation of administration of cell therapy.

[0040] In some embodiments, the method further comprises administering lymphodepleting therapy to the subject prior to administration of the cell therapy. In some embodiments, the subject has been preconditioned with lymphodepleting therapy. In some embodiments, the lymphodepleting therapy comprises administration of fludarabine and / or cyclophosphamide. In some embodiments, the biological sample is obtained from the subject prior to administering lymphodepleting therapy to the subject. In some embodiments, the value of the one or more disease burden parameters is the value of the one or more disease burden parameters prior to administering lymphodepleting therapy to the subject. In some embodiments, the one or more disease burden parameters are assessed prior to administering lymphodepleting therapy to the subject.

[0041] In some embodiments, the lymphodepleting therapy includes administration of fludarabine. In some embodiments, the lymphodepleting therapy includes administration of cyclophosphamide. In some embodiments, the lymphodepleting therapy includes administration of fludarabine and cyclophosphamide. In some embodiments, the lymphodepleting therapy includes administration of about 200 to 400 mg / m, inclusive. 2 , optionally 300 or about 300 mg / m 2 of cyclophosphamide, and / or approximately 20–40 mg / m 2 , optionally 30 mg / m 2 of fludarabine daily for 2-4 days, optionally 3 days. In some of the embodiments, the lymphodepletion therapy comprises administration of at or about 300 mg / m 2 of cyclophosphamide and approximately 30 mg / m 2 of fludarabine daily for three days, optionally wherein said dose of cells is administered at least 2-7 days or at least about 2-7 days after lymphodepletion therapy or at least 2-7 days or at least about 2-7 days after initiation of lymphodepletion therapy.

[0042] In some embodiments, the method further comprises administering to the subject a Bruton's tyrosine kinase inhibitor (BTKi). In some embodiments, the BTKi is ibrutinib. In some embodiments, BTKi administration is initiated before initiation of cell therapy administration. In some embodiments, BTKi administration is continued after initiation of cell therapy administration. In some embodiments, BTKi administration is continued for at least 90 days or at least about 90 days after initiation of cell therapy administration. In some embodiments, ibrutinib is administered at a dose of 140 or about 140 mg to 840 or about 840 mg per day. In some embodiments, ibrutinib is administered at a dose of 280 or about 280 mg to 560 or about 560 mg per day. In some embodiments, ibrutinib is administered at a dose of 420 or about 420 mg per day. In some of any of the embodiments, the disease or condition is relapsed or refractory (r / r) CLL. In some of any of the embodiments, the disease or condition is relapsed or refractory (r / r) SLL.

[0043] In some of the embodiments, the dose of engineered cells is a CAR-expressing CD4 + Cells vs. CAR-expressing CD8 + In some embodiments, the dose of engineered cells comprises a predetermined ratio of CAR-expressing CD4 + Cells vs. CAR-expressing CD8 + In some embodiments, the ratio is about 1:3 to about 3:1. In some embodiments, the dose of engineered cells is 1:1 or about 1:1, and the dose of engineered cells is 1:1 or about 1:1. + Cells vs. CAR-expressing CD8 + In some embodiments, the dose of engineered cells comprises a predetermined ratio of 2.5 x 10 cells. 7 or approximately 2.5 x 10 7 Total CAR-expressing cells ~1.0 x 10 8 or approximately 1.0 x 10 8In some of the embodiments, the dose of engineered cells comprises 2.5 x 10 total CAR-expressing cells. 7 or approximately 2.5 x 10 7 Contains total CAR-expressing cells.

[0044] In some of the embodiments, the dose of engineered cells is 5×10 7 or about 5 x 10 7 In some of the embodiments, the dose of engineered cells comprises 1 x 10 total cells or CAR-expressing cells. 8 or about 1 x 10 8 In some embodiments, administering the cell therapy comprises administering a plurality of separate compositions, wherein the plurality of separate compositions comprises CD4 + T cells and CD8 + a first composition comprising one of a CD4 T cell and a CD4 + T cells and CD8 + In some embodiments, the first composition comprises a second composition comprising another of the CD8 T cells. + the second composition comprises CD4 T cells; + Contains T cells.

[0045] In some embodiments, the initiation of administration of the first composition occurs before the initiation of administration of the second composition, optionally not more than 48 hours apart. In some embodiments, the initiation of administration of the first composition occurs within 48 hours before the initiation of administration of the second composition. In some embodiments, CD4 + CAR and / or CD8 contained in T cells + The CAR contained in the T cells contains the same CAR and / or CD4 + T cells and / or CD8 + The T cells are genetically engineered to express the same CAR. + CAR and CD8 expressed by T cells + The CAR expressed by the T cells is the same. In some embodiments, the CD4 + T cells and CD8+ The T cells are genetically engineered to express the same CAR. In some of any of the embodiments, the subject has been treated with one or more prior therapies for CLL or SLL, optionally with at least two prior therapies, in addition to another dose of CAR-expressing cells and lymphodepleting therapy, prior to administration of the cell therapy. In some of any of the embodiments, the subject has been treated with one or more prior therapies for CLL or SLL, in addition to another dose of CAR-expressing cells and lymphodepleting therapy, prior to administration of the cell therapy. In some of any of the embodiments, the subject has been treated with at least two prior therapies for CLL or SLL, in addition to another dose of CAR-expressing cells and lymphodepleting therapy, prior to administration of the cell therapy. In some of any of the embodiments, the subject has relapsed following remission after treatment with two or more prior therapies, has become resistant to treatment with two or more prior therapies, has failed treatment with two or more prior therapies, and / or is intolerant to treatment with two or more prior therapies, prior to administration of the cell therapy.

[0046] In some embodiments, the one or more prior treatments are selected from a kinase inhibitor, optionally an inhibitor of Bruton's tyrosine kinase (BTK), optionally ibrutinib; venetoclax; combination therapy including fludarabine and rituximab; radiation therapy; and hematopoietic stem cell transplant (HSCT). In some embodiments, the one or more prior treatments include ibrutinib. In some embodiments, the one or more prior treatments include venetoclax. In some embodiments, the one or more prior treatments include an inhibitor of Bruton's tyrosine kinase (BTK) and / or venetoclax. In some embodiments, the one or more prior treatments include ibrutinib and venetoclax.

[0047] In some of any of the embodiments, the subject has relapsed following remission after treatment with an inhibitor of Bruton's tyrosine kinase (BTK) and / or venetoclax, has become resistant to treatment with an inhibitor of Bruton's tyrosine kinase (BTK) and / or venetoclax, has failed treatment with an inhibitor of Bruton's tyrosine kinase (BTK) and / or venetoclax, and / or is intolerant to an inhibitor of Bruton's tyrosine kinase (BTK) and / or venetoclax. In some of any of the embodiments, the subject has relapsed following remission after treatment with ibrutinib, has become resistant to treatment with ibrutinib, has failed treatment with ibrutinib, and / or is intolerant to ibrutinib. In some embodiments, the subject has relapsed following remission after treatment with venetoclax, has become resistant to treatment with venetoclax, has failed treatment with venetoclax, and / or is intolerant to venetoclax. In some embodiments, the subject has relapsed following remission after treatment with ibrutinib and venetoclax, has become resistant to treatment with ibrutinib and venetoclax, has failed treatment with ibrutinib and venetoclax, and / or is intolerant to ibrutinib and venetoclax. In some embodiments, the engineered cells are primary T cells obtained from the subject. In some embodiments, the engineered cells are autologous to the subject.

[0048] In some embodiments, the CAR comprises an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, optionally 4-1BB, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, optionally CD3 zeta, wherein the CAR, in turn, comprises an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule. In some embodiments, the antigen-binding domain is an scFv.

[0049] In some embodiments, the scFv comprises a CDRL1 sequence of RASQDISKYLN (SEQ ID NO:35), a CDRL2 sequence of SRLHSGV (SEQ ID NO:36), and / or a CDRL3 sequence of GNTLPYTFG (SEQ ID NO:37), and / or a CDRH1 sequence of DYGVS (SEQ ID NO:38), a CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and / or a CDRH3 sequence of YAMDYWG (SEQ ID NO:40). the scFv comprises the variable heavy chain region of FMC63 and the variable light chain region of FMC63, and / or the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63 and the CDRH3 sequence of FMC63, or binds to the same epitope as or competes for binding with any of the foregoing; the scFv comprises the V as set forth in SEQ ID NO:41 H and V as shown in SEQ ID NO:42 L and optionally, the V H and the V L and the scFv is separated from the scFv by a flexible linker, optionally the flexible linker is or comprises the sequence set forth in SEQ ID NO:24; and / or the scFv is or comprises the sequence set forth in SEQ ID NO:43.

[0050] In some embodiments, the costimulatory signaling region is the signaling domain of CD28 or 4-1BB. In some embodiments, the costimulatory signaling region is the signaling domain of 4-1BB. In some embodiments, the costimulatory domain comprises SEQ ID NO:12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto. In some embodiments, the primary signaling domain is a CD3 zeta signaling domain. In some of any of the embodiments, the primary signaling domain comprises SEQ ID NO: 13 or 14 or 15 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto.

[0051] In some embodiments, the CAR further comprises a spacer between the transmembrane domain and the scFv. In some embodiments, the spacer is a polypeptide spacer comprising, or consisting of, all or part of an immunoglobulin hinge or a modified version thereof, optionally an IgG4 hinge or a modified version thereof. In some embodiments, the spacer is about 15 amino acids or less and does not comprise the CD28 or CD8 extracellular region. In some embodiments, the spacer is 12 or about 12 amino acids in length. In some embodiments, the spacer has or consists of the sequence of SEQ ID NO:1, the sequence encoded by SEQ ID NO:2, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto, and / or comprises or consists of the formula X1PPX2P, where X1 is glycine, cysteine, or arginine and X2 is cysteine ​​or threonine.

[0052] In some embodiments, the scFv has the amino acid sequence of RASQDISKYLN (SEQ ID NO:35), the amino acid sequence of SRLHSGV (SEQ ID NO:36), and / or the amino acid sequence of GNTLPYTFG (SEQ ID NO:37), and / or the amino acid sequence of DYGVS (SEQ ID NO:38), the amino acid sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and / or the amino acid sequence of YAMDYWG (SEQ ID NO:40). or the scFv comprises the amino acid sequence of FMC63 (V, V ... H , a linker, optionally comprising SEQ ID NO: 24, and V Land / or the scFv comprises a flexible linker and / or comprises the amino acid sequence shown in SEQ ID NO:43; and / or the spacer (a) comprises or consists of all or a portion of an immunoglobulin hinge or a modified version thereof, or comprises about 15 amino acids or less and does not include the CD28 or CD8 extracellular region, (b) comprises or consists of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge or a modified version thereof, and / or comprises about 15 amino acids or less and does not include the CD28 or CD8 extracellular region, or (c) is 12 or about 12 amino acids in length and / or comprises or consists of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge or a modified version thereof, or (d) has the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID or (e) a polypeptide spacer having the formula X1PPX2P, wherein X1 is glycine, cysteine, or arginine and X2 is cysteine ​​or threonine; and / or the costimulatory domain is selected from the group consisting of SEQ ID NO:34, or any variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; or (f) a polypeptide spacer having the formula X1PPX2P, wherein X1 is glycine, cysteine, or arginine and X2 is cysteine ​​or threonine; and / or NO:12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or the primary signaling domain comprises SEQ ID NO:13, 14 or 15 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto.

[0053] In some of any of the embodiments, the antigen binding domain comprises an scFv comprising the variable heavy chain region of FMC63 and the variable light chain region of FMC63; the spacer is a polypeptide spacer comprising the sequence of SEQ ID NO: 1; the costimulatory domain comprises SEQ ID NO: 12; and the primary signaling domain comprises SEQ ID NO: 13, 14, or 15. In some of any of the embodiments, the subject is a human subject.

[0054] Provided herein is an article of manufacture that includes a composition for cell therapy, or one of a plurality of compositions for cell therapy, comprising T cells that express a CAR that binds to CD19, and instructions for administering the cell therapy that specify administering the T cell composition according to any of the provided methods. [The present invention 1001] A method for determining the risk of developing toxicity after administration of a cell therapy, comprising the following steps: In a subject having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, evaluating one or more disease burden parameters selected from the lymph node tumor burden, blood tumor burden, and the ratio of the blood tumor burden to the lymph node tumor burden, wherein the cell therapy comprises a certain dose of engineered cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the parameter is evaluated from the subject before administration of the cell therapy; and Comparing the value of the one or more parameters individually with a threshold level for each parameter, wherein (1) (a) If the lymph node tumor burden is at or above the threshold level for the lymph node tumor burden, (b) the blood tumor burden is below the threshold level for the blood tumor burden, and / or (c) the ratio of the blood tumor burden to the lymph node tumor burden is below the threshold level for that ratio, then identify the subject as having a risk of developing neurotoxicity after administration of the cell therapy, or (2) (a) If the lymph node tumor burden is below the threshold level for the tumor burden, (b) the blood tumor burden is at or above the threshold level for the blood tumor burden, and / or (c) the ratio of the blood tumor burden to the lymph node tumor burden exceeds the threshold level for that ratio, then identify that the subject has no risk of developing neurotoxicity after administration of the cell therapy, step. [The present invention 1002] When the subject is identified as having a risk of developing neurotoxicity, (i) Administering the cell therapy to the subject at an optionally reduced dose, wherein optionally, (a) The method further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce or attenuate the development of neurotoxicity or the risk of developing neurotoxicity, and / or (b) The administration of the cell therapy to the subject is carried out or designated to be carried out in an inpatient setting and / or with an inpatient stay of one or more days, step; or (ii) Administering to the subject an alternative treatment other than the cell therapy for treating CLL or SLL The method of the present invention 1001 further comprising: [The present invention 1003] If a subject is identified as not at risk of developing neurotoxicity, (i) administering a cell therapy to a subject, optionally wherein: (a) optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or is not decreased by more than 1°C after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or (b) optionally, the administration of the cell therapy and any follow-up is performed on an outpatient basis and / or without hospitalizing the subject and / or requiring an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretic medication; Process The method of the present invention 1001 further comprising: [The present invention 1004] A method of selecting a subject for treatment with cell therapy, comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and the ratio of blood tumor burden to lymph node tumor burden in a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), wherein the parameters are assessed in the subject prior to administration of the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually; (1) If (a) the lymph node tumor burden is equal to or greater than a threshold level for lymph node tumor burden, (b) the blood tumor burden is less than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is less than a threshold level for that ratio, (i) administration of the cell therapy at a reduced dose; (ii) administration of an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the manifestation of neurotoxicity or the risk of the manifestation of neurotoxicity; (iii) administration of a cellular therapy that is performed or designated to be performed in an inpatient setting and / or involves a one-day or multiple-day hospital stay; and / or (iv) Administration of alternative treatments other than cell therapy to treat CLL or SLL Select for; or (2) If (a) the lymph node tumor burden is below a threshold level for tumor burden, (b) the blood tumor burden is equal to or greater than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is above a threshold level for that ratio, (i) selected for administration of a cell therapy, and optionally, wherein: (a) optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or is not decreased by more than 1°C after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or (b) optionally, the administration of the cell therapy and any follow-up is performed on an outpatient basis and / or without hospitalizing the subject and / or requiring an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretic medication; Process. [The present invention 1005] The method of the present invention 1004 further comprising administering to the subject a cell therapy, an agent or other treatment that can treat, prevent, delay, reduce or attenuate the onset of toxicity or the risk of the onset of toxicity, and / or an alternative treatment. [The present invention 1006] 1006. The method of any one of claims 1001 to 1005, wherein the step of assessing blood tumor burden comprises determining the lymphocyte concentration in the subject's blood. [The present invention 1007] The method of claim 1006, wherein the concentration is the number of lymphocytes per microliter (μL) of blood. [The present invention 1008] 8. The method of any of claims 1001 to 1007, wherein the threshold level for blood tumor burden is a value between 800 or about 800 lymphocytes / μL and 3000 or about 3000 lymphocytes / μL. [The present invention 1009] A threshold level for blood tumor burden is 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL, or 3000 lymphocytes / μL, or about 800 lymphocytes / μL. 1008. The method of claim 1008, wherein the lymphocyte count is 900 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL or 3000 lymphocytes / μL, or any value between the foregoing. [The present invention 1010] 1009. The method of any one of claims 1001 to 1009, wherein the step of assessing lymph node tumor burden comprises determining the largest lymph node diameter. [The present invention 1011] The method of claim 1010, wherein the largest lymph node diameter is measured in centimeters (cm). [The present invention 1012] Method of invention 1010 or invention 1011, wherein the threshold level for the largest lymph node diameter as lymph node tumor burden is a value of 4 or about 4 cm to 7 or about 7 cm. [The present invention 1013] Any of the methods of the present invention 1010 to 1012, wherein the threshold level for maximum lymph node diameter as lymph node tumor burden is 4cm, 4.25cm, 4.5cm, 4.75cm, 5cm, 5.25cm, 5.5cm, 5.75cm, 6cm, 6.25cm, 6.5cm, 6.75cm or 7cm, or a value of about 4cm, 4.25cm, 4.5cm, 4.75cm, 5cm, 5.25cm, 5.5cm, 5.75cm, 6cm, 6.25cm, 6.5cm, 6.75cm or 7cm, or any value therebetween. [The present invention 1014] Any of the methods of claims 1001 to 1009, wherein the step of assessing the ratio of blood tumor burden to lymph node tumor burden comprises determining the ratio of lymphocyte count per microliter (μL) of blood to the largest lymph node diameter in centimeters (cm). [The present invention 1015] 1014. The method of the present invention, wherein the threshold level for the ratio of lymphocyte count per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of at or about 300 to at or about 1000. [The present invention 1016] 1016. The method of claim 1014 or 1015, wherein the threshold level for the ratio of lymphocyte count per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000, or a value of about 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000, or a value between any of the foregoing. [The present invention 1017] 1009. The method of any of claims 1001 to 1009, wherein the step of assessing lymph node tumor burden comprises determining the sum of two-way products (SPD). [The present invention 1018] SPD is square centimeters (cm 2 ) measured in units of 1017 of the method of the present invention. [The present invention 1019] The threshold level for SPD as lymph node tumor burden is 10 or approximately 10 cm 2 ~40 or about 40cm 2 The method of the present invention 1017 or 1018, wherein the value is [The present invention 1020] The threshold level for SPD as lymph node tumor burden is 10 cm 2 , 12.5cm 2 , 15cm 2 , 17.5cm 2 , 20cm 2 , 22.5cm 2 , 25cm 2 , 27.5cm 2 , 30cm 2 , 32.5cm 2 , 35cm 2 , 37.5cm 2 Or 40cm 2 , or about 10 cm 2 , 12.5cm 2 , 15cm 2 , 17.5cm 2 , 20cm 2 , 22.5cm 2 , 25cm 2 , 27.5cm 2 , 30cm 2 , 32.5cm 2 , 35cm 2 , 37.5cm 2 Or 40cm 2 or any value between the above. [The present invention 1021] The step of assessing the ratio of blood tumor burden to lymph node tumor burden is performed in square centimeters (cm 2 Any of the methods of claims 1001 to 1009 and 1017 to 1020, comprising determining the ratio of the number of lymphocytes per microliter (µL) of blood to the sum of two-way products (SPD) in units of 1001 to 1009 (SPD). [The present invention 1022] The method of the present invention 1021, wherein the threshold level for the ratio of lymphocyte count per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 25 or about 25 to 500 or about 500. [The present invention 1023] 1023. The method of claim 1021 or 1022, wherein the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450 or 500, or a value of about 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450 or 500, or a value between any of the foregoing. [The present invention 1024] The method of any of claims 1001 to 1023, wherein the value of the one or more disease burden parameters is the value of said one or more disease burden parameters before administering lymphodepletion therapy to the subject. [The present invention 1025] 1. A method for determining the risk of developing toxicity following administration of a cell therapy, 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and 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 11 or about 11 days after initiating administration of the cell therapy; and comparing the level, amount or concentration of TNF and / or IL-16 individually with a threshold level for each, the threshold level for TNF is between 7 or about 7 pg / mL and 25 or about 25 pg / mL; and / or the threshold level for IL-16 is a value between 400 or about 400 pg / mL and 1000 or about 1000 pg / mL; (1) identifying a subject as being at risk for developing neurotoxicity following administration of a cell therapy if the level, amount, or concentration of TNF and / or IL-16 is at or above the respective threshold level; or (2) identifying the subject as not at risk for developing neurotoxicity following administration of the cell therapy if the level, amount, or concentration of TNF and / or IL-16 is below the respective threshold level; Process. [The present invention 1026] The method of any of claims 1002 to 1024, wherein the agent or other treatment is or comprises an anti-IL-6 antibody, an anti-IL-6R antibody, or a steroid. [The present invention 1027] The method of any of claims 1002 to 1024, wherein the agent is tocilizumab, siltuximab, or dexamethasone, or comprises tocilizumab, siltuximab, or dexamethasone. [The present invention 1028] The method of any one of claims 1001 to 1027, wherein the neurotoxicity is severe neurotoxicity. [The present invention 1029] The method of any of claims 1001 to 1028, wherein the neurotoxicity is grade 3 or higher. [The present invention 1030] 1. A method for assessing likelihood of success of a cell therapy, 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and individually comparing the level, amount or concentration of VEGFC and / or VEGFR1 in the sample to a threshold level; (1) identifying a subject as likely to achieve a response to cell therapy if the level, amount, or concentration of VEGFC and / or VEGFR1 is below the respective threshold level; or (2) if the level, amount, or concentration of VEGFC and / or VEGFR1 is at or above the respective threshold level, the subject is identified as unlikely to achieve a response to the cell therapy; Process. [The present invention 1031] A method of selecting a subject for treatment with cell therapy, comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and selecting subjects who are likely to respond to treatment based on the results of determining the likelihood of the subject achieving a response to cell therapy by individually comparing the level, amount or concentration of VEGFC and / or VEGFR1 in the sample with a threshold level for each; (1) identifying a subject as likely to achieve a response to cell therapy if the level, amount, or concentration of VEGFC and / or VEGFR1 is below the respective threshold level; or (2) if the level, amount, or concentration of VEGFC and / or VEGFR1 is at or above the respective threshold level, the subject is identified as unlikely to achieve a response to the cell therapy; Process. [The present invention 1032] The method of claim 1030 or claim 1031, further comprising administering a cell therapy to the subject selected for treatment. [The present invention 1033] A method for treatment comprising the steps of: (a) selecting subjects who are likely to respond to treatment based on the results of determining the likelihood of the subject achieving a response to cell therapy by individually comparing 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 with a threshold level for each; (1) identifying a subject as likely to achieve a response to cell therapy if the level, amount, or concentration of VEGFC and / or VEGFR1 is below the respective threshold level; or (2) identifying the subject as unlikely to achieve a response to the cell therapy if the level, amount, or concentration of VEGFC and / or VEGFR1 is at or above the respective threshold level; wherein the biological sample is derived from a subject with CLL or SLL who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy and / or the subject does not comprise T cells expressing a CAR. process; and (b) administering the cell therapy to the subject selected for treatment. [The present invention 1034] the threshold level is within 25%, within 20%, within 15%, within 10%, or within 5%, and / or within one standard deviation of, at, about, or above the median or mean level, amount, or concentration of VEGFC and / or VEGFR1 in biological samples obtained from a group of subjects prior to receiving cell therapy, wherein each of the subjects in the group achieves a response after administration of a dose of engineered cells expressing a CAR to treat CLL or SLL; the threshold level is 1.25-fold or more higher, 1.3-fold or more higher, 1.4-fold or more higher, or 1.5-fold or more higher than the median or mean level, amount, or concentration of VEGFC and / or VEGFR1 in biological samples obtained from a group of subjects prior to receiving cell therapy, wherein each of the subjects in the group achieves a response after administration of a dose of engineered cells expressing a CAR to treat CLL or SLL; The threshold level is 1.25 times or more higher, 1.3 times or more higher, 1.4 times or more higher, or 1.5 times or more higher than the level, amount, or concentration of VEGFC and / or VEGFR1 in a biological sample obtained from a group of normal or healthy subjects who are not candidates for cell therapy treatment; Any of the methods of 1030 to 1033 of the present invention. [This invention 1035] 1035. The method of any of claims 1030 to 1034, wherein the threshold level for VEGFC is a value of 60 or about 60 pg / mL to 70 or about 70 pg / mL. [The present invention 1036] 1036. The method of any of claims 1030 to 1035, wherein the threshold level for VEGFR1 is a value of from 80 or about 80 pg / mL to 120 or about 120 pg / mL. [This invention 1037] The levels, amounts or concentrations of both VEGFC and VEGFR1 are assessed, The threshold level for VEGFC is a value of 60 or about 60 pg / mL to 70 or about 70 pg / mL, The threshold level for VEGFR1 is a value of 80 or about 80 pg / mL to 120 or about 120 pg / mL. Any of the methods 1030 to 1036 of the present invention. [The present invention 1038] 8. The method of any of claims 1030 to 1037, wherein the biological sample is a blood, plasma or serum sample or is obtained from a blood, plasma or serum sample. [This invention 1039] The evaluating step comprises: (a) contacting the biological sample with one or more reagents capable of detecting or specific for VEGFC and / or VEGFR1, optionally wherein the one or more reagents comprise an antibody that specifically recognizes VEGFC and / or VEGFR1; and (b) detecting the presence or absence of a complex comprising said one or more reagents and VEGFC and / or VEGFR1. Any of the methods of 1030 to 1038 of the present invention, comprising: [The present invention 1040] 1039. The method of any one of claims 1030 to 1039, wherein the evaluating step comprises an immunoassay. [The present invention 1041] Any of the methods of claims 1030 to 1040, wherein the evaluating step comprises enzyme-linked immunosorbent assay (ELISA), immunoblotting, immunoprecipitation, radioimmunoassay (RIA), immunostaining, flow cytometry assay, surface plasmon resonance (SPR), chemiluminescence assay, lateral flow immunoassay, inhibition assay, or avidity assay. [The present invention 1042] 1042. The method of any of claims 1030 to 1041, wherein the evaluating step comprises an enzyme-linked immunosorbent assay (ELISA), optionally a bead-based ELISA. [This invention 1043] The method of any of claims 1030 to 1042, wherein the response comprises an objective response. [This invention 1044] The method of the present invention 1043, wherein the objective response includes complete response (CR; sometimes also known as complete remission), complete remission with incomplete blood count recovery (CRi), complete remission (CR), CR with incomplete bone marrow recovery (CRi), nodular partial remission (nPR), partial response (PR). [This invention 1045] The method of any of claims 1030 to 1044, wherein the response is assessed at or about 1, 2, or 3 months or more after initiation of administration of the cell therapy. [The present invention 1046] The method of any of claims 1030 to 1045, wherein the response is a response assessed 3 or about 3 months after initiation of administration of the cell therapy. [This invention 1047] The method of any of claims 1001 to 1046, further comprising administering lymphodepletion therapy to the subject prior to administration of the cell therapy. [This invention 1048] The method of any of claims 1001 to 1047, wherein the subject has been preconditioned by lymphodepletion therapy. [This invention 1049] The method of claim 1048, wherein the biological sample is obtained from the subject prior to administration of lymphodepleting therapy to the subject. [The present invention 1050] The method of claim 1048, wherein one or more disease burden parameters are assessed prior to administration of lymphodepleting therapy to the subject. [This invention 1051] The method of any of claims 1047 to 1050, wherein the lymphodepleting therapy comprises administration of fludarabine and / or cyclophosphamide. [This invention 1052] Lymphocyte depletion therapy is approximately 200-400 mg / m, inclusive. 2 , optionally 300 or about 300 mg / m 2 of cyclophosphamide, and / or approximately 20–40 mg / m 2 , optionally 30 mg / m 2 2. The method of any of claims 1047 to 1051, comprising daily administration of fludarabine of 2 to 4 days, optionally 3 days. [This invention 1053] Lymphocyte depletion therapy is administered at or about 300 mg / m 2 of cyclophosphamide and approximately 30 mg / m 2 of fludarabine daily for three days, and optionally said dose of cells is administered at least 2-7 days or at least about 2-7 days after lymphodepletion therapy or at least 2-7 days or at least about 2-7 days after initiation of lymphodepletion therapy. [This invention 1054] The method of any of claims 1001 to 1053, further comprising the step of administering to the subject a Bruton's tyrosine kinase inhibitor (BTKi). [This invention 1055] The method of claim 1054, wherein the BTKi is ibrutinib. [This invention 1056] The method of claim 1054 or claim 1055, wherein BTKi administration is initiated before the start of administration of the cell therapy. [This invention 1057] The method of claim 1056, wherein the BTKi administration is continued until after the start of administration of the cell therapy. [This invention 1058] The method of claim 1056 or claim 1057, wherein BTKi administration is continued for at least about 90 days or for about 90 days after initiation of administration of the cell therapy. [This invention 1059] The method of any of claims 1055 to 1058, wherein ibrutinib is administered at a dose of from at or about 140 mg to 840 or about 840 mg per day. [The present invention 1060] 1059. The method of any of claims 1055 to 1059, wherein ibrutinib is administered at a dose of from at or about 280 mg to 560 or about 560 mg per day. [This invention 1061] The method of any of claims 1055 to 1060, wherein ibrutinib is administered at a dose of at or about 420 mg per day. [This invention 1062] The method of any of claims 1001 to 1061, wherein the disease or condition is relapsed or refractory (r / r) CLL. [This invention 1063] The method of any of claims 1001 to 1062, wherein the disease or condition is relapsed or refractory (r / r) SLL. [This invention 1064] The dose of engineered cells is a CAR-expressing CD4 + Cells vs. CAR-expressing CD8 + The method of any of claims 1001 to 1063, comprising a predetermined ratio of cells, optionally said ratio being from about 1:3 to about 3:1. [This invention 1065] the dose of engineered cells is 1:1 or approximately 1:1, + Cells vs. CAR-expressing CD8 + The method of any one of claims 1001 to 1064, comprising a predetermined ratio of cells. [The present invention 1066] The dose of engineered cells is 2.5×10 7 or approximately 2.5 x 10 7 Total CAR-expressing cells ~1.0 x 10 8 or approximately 1.0 x 10 8 Any of the methods of claims 1001 to 1065, comprising a total of CAR-expressing cells. [This invention 1067] The dose of engineered cells is 2.5×10 7 or approximately 2.5 x 10 7 The method of any of claims 1001 to 1066, comprising a total of CAR-expressing cells. [The present invention 1068] The dose of engineered cells is 5×10 7 or about 5 x 10 7 The method of any of claims 1001 to 1066, comprising total cells or total CAR-expressing cells. [The present invention 1069] The dose of engineered cells is 1×10 8 or about 1 x 10 8 The method of any of claims 1001 to 1066, comprising total cells or total CAR-expressing cells. [The present invention 1070] The administration of the cell therapy comprises administering a plurality of separate compositions, wherein the plurality of separate compositions are CD4 + T cells and CD8 + a first composition comprising one of a CD4 T cell and a CD4 + T cells and CD8 + The method of any of claims 1001 to 1069, comprising a second composition comprising the other of the T cells. [This invention 1071] The first composition is CD8 + T cells, and the second composition comprises CD4 + The method of any one of claims 1001 to 1070, comprising a T cell. [This invention 1072] The method of claim 1071, wherein the initiation of administration of the first composition is performed before the initiation of administration of the second composition, and optionally, the initiation of administration of the first composition and the initiation of administration of the second composition are performed with an interval of no more than 48 hours between them. [This invention 1073] CD4 + CAR and / or CD8 on T cells + The CAR contained in the T cells contains the same CAR and / or CD4 + T cells and / or CD8 + 1073. The method of any of claims 1064 to 1072, wherein T cells are genetically engineered to express the same CAR. [This invention 1074] Any of the methods of claims 1001-1073, wherein the subject has been treated with one or more prior treatments for CLL or SLL, optionally at least two prior treatments, in addition to another dose of CAR-expressing cells and lymphodepletion therapy, prior to administration of the cell therapy. [This invention 1075] Any of the methods of inventions 1001-1074, wherein the subject has relapsed following remission after treatment with two or more prior therapies, or has become resistant to treatment with two or more prior therapies, has failed treatment with two or more prior therapies, and / or is intolerant to treatment with two or more prior therapies prior to administration of the cell therapy. [This invention 1076] The method of claim 1074 or claim 1075, wherein the one or more prior treatments are selected from a kinase inhibitor, optionally an inhibitor of Bruton's tyrosine kinase (BTK), optionally ibrutinib; venetoclax; combination therapy comprising fludarabine and rituximab; radiation therapy; and hematopoietic stem cell transplantation (HSCT). [This invention 1077] The method of any of claims 1074 to 1076, wherein the one or more prior treatments include an inhibitor of Bruton's tyrosine kinase (BTK) and / or venetoclax. [This invention 1078] The method of any of claims 1074 to 1077, wherein the one or more prior treatments include ibrutinib and venetoclax. [This invention 1079] Any of the methods of inventions 1074 to 1077, wherein the subject has relapsed following remission after treatment with a Bruton's tyrosine kinase (BTK) inhibitor and / or venetoclax, has become resistant to treatment with a Bruton's tyrosine kinase (BTK) inhibitor and / or venetoclax, has failed treatment with a Bruton's tyrosine kinase (BTK) inhibitor and / or venetoclax, and / or is intolerant to a Bruton's tyrosine kinase (BTK) inhibitor and / or venetoclax. [The present invention 1080] Any of the methods of claims 1074 to 1079, wherein the subject has relapsed following remission after treatment with ibrutinib and venetoclax, has become resistant to treatment with ibrutinib and venetoclax, has failed treatment with ibrutinib and venetoclax, and / or is intolerant to ibrutinib and venetoclax. [This invention 1081] The method of any of claims 1001 to 1080, wherein the engineered cells are primary T cells obtained from the subject. [This invention 1082] The method of any of claims 1001 to 1081, wherein the engineered cells are autologous to the subject. [This invention 1083] the CAR comprises an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, optionally 4-1BB, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, optionally CD3 zeta; and / or The CAR, in turn, comprises an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule. Any of the methods of 1001 to 1082 of the present invention. [This invention 1084] The method of claim 1083, wherein the antigen-binding domain is an scFv. [This invention 1085] The scFv comprises the CDRL1 sequence of RASQDISKYLN (SEQ ID NO:35), the CDRL2 sequence of SRLHSGV (SEQ ID NO:36), and / or the CDRL3 sequence of GNTLPYTFG (SEQ ID NO:37), and / or the CDRH1 sequence of DYGVS (SEQ ID NO:38), the CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and / or the CDRH3 sequence of YAMDYWG (SEQ ID NO:40); the scFv comprises the variable heavy chain region of FMC63 and the variable light chain region of FMC63, and / or the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binds to the same epitope as any of the foregoing, or competes for binding with any of the foregoing; scFv is V as shown in SEQ ID NO:41 H and V as shown in SEQ ID NO:42 L and optionally, the V H and the V L and is separated by a flexible linker, optionally the flexible linker is or comprises the sequence set forth in SEQ ID NO:24; and / or The scFv has or comprises the sequence shown in SEQ ID NO: 43; The method of the present invention 1084. [This invention 1086] 1086. The method of any of claims 1083 to 1085, wherein the costimulatory signaling region is the signaling domain of CD28 or 4-1BB. [This invention 1087] 1087. The method of any one of claims 1083 to 1086, wherein the costimulatory signaling region is the signaling domain of 4-1BB. [This invention 1088] 8. The method of any of claims 1083 to 1087, wherein the costimulatory domain comprises SEQ ID NO:12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto. [This invention 1089] 1089. The method of any of claims 1083 to 1088, wherein the primary signaling domain is a CD3 zeta signaling domain. [The present invention 1090] Any of the methods of claims 1083 to 1089, wherein the primary signaling domain comprises SEQ ID NO: 13, 14 or 15 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto. [This invention 1091] 1090. The method of any of claims 1083 to 1090, wherein the CAR further comprises a spacer between the transmembrane domain and the antigen-binding domain. [This invention 1092] 1091. The method of claim 1091, wherein the spacer is a polypeptide spacer comprising or consisting of all or part of an immunoglobulin hinge or a modified version thereof, optionally an IgG4 hinge or a modified version thereof. [This invention 1093] The method of claim 1091 or claim 1092, wherein the spacer is about 15 amino acids or less and does not contain the extracellular region of CD28 or CD8. [This invention 1094] 1094. The method of any of claims 1091 to 1093, wherein the spacer is 12 or about 12 amino acids in length. [This invention 1095] the spacer has or consists of the sequence of SEQ ID NO:1, the sequence encoded by SEQ ID NO:2, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or formula 1 PPX 2 P, wherein X 1 is glycine, cysteine, or arginine, and X 2 is cysteine ​​or threonine, Any of methods 1091 to 1094 of the present invention. [This invention 1096] The scFv is selected from the group consisting of the amino acid sequence of RASQDISKYLN (SEQ ID NO:35), the amino acid sequence of SRLHSGV (SEQ ID NO:36), and / or the amino acid sequence of GNTLPYTFG (SEQ ID NO:37), and / or the amino acid sequence of DYGVS (SEQ ID NO:38), the amino acid sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and / or the amino acid sequence of YAMDYWG (SEQ ID NO:40). or the scFv comprises the amino acid sequence of FMC63 (V, V ... H and optionally a linker comprising SEQ ID NO: 24; and V L and / or the scFv comprises a flexible linker and / or comprises the amino acid sequence shown in SEQ ID NO:43; The spacer is (a) comprising or consisting of all or a portion of an immunoglobulin hinge or a modified version thereof, or comprising about 15 amino acids or less and not comprising the CD28 or CD8 extracellular region; (b) comprising or consisting of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified version thereof, and / or comprising about 15 amino acids or less and not comprising the CD28 or CD8 extracellular region; or (c) being 12 or about 12 amino acids in length and / or comprising or consisting of all or a portion of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified version thereof; or (d) having the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO: (e) having or consisting of a sequence encoded by NO:34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; or (f) a sequence of formula X 1 PPX 2 P, where X 1 is glycine, cysteine, or arginine, and X 2 is a cysteine ​​or threonine, and; the costimulatory domain comprises SEQ ID NO:12, or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or the primary signaling domain comprises SEQ ID NO: 13, 14 or 15 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; Any of methods 1083 to 1095 of the present invention. [This invention 1097] the antigen-binding domain comprises an scFv comprising the variable heavy chain region of FMC63 and the variable light chain region of FMC63; the CAR further comprises a spacer that is a polypeptide spacer comprising the sequence of SEQ ID NO:1; the costimulatory domain comprises SEQ ID NO:12; the primary signaling domain comprises SEQ ID NO: 13, 14 or 15; Any of methods 1083 to 1096 of the present invention. [This invention 1098] The method of any one of claims 1001 to 1097, wherein the subject is a human subject. [This invention 1099] An article of manufacture comprising a composition for cell therapy, or one of a plurality of compositions for cell therapy, comprising T cells expressing a CAR that binds to CD19, and instructions for administering the cell therapy, specifying administering the T cell composition according to any of the methods of inventions 1001-1098. [The present invention 1100] A cell therapy comprising T cells expressing a CAR that binds to CD19 for use in a method of treating a subject having chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) according to any of the methods of inventions 1001-1098. [Brief explanation of the drawings]

[0055] [Figure 1A] Figure 1A shows the best overall response outcomes in subjects (N=22) with R / R CLL who received anti-CD19 CAR T cells in DL1 (5x107 CAR-expressing T cells) or DL2 (1x108 CAR-expressing T cells). PD, progressive disease; SD, stable disease; PR, partial response; nPR, nodal partial response; CR, complete response; CRi, complete response with incomplete marrow recovery. [Figure 1B]Figure 1B shows the results of undetectable minimal residual disease (uMRD) in blood by flow cytometry or in bone marrow by next-generation sequencing (NGS) at any time point after administration of DL1 (5 x 107 CAR-expressing T cells) or DL2 (1 x 108 CAR-expressing T cells) anti-CD19 CAR-expressing T cells to subjects with R / R CLL. [Figure 2] Figure 2 shows swimmer plots of response duration over time in subjects (N=22) with R / R CLL who received anti-CD19 CAR+ T cells in DL1 (5×107 CAR-expressing T cells) or DL2 (1×108 CAR-expressing T cells). b Depth of detection = 10-4. [Figure 3] Figure 3 depicts a graph of median cell counts / μl over time by dose level in subjects with R / R CLL who received DL1 (5×10 CAR-expressing T cells) or DL2 (1×10 CAR-expressing T cells) anti-CD19 CAR+ T cells. The upper error bar represents the third quartile, and the lower error bar represents the first quartile. The dose of anti-CD19 CAR+ T cells was given on day 1. The upper error bar represents the third quartile, and the lower error bar represents the first quartile. [Figure 4A] Figure 4A shows best overall response results in subjects with R / R CLL (N=22) or subjects who failed prior treatment with both a Bruton's tyrosine kinase inhibitor (BTKi) and venetoclax (N=9). [Figure 4B]Figure 4B shows the results of undetectable minimal residual disease (uMRD) in blood by flow cytometry or in bone marrow by next-generation sequencing (NGS) at any time point after administration in subjects with R / R CLL (N = 20) or subjects (N = 8) who failed pretreatment with both BTKi and venetoclax. aEvaluable for response was defined as having a pretreatment evaluation and ≥1 post-baseline evaluations; evaluable for MRD was defined as patients with detectable MRD at baseline. One subject was not evaluable for response. bVenetoclax failure was defined as PD or discontinuation due to <PR after ≥3 months of treatment. cTwo subjects were not evaluable for MRD. dOne subject was not evaluable for MRD. CI, confidence interval; CRi, complete response with incomplete blood count recovery; NGS, next-generation sequencing; nPR, nodular partial response; PD, progression; PR, partial response; SD, stable; uMRD, undetectable minimal residual disease. [Figure 5] Figure 5 shows a swimmer plot of the duration of response over time in individual subjects with R / R CLL who failed pretreatment with both BTKi and venetoclax and other treated subjects. *MRD not evaluable. There were 7 deaths during the study, 5 subjects died due to disease progression, 1 subject had grade 5 respiratory failure (DL1) unrelated to CAR + T cell therapy treatment, and 1 subject had septic shock, acute kidney injury, and pneumonia (DL2) unrelated to CAR + T cell therapy treatment. There were no deaths within the first 30 days. ND, not done; RT, Richter transformation. [Figure 6] Figure 6 shows a graph of the median cell count / μL over time by dose level in evaluable treated subjects and subjects who failed pretreatment with both BTKi and venetoclax. The upper error bar represents the third quartile. The lower error bar represents the first quartile. CAR + T cell therapy was administered on day 1. [Figure 7A]Figure 7A shows the blood tumor burden (measured by lymphocyte count (1000 cells / µL)) and lymph node tumor burden (measured by maximum observed lymph node diameter (cm)) in subjects who did not experience any neurological events (N = Gr0) or who experienced grades 1 to 5 of neurotoxicity (Y = Gr1 to 5) (blood p = 0.018; lymph node p = 0.043). Subjects who experienced severe neurotoxicity (grade 3 or higher) are indicated by black circles. [Figure 7B] Figure 7B depicts lymph node tumor burden (as measured by two-way product sum (SPD)) in subjects who did not experience any neurological events (Gr0) or who experienced grade 1–4 neurotoxicity (Gr1–4; no grade 5 NE) (p = 0.025). a No grade 5 NE. [Figure 7C] Figure 7C depicts the relationship between blood tumor burden and lymph node tumor burden in subjects with no neurological events (open circles), subjects with grade 1 or 2 neurological events (open squares), and subjects with severe (grade 3 or higher) neurological events (Y, black diamonds). The boxed areas indicate that five of the five subjects with severe (grade 3 or higher) neurological events exhibited low blood tumor burden. [Figure 7D] Figure 7D shows the ratio of blood tumor burden to lymph node tumor burden in subjects who did not experience any neurological events (N = Gr0) or who experienced grades 1 to 5 of neurotoxicity (Y = Gr1 to 5) (P = 0.005). Subjects who experienced severe neurotoxicity (grade 3 or higher) are indicated by black circles. [Figure 8] Figure 8 depicts the geometric mean (±SEM) concentrations of TNF and IL-16 at various time points prior to and within 30 days after CAR+T cell administration in subjects who did not experience a neurological event (Ntx Gr=0) or experienced a neurological event of grade 1 or higher (Ntx Gr>0). [Figure 9A]Figure 9A shows the levels of IL-16 and TNF in samples obtained from subjects in the group of subjects who did not experience a neurological event (Gr0) or in the group of subjects who experienced a neurological event of grade 1 or higher, respectively, for IL-16 (Gr1-4; p=0.0001) and TNF (Gr1-4; p=0.0028). Grade 5 NE was not observed. [Figure 9B] Figure 9B depicts the relationship between blood IL-16 and TNF levels and lymph node tumor burden (as measured by two-way product sum (SPD)) 2 days after CAR+ T cell administration in subjects with no neurological events (Gr0 NE; open circles), subjects with grade 1 or 2 neurological events (Gr1-2 NE; open squares), or subjects with grade 3 or 4 neurological events (Gr3-4 NE; closed diamonds). [Figure 9C] Figure 9C depicts the relationship between blood IL-16 and TNF levels and lymph node tumor burden (as measured by maximum observed lymph node diameter (cm)) 2 days after administration of CAR+ T cells in subjects who did not experience any neurological events (Gr0 NE; open circles), subjects who experienced grade 1 or 2 neurological events (Gr1-2 NE; open squares), or subjects who experienced grade 3 or 4 neurological events (Gr3-4 NE; closed diamonds). [Figure 10] Figures 10A-10B represent the levels of vascular endothelial growth factor C (VEGFC; Figure 10A) and vascular endothelial growth factor receptor 1 (VEGFR1; Figure 10B), measured in pg / mL, in samples obtained from subjects immediately prior to CAR+ T cell administration in responders at 3 months (M3 R; subjects who achieved CR, CRi, PR, or nPR at 3 months post-administration) and non-responders at 3 months (M3 NR; subjects who experienced SD or PD at or before 3 months post-administration) after CAR+ T cell administration. [Figure 11A]Figure 11A depicts the mean CD3+CAR+ T-cell concentrations (measured as cells / μL) assessed from day 1 through month 3 post-infusion in 3-month responders (M3 R; subjects who achieved CR, CRi, PR, or nPR at 3 months post-dose) and 3-month non-responders (M3 NR; subjects who experienced SD or PD at or before 3 months post-dose). [Figure 11B] Figure 11B depicts the mean CD3 CAR+ T cell concentrations assessed for subjects receiving CAR+ T cells alone (CAR T cells only) and subjects receiving CAR+ T cells in combination with ibrutinib (CAR T cells and ibrutinib), assessed from day 1 to month 3 post-infusion. [Figure 12] Figure 12 depicts the number of concordant and discordant MRD status and total concordance between bone marrow (BM) minimal residual disease (MRD) status measured by an NGS-based assay (with a sensitivity of 10-4) and peripheral blood (PB) MRD status measured by flow cytometry (with a sensitivity of 10-4) at 30 days or 3 months after administration of anti-CD19 CAR+ T cells. DETAILED DESCRIPTION OF THE INVENTION

[0056] Detailed Description Provided herein are methods for determining the risk of developing toxicity associated with cell therapy in a subject who is a candidate for cell therapy and / or who has been administered cell therapy, and for determining the likelihood of success of cell therapy. In some aspects, the methods involve assessing one or more parameters related to the subject's disease or disorder, such as a parameter related to tumor burden in the subject. In some aspects, the methods involve assessing the level, concentration, and / or amount of a biomarker or analyte (e.g., blood analytes including cytokines and growth factors, and receptors). In some aspects, the parameter, biomarker, or analyte is associated with, correlates with, or is indicative of toxicity, e.g., neurotoxicity, that may be associated with the cell therapy. In some aspects, the parameter, biomarker, or analyte is associated with, correlates with, or is indicative of success of the cell therapy in the subject (e.g., objective response, partial response, and / or complete response). Optionally, the methods are used in conjunction with, in association with, or as part of cell therapy, e.g., involving the administration of engineered cells, e.g., involving the administration of modified T cells expressing a recombinant receptor such as a chimeric antigen receptor (CAR), and optionally the administration of an additional agent.

[0057] In some embodiments, the provided methods and uses involve, in some aspects, the use of engineered cells (e.g., T cells) and / or compositions thereof to treat subjects having a disease or condition that is or includes, generally, cancer or tumor, e.g., leukemia or lymphoma, most specifically chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In some aspects, the methods and uses provide or achieve improved response and / or more durable response or efficacy and / or reduced risk of toxicity or other side effects, e.g., in particular groups of treated subjects, compared to certain alternative methods. In some embodiments, the methods are advantageous because they can determine the risk of toxicity (e.g., neurotoxicity) and / or the likelihood that a subject will respond to cell therapy after administering CAR+ T cells. In other aspects, the methods can also include cell therapy involving administration of specified or relative numbers of engineered cells, administration of specific types of cells in predetermined ratios, treatment of specific patient populations, e.g., treatment of patient populations with particular risk profiles, disease staging, and / or prior treatment history, and / or combinations thereof.

[0058] In some aspects, methods are provided that include assessing specific parameters, such as tumor burden measurements and / or the expression of specific biomarkers or analytes, that can be correlated with the onset of toxicity, as well as methods of treatment, e.g., interventional therapy, to prevent and / or ameliorate toxicity. Methods are also provided that involve assessing specific parameters, such as tumor burden measurements, tumor burden measurement ratios, and / or the expression of specific biomarkers or analytes, that can be correlated with outcomes after administration of cell therapy, including treatment outcomes, such as objective response (OR), complete response (CR), or partial response (PR), or safety outcomes, such as the onset of toxicity, e.g., neurotoxicity. Methods are also provided for assessing the likelihood of response and / or the likelihood of risk of toxicity based on the assessment of parameters, such as tumor burden measurements, tumor burden measurement ratios, and / or the expression of biomarkers or analytes. Compositions for use in cell therapy are also provided. Articles of manufacture and kits are also provided, e.g., for use in the methods provided herein. In some embodiments, the articles of manufacture and kits optionally include instructions for use in accordance with the methods provided herein.

[0059] Provided embodiments include methods for assessing the risk of developing toxicity and / or likelihood of responding to cell therapy, particularly in subjects with CLL or SLL. In some aspects, CLL is considered an incurable disease, and subjects eventually relapse or become refractory to available therapies or treatments. In some of any of the embodiments, the subject has high-risk disease. In some embodiments of the provided methods, the subject has high-risk CLL or high-risk SLL. In some cases, existing treatment strategies for high-risk and very-high-risk subjects may include fludarabine, cyclophosphamide, and rituximab (FCR), Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib), and / or allogeneic stem cell transplantation. (Puiggros et al., BioMed Research International, Volume 2014 (2014), Article ID 435983). Many existing therapies involve oral targeted agents, which have improved treatment outcomes in some CLL patients. Nevertheless, some patients prove intolerant or resistant to treatment and / or fail to achieve a complete response with undetectable MRD (uMRD). In some aspects, subjects whose disease progresses after treatment with available therapies have poor outcomes. For example, in some aspects, subjects treated for CLL have poor long-term outcomes. For example, in some cases, refractory (R / R) high-risk CLL subjects have low survival rates after discontinuing ibrutinib (Jain et al. (2015) Blood 125(13):2062-2067). There is a need for improved methods for treating CLL, and in some aspects, there is a need for methods suitable for treating high-risk and / or very high-risk CLL and / or subjects with relapsed or refractory to multiple previous therapies.

[0060] In some aspects, adoptive cell therapy (including those involving the administration of cells expressing chimeric receptors, such as chimeric antigen receptors (CARs) and other recombinant antigen receptors, specific for a disease or disorder of interest, as well as adoptive immune cell therapy and adoptive T cell therapy) can be used to treat cancer, e.g., B-cell malignancies, and other diseases and disorders. In certain situations, available adoptive cell therapy approaches may not always be entirely satisfactory. Depending on the circumstances, optimal efficacy may depend on the ability of the administered cells to recognize and bind to a target, e.g., a target antigen; to be transported to, localize to, and successfully infiltrate the appropriate site within the subject, tumor, and its environment; to become activated and expand; to exert various effector functions, including cytotoxic killing and secretion of various factors, such as cytokines; to persist (including persist for long periods of time); to differentiate, transition to, or engage in reprogramming to specific phenotypic states (e.g., effector, long-lived memory, less differentiated, and effector states); to provide an effective and robust recall response following clearance and re-exposure to the target ligand or target antigen, and to avoid or reduce differentiation to exhaustion, anergy, terminal differentiation, and / or suppressive states.

[0061] In some aspects, the provided embodiments are based on the observation that the effectiveness of adoptive cell therapy is limited by the onset of toxicity, such as neurotoxicity, in subjects receiving such cells, and that certain parameters and / or biomarkers can be correlated and associated with the onset of toxicity and can be useful in predicting the onset of toxicity. In some of the embodiments, such findings can be used to determine the risk of toxicity after cell therapy administration for a particular subject, for example, at an early time point after administration of cell therapy, or even before administration of cell therapy. In some cases, toxicity, such as neurotoxicity, can be severe. For example, in some cases, administration of a certain dose of cells expressing a recombinant receptor, such as a CAR, can result in toxicity or a risk thereof, for example, neurotoxicity, including possibly severe neurotoxicity. In some cases, increasing the dose of such cells can increase the effectiveness of treatment, for example, by increasing exposure to the cells through increased expansion and / or survival, but can result in a higher risk of toxicity or more severe toxicity. Additionally, in some cases, subjects with a high disease burden, for example, a high lymph node tumor burden, may be at higher risk of developing toxicity or more severe toxicity.

[0062] Certain methods available for treating or ameliorating toxicity, such as neurotoxicity, that may be associated with cell therapy may not always be entirely satisfactory. Many such approaches focus on targeting the downstream effects of toxicity, for example, by cytokine blockade and / or by delivering agents such as high-dose steroids, which may eliminate or impair the function of the administered cells. In addition, such approaches often administer such interventions only when physical signs or symptoms of toxicity are detected, which may occur after the subject has developed severe toxicity. Furthermore, many of these other approaches do not prevent other forms of toxicity, such as neurotoxicity, that may be associated with adoptive cell therapy. In some cases, such treatments are not administered until the subject shows physical signs or symptoms of toxicity. In some cases, by that time, such symptoms may have become severe, and therefore, more severe or more extreme treatments (e.g., higher dosages or increased frequency of administration) may be required to ameliorate or treat the toxicity. There is also a need for improved methods for treating CLL, and in some aspects, for reducing the risk of toxicity (e.g., neurotoxicity) by determining the risk of toxicity early (e.g., before administration or at an early time point after administration) and taking steps to mitigate or eliminate potential toxicity.

[0063] The use of certain alternative approaches does not provide a satisfactory solution to such problems. For example, approaches in which toxicity-ameliorating agents are administered simultaneously with cell administration or after cell administration but within a time frame prior to the onset of physical or severe signs or symptoms, without at least an appropriate level of risk assessment, may be unsatisfactory. For example, not all subjects administered cell therapy will experience or currently experience a toxic outcome, or a toxic outcome that requires intervention. Thus, such alternatives may unnecessarily treat certain subjects for whom such treatment may not be warranted in some circumstances. Furthermore, in some cases, such agents and treatments (e.g., steroids) are themselves associated with toxic side effects. Such side effects may be exacerbated if higher or more frequent administration of the agent or treatment is required to treat or ameliorate the severity of toxicity that may result from cell therapy. Additionally, in some cases, agents or treatments for treating toxicity can limit the effectiveness of cell therapy, such as the effectiveness of chimeric receptors (e.g., CARs) expressed on cells provided as part of the cell therapy (Sentman (2013) Immunotherapy, 5:10).

[0064] The provided methods have advantages over available approaches and alternative solutions for addressing, predicting, treating, or preventing the risk of toxic outcomes. In particular, in some embodiments, the provided methods identify only subjects who are predicted to be at risk of developing toxicity, such as toxicity related to cell therapy, or who exceed a certain threshold risk level for developing such toxicity. Thus, in some embodiments, the provided methods allow intervention in toxic outcomes only in a subset of subjects who are more likely to develop toxicity. In many cases, this avoids treating toxicity in all subjects who receive cell therapy (which, as mentioned above, may not be justified and / or may result in unnecessary effects if many subjects would never develop toxicity).

[0065] In some aspects, provided embodiments also have advantages associated with the feature that the risk of developing toxicity, such as neurotoxicity (e.g., severe neurotoxicity), and / or likelihood of response can be predicted early, e.g., before administering a treatment, such as a cell therapy, or shortly after administering or initiating such treatment, or after administering or initiating the first dose of cell therapy. Thus, in some cases, subjects predicted to be at risk of developing toxicity (e.g., neurotoxicity, such as severe neurotoxicity) and / or subjects more likely to be at risk of developing such toxicity can receive intervention early, generally before the onset of physical signs or symptoms of toxicity (e.g., severe neurotoxicity) that would otherwise lead to intervention. In some cases, being able to intervene early to treat a toxic outcome or potential toxic outcome can mean being able to reduce the dosage of an agent to treat or ameliorate toxicity and / or reduce the frequency of administration of such an agent or treatment.

[0066] In some embodiments, the provided methods are based on the observation that certain parameters, biomarkers, or analytes, such as certain cytokine biomarkers, differ in samples obtained before treatment or early after administration of adoptive cell therapy in subjects who subsequently develop toxicity. In another aspect, the provided methods are also based on the observation that certain parameters, biomarkers, or analytes differ in subjects who subsequently achieve a response, such as a sustained response, after administration of adoptive cell therapy. Accordingly, such biomarkers described herein can be used in predictive methods to identify subjects who are more likely or more likely to develop toxicity and / or less likely to respond to cell therapy, so that subjects and effective doses can be selected prior to treatment and / or treatment modifications (e.g., additional therapeutic agents and / or changes in monitoring) can be made early during treatment. In some cases, such biomarkers described herein can be used in predictive methods to identify subjects who are more likely or more likely to develop toxicity to cell therapy, so that subjects and effective doses can be selected prior to treatment and / or treatment modifications (e.g., additional therapeutic agents and / or changes in monitoring) can be made early during treatment. In some cases, such biomarkers described herein can be used in predictive methods to identify subjects who are likely or more likely to respond to treatment, so that subjects and effective doses can be selected prior to treatment, and / or treatment modifications (e.g., additional therapeutic agents and / or changes in monitoring) can be made early during treatment. Such methods can inform rational strategies for early intervention, thereby facilitating the safe and effective clinical application of adoptive cell therapies, such as CAR-T cell therapy.

[0067] In some embodiments, the provided methods and uses can be used in conjunction with a cell therapy treatment method involving the administration of engineered cells to subjects selected or identified as having a particular prognosis or risk for CLL. Chronic lymphocytic leukemia (CLL) is generally a heterogeneous disease. Some subjects with CLL may survive without treatment, while others may require immediate intervention. Optionally, subjects with CLL can be classified into groups that can inform disease prognosis and / or recommended treatment strategies. Optionally, these groups are "low risk," "intermediate risk," "high risk," and / or "very high risk," and patients can be so classified depending on several factors, including, but not limited to, genetic abnormalities and / or morphological or physical characteristics. In some embodiments, subjects treated according to the present methods are classified or identified based on their risk for CLL. In some embodiments, the subjects are subjects with high-risk CLL. In some embodiments, the provided methods and uses may also provide or achieve improved response or efficacy compared to certain alternative methods, e.g., in certain groups of subjects treated, e.g., in patients with leukemia, e.g., in patients with CLL or SLL.

[0068] In addition, methods are also provided that can be used to predict or assess the likelihood of a particular subject's success with cell therapy.In certain aspects, determining the likelihood that a subject will achieve a particular outcome or condition following cell therapy, including, for example, a specific treatment outcome, including a response outcome or a toxicity outcome, can be a factor in identifying and selecting a subject for treatment and / or modifying a treatment regimen, selecting a subject for treatment with additional therapeutic agents, or identifying an appropriate dose for administration, for example, by selecting a subject who is likely to respond to treatment based on the results of determining the likelihood that a subject will achieve success with cell therapy.In some embodiments, the method is advantageous in that such outcome or condition is determined before treatment or shortly after the start of treatment, so that the success of treatment is improved without increasing the risk of toxicity.

[0069] In some embodiments, the methods also include administering to the subject an additional therapeutic agent, for example, an agent to ameliorate toxicity and / or other additional therapeutic agent, such as a kinase inhibitor.

[0070] All publications mentioned in this application, including patent documents, scientific articles, and databases, are incorporated herein in their entirety for all purposes to the same extent as if each individual publication was individually incorporated herein by reference. To the extent that a definition set forth herein conflicts or is otherwise inconsistent with a definition set forth in a patent, patent application, published patent application, or other publication incorporated herein by reference, the definition set forth herein shall take precedence over the definition incorporated herein by reference.

[0071] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0072] I. Methods for Assessing Parameters and Biomarkers and for Identifying and Selecting Subjects for Cell Therapy Treatment The provided methods and uses include methods of assessing the risk of developing toxicity associated with a cell therapy in a subject, which involves assessing or detecting a biomarker (e.g., analyte) or parameter associated with toxicity, e.g., neurotoxicity, such as severe neurotoxicity. Also provided are methods of assessing the likelihood of a cell therapy in a subject, which involves assessing or detecting a biomarker (e.g., analyte) or parameter associated with a response outcome, e.g., objective response (OR), including complete response (CR), CR with incomplete bone marrow recovery (CRi), nodular partial response (nPR), and partial response (PR).

[0073] In some embodiments, the methods involve assessing one or more disease burden parameters, such as lymph node tumor burden, blood tumor burden, and the ratio of blood tumor burden to lymph node tumor burden. In some embodiments, the methods involve assessing lymph node tumor burden. In some embodiments, the methods involve assessing blood tumor burden. In some embodiments, the methods involve assessing the ratio of blood tumor burden to lymph node tumor burden. In some embodiments, the methods involve assessing the level, concentration, or amount of one or more biomarkers or analytes, such as interleukin-16 (IL-16), tumor necrosis factor (TNF), vascular endothelial growth factor C (VEGFC), or vascular endothelial growth factor receptor 1 (VEGFR1). In some embodiments, the methods involve assessing the level, concentration, or amount of interleukin-16 (IL-16). In some embodiments, the methods involve assessing the level, concentration, or amount of tumor necrosis factor (TNF). In some embodiments, the methods involve assessing the level, concentration, or amount of vascular endothelial growth factor C (VEGFC). In some embodiments, the methods involve assessing the level, concentration, or amount of vascular endothelial growth factor receptor 1 (VEGFR1).

[0074] In some embodiments, the methods involve comparing the value of a parameter or the level, concentration, or amount of a biomarker or analyte to a threshold value for that particular parameter, biomarker, or analyte. In some embodiments, the comparison can be used to determine the risk of toxicity and / or the likelihood of success of the cell therapy.

[0075] In some embodiments, the cell therapy includes a dose of engineered cells, including T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19). In some embodiments, the parameter, biomarker, or analyte is assessed from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL), or is assessed in a sample obtained from such a subject. In some embodiments, the subject is a candidate for and / or is undergoing treatment with cell therapy. In some embodiments, the provided methods can be used to identify or select subjects at risk of developing toxicity and / or likely to benefit from cell therapy, and / or to select subjects for a particular treatment, e.g., treatment with an additional therapeutic agent, e.g., an agent or treatment to ameliorate any toxicity.

[0076] In some aspects, the methods also involve further monitoring the subject for symptoms of possible toxicity based on a risk of toxicity determined according to provided embodiments, such as by evaluating a parameter or biomarker and / or comparing the parameter or biomarker to a reference value or threshold level for that particular parameter or biomarker. In some aspects, the methods also involve further monitoring the subject for possible response based on a likelihood of response, such as by evaluating a parameter or biomarker and / or comparing the parameter or biomarker to a reference value or threshold level for that particular parameter or biomarker, for which a dose is determined according to provided embodiments.

[0077] In some embodiments, the methods involve assessing or detecting the presence or absence of a biomarker (e.g., an analyte) or a panel of biomarkers (e.g., an analyte) and / or a parameter (e.g., concentration, amount, level, or activity) associated with a biomarker (e.g., an analyte) or a panel of biomarkers (e.g., an analyte). Optionally, the methods can include comparing one or more parameters, such as those associated with the risk of developing toxicity (e.g., neurotoxicity), or with a particular response, e.g., OR, CR, ORR, CRi, PR, nPR, SD, or PD, and / or a durable response, e.g., a response that is sustained for 3, 6, 9, 12, or more months after the initial response, to a particular reference value, such as a threshold level. In some embodiments, the methods also involve selecting a subject for cell therapy treatment based on assessing the presence or absence of a biomarker and / or comparing the biomarker to a reference or threshold level for the biomarker.

[0078] In some embodiments, the parameter evaluated is or includes an attribute, factor, feature, and / or expression of a biomarker of the patient and / or the disease or condition. In some embodiments, the parameter is or includes one or more factors indicative of the patient's condition and / or the patient's disease or condition. In some embodiments, the parameter is indicative of tumor burden. In some embodiments, the parameter is indicative of tumor burden in a specific organ or tissue, e.g., lymph node tumor burden or blood tumor burden. In some embodiments, the parameter is or includes an attribute, factor, feature of the patient and / or the disease or condition. In some embodiments, the parameter is a parameter related to tumor burden, e.g., a measure of tumor burden.

[0079] In some aspects, a biological sample, e.g., a blood or tissue sample, from a subject can be obtained to detect the presence or absence of a biomarker (e.g., an analyte), e.g., to detect or measure a parameter (e.g., concentration, amount, level, or activity) of the biomarker and / or to assess the presence of the biomarker for the purpose of analyzing, correlating, and / or detecting a particular outcome and / or toxicity. In some embodiments, a particular physiological or biological parameter associated with a biomarker, e.g., biomarker expression and / or clinical and laboratory parameters, can be assessed from a biological sample, e.g., blood, from a subject before or after administration of a cell therapy. In some embodiments, biomarker or analyte expression and / or clinical and laboratory parameters can be assessed from a biological sample, e.g., blood, from a subject before administration of a cell therapy (pre-treatment). In some embodiments, biomarker or analyte expression and / or clinical and laboratory parameters can be assessed from a biological sample, e.g., blood, from a subject after administration of a cell therapy (post-treatment). In some embodiments, the concentration, amount, level, or activity of a biomarker (e.g., an analyte) and / or clinical and laboratory parameter can be assessed at one or more time points before or after administration of a cell therapy. In some embodiments, the peak concentration, amount, level or activity of a biomarker (eg, analyte) and / or clinical and laboratory parameter during a specified period of time can also be determined.

[0080] In some embodiments, a biomarker or analyte is an objectively measurable characteristic or molecule expressed by or in a biological sample containing cells that can indicate or be associated with a particular condition or phenomenon, such as a biological process, a treatment outcome, a cell phenotype, or a disease state. In some aspects, a biomarker or analyte or a parameter associated with a biomarker or analyte can be measured or detected. For example, the presence or absence of expression of a biomarker or analyte can be detected. In some aspects, a parameter, such as the concentration, amount, level, or activity of a biomarker or analyte, can be measured or detected. In some embodiments, the presence, absence, expression, concentration, amount, level, and / or activity of a biomarker can be associated with, correlated with, indicative of, and / or predict a particular condition, such as a particular treatment outcome or condition of a subject. In some aspects, the presence, absence, expression, concentration, amount, level, and / or activity of a biomarker or analyte, such as any described herein, can be used to assess the likelihood of a particular outcome or condition, such as a particular treatment outcome, including a response outcome or a toxicity outcome. In some embodiments, exemplary biomarkers include cytokines, cell surface molecules, chemokines, receptors, soluble receptors, soluble serum proteins and / or degradation products. In some embodiments, biomarkers or analytes can also include specific attributes, factors, characteristics of a patient and / or a disease or condition, or factors indicative of the state of a patient and / or a disease or condition (including disease burden), and / or clinical or laboratory parameters. In some aspects, the biomarker is a cytokine. In some aspects, the biomarker is a chemokine. In some aspects, the biomarker is a growth factor. In some aspects, the biomarker is a receptor. In some aspects, the biomarker is a soluble receptor.

[0081] In some embodiments, biomarkers can be used alone or in combination with other biomarkers, for example, in a panel of biomarkers. In some embodiments, the expression of a particular biomarker can be correlated with a particular outcome or toxicity, such as the development of neurotoxicity. In some embodiments, the expression of a particular biomarker can be correlated with a particular outcome or response, such as objective response (OR), complete response (CR), CR with incomplete bone marrow recovery (CRi), nodal partial response (nPR), or partial response (PR).

[0082] In some embodiments, the method includes detecting the presence or absence of one or more biomarkers, e.g., a parameter associated with one or more biomarkers (e.g., concentration, amount, level, or activity), wherein the one or more biomarkers are selected from interleukin-16 (IL-16), tumor necrosis factor (TNF), vascular endothelial growth factor C (VEGFC), or vascular endothelial growth factor receptor 1 (VEGFR1).

[0083] In some embodiments, the presence or absence and / or parameter of one or more biomarkers (e.g., analytes) is evaluated from biological samples.In some aspects, the biological sample is body fluid or tissue.In some such embodiments, the biological sample, for example, body fluid, is whole blood, serum or plasma, or contains whole blood, serum or plasma.

[0084] In some embodiments, the parameter and / or the presence or absence of one or more biomarkers (e.g., analytes) and / or parameters are assessed prior to administration (e.g., pre-infusion) of the cell therapy, e.g., obtained up to 2, 7, 14, 21, 28, 35, or 40 days prior to initiating administration of the engineered cells. In some embodiments, a biological sample is obtained from the subject prior to administration (e.g., pre-infusion) of the cell therapy, e.g., obtained up to 2, 7, 14, 21, 28, 35, or 40 days prior to initiating administration of the engineered cells.

[0085] In some embodiments, the biological sample is a blood, serum, or plasma sample. In some embodiments, the biological sample is a blood sample. In some embodiments, the biological sample is an apheresis sample or a leukapheresis sample. In some embodiments, after administration of cell therapy, a parameter and / or the presence or absence of one or more biomarkers (e.g., analytes) and / or parameters are evaluated, and a biological sample is obtained. In some embodiments, reagents can be used before or after administration of cell therapy for diagnostic purposes, to identify subjects, and / or to evaluate treatment outcomes and / or toxicity.

[0086] In some embodiments, the parameter and / or the presence or absence of one or more biomarkers (e.g., analytes) and / or parameters are assessed and / or a sample is obtained from the subject within, or within about, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or 15 days after initiation of administration of the engineered cells. In some of any such embodiments, the parameter and / or the presence or absence of one or more biomarkers (e.g., analytes) and / or parameters are assessed and / or a sample is obtained from the subject at or about 1 to 15 days, 1 to 12 days, 1 to 8 days, 1 to 5 days, 1 to 3 days, or 1 to 2 days, inclusive, after initiation of administration of the engineered cells.

[0087] In some embodiments, measuring the value of one or more biomarkers comprises performing an in vitro assay. In some aspects, the in vitro assay is an immunoassay, an aptamer-based assay, a histological or cytological assay, or an mRNA expression level assay. In some embodiments, the value of one or more biomarkers is measured by enzyme-linked immunosorbent assay (ELISA), immunoblotting, immunoprecipitation, radioimmunoassay (RIA), immunostaining, flow cytometry assay, surface plasmon resonance (SPR), chemiluminescence assay, lateral flow immunoassay, inhibition assay, or avidity assay. Optionally, the value of at least one of the one or more biomarkers is determined using a binding reagent that specifically binds to at least one biomarker. In some aspects, the binding reagent is an antibody or an antigen-binding fragment thereof, an aptamer, or a nucleic acid probe.

[0088] In some embodiments, measuring the value of one or more biomarkers (e.g., analytes) comprises contacting a reagent capable of directly or indirectly detecting the analyte with the biological sample to determine the presence, absence, level, amount, or concentration of the analyte in the biological sample. In some embodiments, the one or more biomarkers (e.g., analytes) are interleukin-16 (IL-16), tumor necrosis factor (TNF), vascular endothelial growth factor C (VEGFC), or vascular endothelial growth factor receptor 1 (VEGFR1). In some embodiments, the one or more biomarkers (e.g., analytes) are or comprise TNF. In some embodiments, the one or more biomarkers (e.g., analytes) are or comprise IL-16. In some embodiments, the one or more biomarkers (e.g., analytes) are or comprise VEGFR1. In some embodiments, the one or more biomarkers (e.g., analytes) are or comprise VEGFR1.

[0089] In some embodiments, a parameter, eg, a biomarker and / or an analyte, is detected using one or more reagents capable of detecting or specific for that parameter.

[0090] In some embodiments, measuring the value of one or more parameters, e.g., the value of a biomarker, comprises contacting a reagent capable of directly or indirectly detecting the analyte with the biological sample to determine the presence, level, amount, or concentration of the analyte in the biological sample. In some embodiments, the one or more parameters, e.g., biomarkers, are one or more of IL-16, TNF, VEGFC, or VEGFR1, or include one or more of IL-16, TNF, VEGFC, or VEGFR1. In some aspects, the reagent is a binding molecule that specifically binds to the biomarker. For example, in some embodiments, the reagent is an antibody or an antigen-binding fragment thereof. In some embodiments, the reagent is a substrate or binding partner of the biomarker, or includes a substrate or binding partner of the biomarker.

[0091] In some embodiments, the parameters and / or biomarkers are assessed using immunoassays. For example, enzyme-linked immunosorbent assays (ELISAs), enzyme immunoassays (EIAs), radioimmunoassays (RIAs), surface plasmon resonance (SPR), Western blots, lateral flow assays, immunohistochemistry, protein arrays, or immuno-PCR (iPCR) can be used to detect patient attributes, factors, and / or biomarkers. In some embodiments, the ELISA is a sandwich ELISA. In some embodiments, the ELISA is a bead-based ELISA. In some embodiments, using the article of manufacture includes detecting patient attributes, factors, and / or biomarkers indicative of tumor burden. Optionally, assaying or evaluating the patient attributes, factors, and / or biomarkers uses flow cytometry. Optionally, the reagent is a soluble protein that binds to the patient attributes, factors, and / or biomarkers. In some aspects, the assay for assessing the parameters and / or one or more biomarkers is an immunoassay. In some aspects, the assay for assessing a parameter and / or one or more biomarkers is a multiplex immunoassay, e.g., for determining multiple, e.g., two or more, parameters such as the level, concentration, or amount of biomarkers or analytes.

[0092] In some embodiments, the methods involve individually comparing the level, amount, or concentration of an analyte in a sample to a threshold level to thereby determine the risk of developing toxicity after administration of the cell therapy or thereby determine the likelihood that the subject will achieve a response to the cell therapy. In some aspects, an exemplary threshold level can be determined based on the mean or median level, amount, or concentration of a biomarker (e.g., an analyte) in biological samples obtained before receiving cell therapy from a group of subjects, each of whom will experience a particular outcome, e.g., a particular treatment outcome including either a response or no response, or either toxicity or no toxicity, and a value within a range or standard deviation of the mean or median. In some embodiments, specific aspects of determining a threshold include those described in Sections IA1 and IA2 below.

[0093] A. Exemplary Biomarkers, Analytes, or Parameters Associated with Toxicity Outcomes In some embodiments, the analytes or biomarkers are associated with, correlated with, indicative of, and / or predict a particular outcome, e.g., the onset of toxicity, in a subject administered a cell therapy, e.g., a cell therapy with a composition containing genetically engineered cells. In some embodiments, the presence, expression, level, amount, or concentration of one or more biomarkers, e.g., analytes, in a biological sample obtained from a subject prior to administration of a cell therapy can be associated with, correlated with, indicative of, and / or predict a particular outcome, e.g., the onset of toxicity, e.g., any of the toxicity outcomes described herein, e.g., in Section II.D. In some embodiments, the presence, expression, level, amount, or concentration of a particular biomarker can be correlated with a particular outcome or toxicity, e.g., the onset of NT. In some embodiments, the toxicity is a toxicity potentially associated with a cell therapy, e.g., any of the toxicities described herein, e.g., in Section II.D. In some embodiments, the toxicity is neurotoxicity (NT; sometimes referred to as a neurological event, neurologic event, or NE). In some embodiments, the toxicity is any grade of neurotoxicity, e.g., grade 1 or higher neurotoxicity (NT). In some embodiments, the toxicity is severe NT. In some embodiments, the toxicity is grade 2 or higher NT. In some embodiments, the toxicity is grade 3 or higher NT. In some embodiments, the toxicity is grade 4 or grade 5 NT.

[0094] In some embodiments, the parameter is a parameter related to tumor burden, e.g., a measure of tumor burden, such as lymph node tumor burden or blood tumor burden. In some embodiments, the parameter is a parameter related to tumor burden, e.g., a ratio of two tumor burden measures, such as blood tumor burden and lymph node tumor burden. In some embodiments, the biomarkers (e.g., analytes) (which comprise the parameter) include IL-16 and TNF.

[0095] In some embodiments, the method involves assessing the risk of developing toxicity after administering cell therapy. In some embodiments, the method involves assessing the level, amount, or concentration of one or more biomarkers, such as analytes, in a biological sample, where the biological sample is a sample from a subject who is a candidate for cell therapy treatment, and the cell therapy optionally includes the dose or composition of genetically engineered cells that express a recombinant receptor (e.g., CAR), and the biological sample is obtained from the subject before administering cell therapy, and / or the biological sample does not include the recombinant receptor and / or the engineered cells. In some aspects, the method involves individually comparing the level, amount, or concentration of the analyte in the sample with a threshold level, thereby determining the risk of developing toxicity after administering cell therapy. In some aspects, the comparison can be used to determine the subject's likelihood of response or the risk of developing toxicity after administering cell therapy.

[0096] In some embodiments, the methods involve assessing a subject's likelihood of response or risk of developing toxicity after administration of a cell therapy. In some embodiments, the methods involve assessing the level, amount, or concentration of one or more biomarkers, e.g., analytes, in a biological sample, where the biological sample is from a subject receiving cell therapy (optionally comprising the dose or composition of engineered cells expressing a recombinant receptor (e.g., CAR)), e.g., at an early time point, e.g., before peak CAR+ T-cell expansion, and / or within 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day, or within about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day after initiating administration of the cell therapy, or within a range defined by any of the foregoing. In some aspects, the methods involve individually comparing the level, amount, or concentration of the analyte in the sample to a threshold level, thereby determining the risk of developing toxicity after administration of the cell therapy. In some aspects, the comparison can be used to determine the subject's likelihood of response or risk of developing toxicity after administration of the cell therapy. In some embodiments, the method also involves selecting the subject for treatment with a cell therapy, e.g., a particular dose of cell therapy, including administration of a particular dose of a cell therapy as described herein, based on assessing the presence or absence of a biomarker and / or comparing the biomarker to a reference value or threshold level for the biomarker. In some embodiments, the method also involves selecting the subject for treatment with an additional agent, e.g., an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the development of toxicity or the risk of developing toxicity, based on assessing the presence or absence of a biomarker and / or comparing the biomarker to a reference value or threshold level for the biomarker.

[0097] In some embodiments, the method includes individually comparing the level, amount, or concentration of the analyte in the sample with a threshold level, thereby determining the risk of developing toxicity after administration of the cell therapy. In some embodiments, the method includes individually comparing the level, amount, or concentration of the analyte in the sample with a threshold level, thereby identifying a subject at risk of developing toxicity after administration of the cell therapy. In some embodiments, the method also includes administering to the subject the cell therapy, and optionally an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the development of toxicity or the risk of developing toxicity, according to or based on the results of the assessment. In some embodiments, the method also involves administering the cell therapy to the subject and monitoring the subject for symptoms of toxicity if the subject is identified as being at risk of developing toxicity.

[0098] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5%, and / or within one standard deviation of, around, or above the median or mean value of a parameter assessed from biological samples obtained from a group of subjects prior to receiving cell therapy, or the median or mean level, amount, or concentration in said biological samples, and each of the subjects in the group did not experience any grade of neurotoxicity after administration of a dose of engineered cells expressing a CAR to treat CLL or SLL. In some embodiments, the threshold level is 1.25-fold or more higher, 1.3-fold or more higher, 1.4-fold or more higher, or 1.5-fold or more higher than the median or mean value of a parameter assessed from biological samples obtained from a group of subjects prior to receiving cell therapy, or the median or mean level, amount, or concentration in said biological samples, and each of the subjects in the group did not experience any grade of neurotoxicity after administration of a dose of engineered cells expressing a CAR to treat CLL or SLL. In some of any of the embodiments, the threshold level is 1.25-fold or more higher, 1.3-fold or more higher, 1.4-fold or more higher, or 1.5-fold or more higher than the parameter assessed from the level, amount, or concentration in a biological sample obtained from a group of normal or healthy subjects who are not candidates for cell therapy treatment.

[0099] In some embodiments, a parameter or marker measurement above the threshold is associated with an approximately 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-fold or more increased risk of developing NT. In some embodiments, a parameter or marker measurement below the threshold is associated with an approximately 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-fold or less decreased risk of developing NT.

[0100] In some aspects, the methods also involve further monitoring the subject for possible symptoms of toxicity based on the risk of toxicity determined according to the provided embodiments, e.g., by evaluation of a parameter or biomarker and / or comparison of the parameter or biomarker to a reference value or threshold level for that particular parameter or biomarker.

[0101] In some embodiments, if the level, amount, or concentration of a biomarker (e.g., analyte) in the sample is at or above a threshold level for that analyte, then an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the onset of toxicity or the risk of onset of toxicity is administered to the subject prior to initiation of administration of the cell therapy to the subject, within 1, 2, or 3 days of initiation of administration, concurrently with initiation of administration, and / or at the time of the first fever after initiation of administration. Exemplary agents or interventions for use in connection with the provided methods to treat, prevent, delay, reduce, or attenuate the risk of onset of toxicity are described in Section III.

[0102] Optionally, if the level, amount, or concentration of the biomarker in the sample is at or above a threshold level, the cell therapy is administered to the subject at a reduced dose or at a dose that is not associated with a risk of developing toxicity or severe toxicity after administration of the cell therapy, or that is not associated with a risk of developing toxicity or severe toxicity in a majority of subjects and / or in a majority of subjects with a disease or condition that the subject has or is suspected of having. Optionally, if the level, amount, or concentration of the biomarker in the sample is at or above a threshold level, the cell therapy is administered to the subject in an inpatient setting and / or with one or more days of hospitalization, although optionally, the cell therapy is administered to the subject on an outpatient basis or without one or more days of hospitalization, as would be the case otherwise.

[0103] In some embodiments, if the level, amount, or concentration of a biomarker (e.g., an analyte) is below a threshold level for that analyte, the cell therapy is administered to the subject, optionally at a non-reduced dose. Optionally, the cell therapy is administered on an outpatient basis or without one or more days of hospitalization. In some embodiments, if the level, amount, or concentration of the analyte is below a threshold level, the administration of the cell therapy does not include administering an agent or treatment that can treat, prevent, delay, or attenuate the onset of toxicity prior to or concurrently with the administration of the cell therapy, and / or prior to the onset of signs or symptoms of toxicity other than fever; and / or the administration of the cell therapy is or can be administered in an outpatient setting, and / or without hospitalizing the subject overnight or for one or several consecutive days, and / or without hospitalizing the subject for one or more days.

[0104] In some aspects of the provided methods, the subject is determined to be at risk for developing toxicity (e.g., neurotoxicity, e.g., severe neurotoxicity or grade 3 or higher neurotoxicity) by comparing a parameter (e.g., concentration, amount, level, or activity) of a biomarker (e.g., an analyte), or each individual parameter of a plurality of biomarkers (e.g., a plurality of analytes), to a reference value, e.g., a threshold level, for that biomarker or the corresponding parameter for each biomarker. In some embodiments, this comparison indicates whether the subject is at risk for developing toxicity, such as neurotoxicity, e.g., severe neurotoxicity or grade 3 or higher neurotoxicity, and / or indicates the degree of risk for developing said toxicity. In some embodiments, the reference value is a threshold level or cutoff that, alone or in combination with one or more biomarkers in the panel, provides good predictive value (e.g., accuracy, sensitivity, and / or specificity) that such toxicity will or is likely to develop. Optionally, such reference value, e.g., threshold level, can be, is, or is known in advance, e.g., from a plurality of subjects previously treated with a cell therapy and assessed for correlation of the biomarker, or each individual biomarker in the panel, with the presence of a toxic outcome (e.g., the presence of neurotoxicity, such as severe neurotoxicity or grade 3 or higher neurotoxicity), prior to performing the method.

[0105] In some embodiments, a reference value for the corresponding parameter, e.g., a parameter for a biomarker (e.g., TNF or IL-16) that is higher or greater than a threshold level (alone or in conjunction with evaluation of other biomarkers in the panel) is associated with a positive prediction of toxicity risk. In some embodiments, a reference value for the corresponding parameter, e.g., a parameter for a biomarker that is below a threshold level (alone or in conjunction with evaluation of other biomarkers in the panel) is associated with a negative prediction of toxicity risk.

[0106] In some embodiments, the threshold level is determined based on the level, amount, concentration, or other measure of a biomarker (e.g., analyte) in a sample that is positive for that biomarker. In some aspects, the threshold level is within 25%, 20%, 15%, 10%, or 5% of the mean level, amount, concentration, or measure of the analyte or parameter in a biological sample obtained before administration of a recombinant receptor-expressing therapeutic cell composition from a group of subjects, each of whom developed neurotoxicity, e.g., severe neurotoxicity or grade 3 or higher neurotoxicity, after being administered the recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0107] In some embodiments of any of the provided methods, the biomarker (e.g., analyte) correlates with and / or predicts the risk of developing severe neurotoxicity, e.g., severe neurotoxicity or grade 3 or higher neurotoxicity. In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% of the mean level, amount, concentration, or measure of the analyte or parameter in a biological sample obtained before administration of a recombinant receptor-expressing therapeutic cell composition from a group of subjects, each of whom will develop severe neurotoxicity or grade 3 or higher neurotoxicity after being administered the recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0108] In some embodiments, parameters such as tumor volume measurements correlate with the success of cell therapy and / or the risk of developing toxicity, such as neurotoxicity (NT).

[0109] Provided herein is a method of treatment involving the steps of: (1) If the subject has a lymph node tumor burden and / or a level, amount, or concentration of TNF and / or IL-16 at or above a threshold level; and / or a blood tumor burden and / or a ratio of blood tumor burden to lymph node tumor burden below a threshold level, the subject is identified as being at risk for developing neurotoxicity following administration of a cell therapy, and the method includes (i) administering a cell therapy to the subject at a reduced dose; (ii) administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the development of toxicity or the risk of developing toxicity. and / or (iii) administration of the cell therapy to the subject is performed or designated to be performed in an inpatient setting and / or with one or more days of hospitalization; or (2) if the subject has a lymph node tumor burden and / or a level, amount, or concentration of TNF and / or IL-16 below a threshold level; and / or a blood tumor burden and / or ratio of blood tumor burden to lymph node tumor burden equal to or greater than a threshold level, the subject is identified as not at risk of developing neurotoxicity following administration of the cell therapy, and the method comprises: (i) optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or (ii) optionally, the administration of cell therapy and any follow-up is carried out on an outpatient basis, and / or without hospitalizing the subject, and / or without requiring an overnight stay in the hospital, and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject exhibits persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretics; wherein the parameter is assessed from a subject with CLL or SLL who is a candidate for treatment with cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), and the parameter is assessed from the subject prior to administration of the cell therapy, and / or the subject does not comprise T cells expressing a CAR.

[0110] 1. Disease Burden In some embodiments, the parameter or factor is a parameter indicative of disease burden, such as tumor burden. In some aspects, the parameter indicative of tumor burden is a tumor volume measure. In some aspects, the parameter indicative of tumor burden is blood tumor burden. In some embodiments, exemplary parameters include the ratio of blood tumor burden to lymph node tumor burden.

[0111] In some embodiments, the volumetric measure is a measure of lesions, such as tumor size, tumor diameter, tumor volume, tumor mass, tumor volume or bulk, tumor-associated edema, tumor-associated necrosis, and / or the number or extent of metastases. In some embodiments, the measure is a two-dimensional measure. For example, in some embodiments, the area of ​​a lesion is calculated as the product of the longest diameter and the longest orthogonal diameter of all measurable tumors. Optionally, the measure is a one-dimensional measure. Optionally, the size of a measurable lesion is assessed as the longest diameter. In some embodiments, the sum of two-way products (SPD), longest tumor diameter (LD), sum of longest tumor diameters (SLD), necrosis, tumor volume, necrotic volume, necrosis-tumor ratio (NTR), peritumoral edema (PTE), and edema-tumor ratio (ETR) are measured. In some aspects, a parameter indicative of tumor burden, such as lymph node tumor burden, is the sum of two-way products (SPD) (determined as the longest overall tumor diameter and the largest diameter perpendicular to the longest overall diameter).

[0112] In some embodiments, the factor indicative of tumor burden is the tumor burden in the blood, eg, the number of lymphocytes per unit volume of blood, eg, the number of lymphocytes per microliter (μL) of blood.

[0113] Exemplary methods for measuring and assessing tumor burden include those described, for example, in Carceller et al., Pediatr Blood Cancer. (2016) 63(8):1400-1406 and Eisenhauer et al., Eur J Cancer. (2009) 45(2):228-247. In some embodiments, the parameter is the sum of two-way products (SPD), measured by determining the sum of the products of the longest orthogonal diameters of all measurable tumors. In the case of CLL or SLL, such parameters can be measured for lymph nodes. In some aspects, tumors or lesions are measured in one dimension by the longest diameter (LD) and / or by determining the sum of the longest tumor diameters (SLD) of all measurable lesions. In the case of CLL or SLL, such parameters can be measured for lymph nodes. In some embodiments, the parameter indicative of tumor burden is a volumetric quantification of tumor necrosis, such as necrotic volume and / or necrosis-to-tumor ratio (NTR). See Monsky et al., Anticancer Res. (2012) 32(11):4951-4961. In some aspects, the parameter indicative of tumor burden is a volumetric quantification of tumor-associated edema, such as peritumoral edema (PTE) and / or edema-tumor ratio (ETR). In some embodiments, the measuring step can be performed using imaging techniques such as computed tomography (CT), positron emission tomography (PET), and / or magnetic resonance imaging (MRI) of the subject.

[0114] In some embodiments, the parameter indicative of tumor burden is determined during a screening session, such as a routine evaluation or blood sampling, to confirm and / or identify a condition or disease in a subject. In some embodiments, the parameter indicative of tumor burden is determined before administering lymphodepleting therapy to the subject. In some embodiments, the parameter is assessed from the subject before administering lymphodepleting therapy to the subject.

[0115] In the case of CLL or SLL, tumor cells can reside in various organs or compartments of the host, such as the blood, bone marrow, lymph nodes, or spleen. The organ or compartment in which tumor cells reside can affect their survival and proliferation, with blood being the least supportive microenvironment for tumor cells. In some cases, CLL or SLL tumor cells may begin to die when starved in the microenvironment. Within secondary lymphoid organs, such as lymph nodes, interactions between tumor cells and T cells can support the growth of CLL or SLL tumor cells, while B cell activation is important for maintaining CLL or SLL tumor cells in secondary lymphoid organs. In some aspects, particularly in the case of CLL and SLL, the tumor burden in lymph nodes can be measured differently and does not necessarily correlate with the tumor burden in the blood.

[0116] In some embodiments, the evaluating step includes identifying the subject as at risk for developing neurotoxicity after administration of the cell therapy if (a) the lymph node tumor burden is equal to or greater than a threshold level for lymph node tumor burden; (b) the blood tumor burden is less than a threshold level for blood tumor burden; and / or (c) the ratio of blood tumor burden to lymph node tumor burden is less than a threshold level for that ratio, or (2) identifying the subject as not at risk for developing neurotoxicity after administration of the cell therapy if (a) the lymph node tumor burden is less than a threshold level for tumor burden; (b) the blood tumor burden is equal to or greater than a threshold level for blood tumor burden; and / or (c) the ratio of blood tumor burden to lymph node tumor burden is greater than a threshold level for that ratio. Thus, in some embodiments, if the ratio of blood tumor burden to lymph node tumor burden is greater than a threshold level, the subject is identified as not at risk for developing neurotoxicity after administration of the cell therapy. Conversely, in some embodiments, a subject is identified as being at risk for developing neurotoxicity following administration of a cell therapy if the ratio of blood tumor burden to lymph node tumor burden is below a threshold level.

[0117] Also provided herein is a method for determining the risk of developing toxicity following administration of a cell therapy, the method comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and the ratio of blood tumor burden to lymph node tumor burden in a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and wherein the parameters are assessed in the subject prior to administering the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually, wherein (1) if (a) the lymph node tumor burden is equal to or greater than the threshold level for lymph node tumor burden, (b) the blood tumor burden is less than the threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is less than the threshold level for that ratio, the subject is identified as being at risk for developing neurotoxicity after administration of the cell therapy; or (2) if (a) the lymph node tumor burden is less than the threshold level for tumor burden, (b) the blood tumor burden is equal to or greater than the threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is greater than the threshold level for that ratio, the subject is identified as not being at risk for developing neurotoxicity after administration of the cell therapy.

[0118] In some of the provided embodiments, if the subject is identified as being at risk for developing neurotoxicity, the method further includes (i) administering to the subject a cell therapy, optionally at a reduced dose, optionally wherein (a) the method further includes administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of the onset of neurotoxicity, and / or (b) the administration of the cell therapy to the subject is performed or is designated to be performed in an inpatient setting and / or with one or more days of hospitalization; or (ii) administering to the subject an alternative treatment other than cell therapy for treating CLL or SLL.

[0119] In some of any of the provided embodiments, if the subject is identified as not at risk for developing neurotoxicity, the method further includes (i) administering a cell therapy to the subject, optionally wherein: (a) optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or is not decreased by more than 1°C after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or (b) Optionally, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or requiring an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretic medication.

[0120] Also provided herein is a method of selecting a subject for treatment with cell therapy, comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and the ratio of blood tumor burden to lymph node tumor burden in a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, wherein the cell therapy comprises a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and wherein the parameters are assessed in the subject prior to administering the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually; (1) If (a) the lymph node tumor burden is equal to or greater than a threshold level for lymph node tumor burden, (b) the blood tumor burden is less than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is less than a threshold level for that ratio, (i) administration of the cell therapy at a reduced dose; (ii) administration of an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the manifestation of neurotoxicity or the risk of the manifestation of neurotoxicity; (iii) administration of a cellular therapy that is performed or designated to be performed in an inpatient setting and / or involving a one or more day hospital stay; and / or (iv) Administration of alternative treatments other than cell therapy to treat CLL or SLL Select for; or (2) If (a) the lymph node tumor burden is below a threshold level for tumor burden, (b) the blood tumor burden is equal to or greater than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is above a threshold level for that ratio, (i) selected for administration of a cell therapy, and optionally, wherein: (a) optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or is not decreased by more than 1°C after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or (b) optionally, the administration of the cell therapy and any follow-up is performed on an outpatient basis and / or without hospitalizing the subject and / or requiring an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretic medication; Process.

[0121] In some of any of the provided embodiments, the methods also include administering to the subject a cell therapy, an agent or other treatment that can treat, prevent, delay, reduce or attenuate the onset of toxicity or the risk of the onset of toxicity, and / or an alternative treatment.

[0122] In some embodiments, exemplary parameters include blood tumor burden. In some embodiments, the assessing step includes determining the lymphocyte concentration in the subject's blood. In some embodiments, the concentration is lymphocytes per microliter (μL) of blood. In some embodiments, the threshold level for blood tumor burden is a value between 800 or about 800 lymphocytes / μL and 3000 or about 3000 lymphocytes / μL, inclusive. In some embodiments, the threshold level for blood tumor burden is 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL, or 3000 lymphocytes / μL. / μL, or a value of about 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL, or 3000 lymphocytes / μL, or any value therebetween. In some embodiments, the threshold level for blood tumor burden is a value of 1250 or about 1250 lymphocytes / μL to 1750 or about 1750 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 800 or about 800 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 900 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 1000 or about 1000 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 1250 or about 1250 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 1500 or about 1500 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 1750 or about 1750 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 2000 or about 2000 lymphocytes / μL.In some embodiments, the threshold level for blood tumor burden is a value of 2250 or about 2250 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 2500 or about 2500 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 2750 or about 2750 lymphocytes / μL. In some embodiments, the threshold level for blood tumor burden is a value of 3000 or about 3000 lymphocytes / μL.

[0123] In some embodiments, exemplary parameters include lymph node tumor burden. In some embodiments, assessing lymph node burden includes determining the largest lymph node diameter in the subject. In some embodiments, assessing lymph node burden includes determining the largest lymph node diameter in centimeters (cm). In some embodiments, the threshold level for the largest lymph node diameter as lymph node burden is a value of 4 or about 4 cm to 7 or about 7 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is 4 cm, 4.25 cm, 4.5 cm, 4.75 cm, 5 cm, 5.25 cm, 5.5 cm, 5.75 cm, 6 cm, 6.25 cm, 6.5 cm, 6.75 cm, or 7 cm, or a value of about 4 cm, 4.25 cm, 4.5 cm, 4.75 cm, 5 cm, 5.25 cm, 5.5 cm, 5.75 cm, 6 cm, 6.25 cm, 6.5 cm, 6.75 cm, or 7 cm, or any value therebetween. In some embodiments, the threshold level for lymph node burden is a value of 4.5 or about 4.5 cm to 5.5 or about 5.5 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 4 or about 4 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 4.25 or about 4.25 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 4.5 or about 4.5 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 4.75 or about 4.75 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 5 or about 5 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 5.25 or about 5.25 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 5.5 or about 5.5 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 5.75 or about 5.75 cm.In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 6 or about 6 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 6.25 or about 6.25 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 6.5 or about 6.5 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 6.75 or about 6.75 cm. In some embodiments, the threshold level for maximum lymph node diameter as lymph node burden is a value of 7 or about 7 cm.

[0124] In some embodiments, exemplary parameters include the ratio of blood tumor burden to lymph node tumor burden. In some embodiments, the evaluating step comprises determining the ratio of lymphocyte count per microliter (μL) of blood to the largest lymph node diameter in centimeters (cm). In some embodiments, the threshold level for the ratio of lymphocyte count per microliter (μL) of blood to the largest lymph node diameter in centimeters (cm) as the ratio of blood tumor burden to lymph node tumor burden is a value of 300 or about 300 to 1000 or about 1000. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is at or about a value of 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000, or a value between any of the foregoing. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is at or about a value of 300. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 350 or about 350. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 400 or about 400.In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 450 or about 450. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 500 or about 500. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 550 or about 550. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 600 or about 600. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 650 or about 650. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 700 or about 700. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 750 or about 750. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 800 or about 800.In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 850 or about 850. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 900 or about 900. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 950 or about 950. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is a value of 1000 or about 1000.

[0125] In some embodiments, exemplary parameters include lymph node tumor burden. In some embodiments, assessing lymph node burden comprises determining the sum of two-way products (SPD). In some embodiments, SPD is measured in square centimeters (cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 10 cm 2 ~40 or about 40cm 2 In some embodiments, the threshold level for SPD as lymph node burden is 10 cm 2 , 12.5cm 2 , 15cm 2 , 17.5cm 2 , 20cm 2 , 22.5cm 2 , 25cm 2 , 27.5cm 2 , 30cm 2 , 32.5cm 2 , 35cm 2 , 37.5cm2 Or 40cm 2 , or about 10 cm 2 , 12.5cm 2 , 15cm 2 , 17.5cm 2 , 20cm 2 , 22.5cm 2 , 25cm 2 , 27.5cm 2 , 30cm 2 , 32.5cm 2 , 35cm 2 , 37.5cm 2 Or 40cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 10 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 12.5 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 15 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 17.5 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 20 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 22.5 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 25 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 27.5 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 30 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 32.5 cm 2In some embodiments, the threshold level for SPD as lymph node burden is at or about 35 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 37.5 cm 2 In some embodiments, the threshold level for SPD as lymph node burden is at or about 40 cm 2 is the value.

[0126] In some embodiments, exemplary parameters include the ratio of blood tumor burden to lymph node tumor burden. In some embodiments, the assessing step is performed in square centimeters (cm 2In some embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value from at or about 25 to 500 or about 500. In some embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is at or about 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500, or a value of about 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, or 500, or any value between the foregoing. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 25 or about 25. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 50 or about 50. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 75 or about 75. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 100 or about 100. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 150 or about 150. In some embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 200 or about 200.In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 250 or about 250. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 300 or about 300. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 350 or about 350. In some embodiments, the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value of 400 or about 400. In some embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 450 or about 450. In some embodiments, the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value of 500 or about 500.

[0127] 2. Blood analytes In some embodiments, one or more biomarkers or analytes (including parameters thereof) that can be evaluated include interleukin-16 (IL-16) or tumor necrosis factor (TNF). In some embodiments, elevated or increased levels of one or more of such biomarkers (e.g., multiple biomarkers), e.g., compared to a reference value or threshold level, can be associated with the onset of neurotoxicity. In some embodiments, elevated or increased levels of one or more of such biomarkers (e.g., analytes), e.g., compared to a reference value or threshold level, can be associated with the onset of neurotoxicity. In some embodiments, exemplary biomarkers, e.g., blood analytes, indicative of or associated with toxicity, such as neurotoxicity, are one or more of TNF and IL-16.

[0128] In some embodiments, if a subject is identified as being at risk for developing toxicity, one or more of the following steps can be performed: (a) administering to the subject (1) an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the development of toxicity or the risk of developing toxicity, and (2) a cell therapy, wherein the administration of the agent is administered (i) before, (ii) within 1, 2, or 3 days of, (iii) simultaneously with, and / or (iv) at the time of first fever after the initiation of administration of the cell therapy to the subject; and / or (b) administering the cell therapy to a subject at a reduced dose. and / or (c) administering the cell therapy to the subject in an inpatient setting and / or with one or more days of hospitalization, wherein optionally the cell therapy would otherwise be administered to the subject on an outpatient basis or without one or more days of hospitalization.

[0129] In some aspects, exemplary analytes or biomarkers that can be evaluated or analyzed for assessing the risk of developing toxicity after administration of a cell therapy include one or more analytes selected from IL-16 or tumor necrosis factor (TNF). In some embodiments, if the level, amount, or concentration of one or more of the analytes is above a threshold level for any of the analytes or biomarkers, the subject is at risk of developing toxicity, and if the level, amount, or concentration of one or more of the analytes is below the threshold level, the subject is at low risk of developing toxicity. In some embodiments, the toxicity is neurotoxicity. In some aspects, elevated levels of IL-16 or tumor necrosis factor (TNF) in a biological sample obtained from a subject prior to administration of a cell therapy (pre-treatment) can be associated with an increased risk of developing neurotoxicity.

[0130] In some embodiments, the threshold level is within 25%, within 20%, within 15%, within 30%, or within 5%, and / or within one standard deviation above the median or mean level, amount, or concentration of IL-16 or TNF in a biological sample obtained prior to receiving cell therapy from a group of subjects, each of whom did not develop any toxicity after being administered a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0131] In some embodiments, the threshold level is within 25%, within 20%, within 15%, within 30%, or within 5%, and / or within one standard deviation, below the median or mean level, amount, or concentration of IL-16 or TNF in a biological sample obtained prior to receiving cell therapy from a group of subjects, each of whom developed toxicity after being administered a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0132] Also provided herein is a method for determining the risk of developing toxicity following administration of a cell therapy, the method comprising the steps of: assaying a biological sample for a level, amount, or concentration of tumor necrosis factor (TNF) and / or interleukin-16 (IL-16), wherein the biological sample is derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and 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 11 days or about 11 days after initiating administration of the cell therapy; and comparing 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 7 or about 7 pg / mL and 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value between 400 or about 400 pg / mL and 1000 or about 1000 pg / mL, and (1) if the level, amount, or concentration of TNF and / or IL-16 is equal to or greater than the respective threshold level, identifying the subject as at risk for developing neurotoxicity after administration of the cell therapy, or (2) if the level, amount, or concentration of TNF and / or IL-16 is less than the respective threshold level, identifying the subject as not at risk for developing neurotoxicity after administration of the cell therapy.

[0133] Also provided herein is a method for determining the risk of developing toxicity following administration of a cell therapy, the method comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and comparing 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 7 or about 7 pg / mL and 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value between 400 or about 400 pg / mL and 1000 or about 1000 pg / mL, and (1) if the level, amount, or concentration of TNF and / or IL-16 is equal to or greater than the respective threshold level, identifying the subject as at risk for developing neurotoxicity after administration of the cell therapy, or (2) if the level, amount, or concentration of TNF and / or IL-16 is less than the respective threshold level, identifying the subject as not at risk for developing neurotoxicity after administration of the cell therapy.

[0134] In some embodiments, if the subject is identified as being at risk of developing neurotoxicity, the method further comprises: (i) administering to the subject a cell therapy, optionally at a reduced dose, optionally wherein (a) the method further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of the onset of neurotoxicity, and / or (b) the administration of the cell therapy to the subject is performed or is designated to be performed in an inpatient setting and / or with one or more days of hospitalization; or (ii) administering to the subject an alternative treatment other than cell therapy for treating CLL or SLL.

[0135] In some embodiments, if the subject is identified as not at risk for developing neurotoxicity, the method further comprises (i) administering a cell therapy to the subject, optionally wherein: (a) optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or is not decreased by more than 1°C after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or (b) Optionally, the administration of the cell therapy and any follow-up is carried out on an outpatient basis and / or without hospitalizing the subject and / or requiring an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with antipyretic medication.

[0136] Also provided herein is a method of selecting a subject for treatment with cell therapy, comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and comparing the level, amount, or concentration of TNF and / or IL-16 to a threshold level for each, wherein the threshold level for TNF is between 7 or about 7 pg / mL and 25 or about 25 pg / mL, and / or the threshold level for IL-16 is between 400 or about 400 pg / mL and 1000 or about 1000 pg / mL; (1) if the level, amount, or concentration of TNF and / or IL-16 is at or above the respective threshold level, treating the subject with (i) administration of a reduced dose of cell therapy; (ii) treatment for the development of neurotoxicity or (iii) administration of a cell therapy that is performed or designated to be performed in an inpatient setting and / or with one or more days of hospitalization; and / or (iv) selecting for administration of an alternative treatment other than a cell therapy to treat CLL or SLL; or (2) if the level, amount, or concentration of TNF and / or IL-16 is below the respective threshold levels, then the subject (i) is selected for administration of a cell therapy, optionally wherein: (a) optionally, at or after the subject presents with a persistent fever or a fever that does not decrease or is not decreased by more than 1°C after treatment with an antipyretic, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents and other treatments that can treat, prevent, delay, reduce, or attenuate the onset of toxicity or the risk of the onset of toxicity; and / or (b) optionally, administering the cell therapy and any follow-up is performed on an outpatient basis and / or without hospitalizing the subject and / or requiring an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1° C. after treatment with antipyretics.

[0137] In some embodiments, the method also includes administering to the subject a cell therapy, an agent or other treatment that can treat, prevent, delay, reduce or attenuate the onset of toxicity or the risk of the onset of toxicity, and / or an alternative treatment.

[0138] Also provided herein is a method for determining the risk of developing toxicity following administration of a cell therapy, the method comprising the steps of: Assaying a biological sample from a subject who has received a cell therapy comprising a dose of engineered cells comprising T cells expressing a CAR for treating CLL or SLL for the level, amount, or concentration of TNF and / or IL-16, wherein the biological sample is obtained from the subject prior to peak CAR+ T cell expansion and / or within 11 days or about 11 days after initiation of administration of the cell therapy; and comparing the level, amount, or concentration of TNF and / or IL-16 with a threshold level for each, wherein the threshold level for TNF is between 7 or about 7 pg / mL and 25 or about 25 pg / mL, and / or the threshold level for IL-16 is between 400 or about 400 pg / mL and 1000 or about 1000 pg / mL, and (1) identifying the subject as being at risk for developing neurotoxicity if the level, amount, or concentration of TNF and / or IL-16 is equal to or greater than the respective threshold level; or (2) identifying the subject as not being at risk for developing neurotoxicity if the level, amount, or concentration of TNF and / or IL-16 is less than the respective threshold level.

[0139] In some embodiments, if the subject is identified as being at risk for developing neurotoxicity, the method further comprises administering to the subject an agent or other treatment that can treat, prevent, delay, reduce, or attenuate the onset of neurotoxicity or the risk of the onset of neurotoxicity, optionally prior to peak CAR+ T cell expansion and / or within 11 days or about 11 days of administration of the cell therapy to the subject; and / or follow-up is performed in an inpatient setting and / or with one or more days of hospitalization.

[0140] In some embodiments, if a subject is identified as not at risk of developing neurotoxicity, follow-up is optionally performed on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject presents with a persistent fever or a fever that does not decrease or does not decrease by more than 1°C after treatment with an antipyretic.

[0141] Also provided herein are methods of treatment comprising the steps of: Administering an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the onset of toxicity or the risk of the onset of toxicity to a subject identified as being at risk for developing neurotoxicity, wherein the subject has previously received a cell therapy for treating CLL or SLL, and the subject is selected or identified as being at risk for developing neurotoxicity if, at the time of administration of the agent or immediately prior to administration of the agent, the level, amount or concentration of TNF and / or IL-16 in a biological sample obtained from the subject prior to peak CAR+ T cell expansion and / or within 11 days or about 11 days of initiating administration of the cell therapy is above a threshold level for each, wherein the threshold level for TNF is a value of 7 or about 7 pg / mL to 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value of 400 or about 400 pg / mL to 1000 or about 1000 pg / mL.

[0142] Also provided herein is a method of selecting a subject for treatment with an agent, comprising the steps of: assaying a biological sample from a subject who has received a cell therapy comprising a dose of engineered cells comprising T cells expressing a CAR that binds to CD19 for treating CLL or SLL for the level, amount, or concentration of TNF and / or IL-16, wherein the biological sample is obtained from the subject prior to peak CAR+ T cell expansion and / or within 11 days or about 11 days after initiation of administration of the cell therapy; and comparing the level, amount or concentration of TNF and / or IL-16 to a threshold level for each individually, wherein the threshold level for TNF is a value of 7 or about 7 pg / mL to 25 or about 25 pg / mL, and / or the threshold level for IL-16 is a value of 400 or about 400 pg / mL to 1000 or about 1000 pg / mL, and if the level, amount or concentration of TNF and / or IL-16 is at or above the respective threshold level, selecting the subject for administration of an agent or other treatment that can treat, prevent, delay, reduce or attenuate the manifestation of neurotoxicity or the risk of the manifestation of neurotoxicity.

[0143] In some embodiments, the methods also include administering to the subject an agent or other treatment that can treat, prevent, delay, reduce or attenuate the manifestation of toxicity or the risk of the manifestation of toxicity.

[0144] In some embodiments, administering the agent or other treatment is performed when the subject presents with a persistent fever or a fever that does not subside or does not subside after treatment with an antipyretic agent or a fever that does not subside by more than 1° C. after treatment with an antipyretic agent.

[0145] In some embodiments, administering the cell therapy to the subject is performed on an outpatient basis, and if the level, amount, or concentration of TNF and / or IL-16 is above a threshold level, the method includes hospitalizing the patient for one or more days.

[0146] In some embodiments, the biological sample is obtained from the subject before administering cell therapy. In some embodiments, the biological sample is obtained from the subject before administering lymphodepletion therapy to the subject. In some embodiments, the biological sample is obtained from the subject before peak CAR+ T cell expansion and / or within 11 days or about 11 days after initiation of administration of cell therapy. In some embodiments, the biological sample is obtained from the subject before peak CAR+ T cell expansion and / or within 11 days or about 11 days after initiation of administration of cell therapy.

[0147] In some embodiments, the threshold level is within 25%, within 20%, within 15%, within 32%, or within 5%, and / or within one standard deviation above the median or mean level, amount, or concentration of IL-16 or TNF in a biological sample obtained prior to receiving cell therapy from a group of subjects, each of whom did not develop any toxicity after being administered a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0148] In some embodiments, the threshold level is within 25%, within 20%, within 15%, within 32%, or within 5%, and / or within one standard deviation, below the median or mean level, amount, or concentration of IL-16 or TNF in a biological sample obtained prior to receiving cell therapy from a group of subjects, each of whom developed toxicity after being administered a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0149] In some embodiments, the threshold level for TNF is a value of 7 or about 7 pg / mL to 25 or about 25 pg / mL. In some embodiments, the threshold level for TNF is 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, or 25 pg / mL, or a value of about 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, or 25 pg / mL, or a value between any of the foregoing. In some embodiments, the threshold level for TNF is a value of 7 or about 7 pg / mL. In some embodiments, the threshold level for TNF is a value of 8 or about 8 pg / mL. In some embodiments, the threshold level for TNF is a value of 9 or about 9 pg / mL. In some embodiments, the threshold level for TNF is a value of 10 or about 10 pg / mL. In some embodiments, the threshold level for TNF is a value of 15 or about 15 pg / mL. In some embodiments, the threshold level for TNF is a value of 20 or about 20 pg / mL. In some embodiments, the threshold level for TNF is a value of 25 or about 25 pg / mL. In some embodiments, the threshold level for TNF is a value of 8 or about 8 pg / mL to 10 or about 10 pg / mL.

[0150] In some embodiments, the threshold level for IL-16 is a value of 400 or about 400 pg / mL to 1000 or about 1000 pg / mL. In some embodiments, the threshold level for IL-16 is 400 pg / mL, 500 pg / mL, 600 pg / mL, 700 pg / mL, 800 pg / mL, 900 pg / mL, or 1000 pg / mL, or a value of about 400 pg / mL, 500 pg / mL, 600 pg / mL, 700 pg / mL, 800 pg / mL, 900 pg / mL, or 1000 pg / mL, or a value between any of the foregoing. In some embodiments, the threshold level for IL-16 is a value of 400 or about 400 pg / mL. In some embodiments, the threshold level for IL-16 is a value of 500 or about 500 pg / mL. In some embodiments, the threshold level for IL-16 is a value of 600 or about 600 pg / mL. In some embodiments, the threshold level for IL-16 is a value of 700 or about 700 pg / mL. In some embodiments, the threshold level for IL-16 is a value of 800 or about 800 pg / mL. In some embodiments, the threshold level for IL-16 is a value of 900 or about 900 pg / mL. In some embodiments, the threshold level for IL-16 is a value of 1000 or about 1000 pg / mL. In some embodiments, the threshold level for IL-16 is a value of 500 or about 500 pg / mL to 700 or about 700 pg / mL.

[0151] In some of any of the embodiments, the levels, amounts, or concentrations of both TNF and IL-16 are assessed, and the threshold level for TNF is 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, or 25 pg / mL, or a value of about 7 pg / mL, 8 pg / mL, 9 pg / mL, 10 pg / mL, 15 pg / mL, 20 pg / mL, or 25 pg / mL, or or any value therebetween, and the threshold level for IL-16 is 400pg / mL, 500pg / mL, 600pg / mL, 700pg / mL, 800pg / mL, or 900pg / mL, or a value of about 400pg / mL, 500pg / mL, 600pg / mL, 700pg / mL, 800pg / mL, or 900pg / mL, or any value therebetween.

[0152] In some of any of the embodiments, the levels, amounts, or concentrations of both TNF and IL-16 are assessed, with the threshold level for TNF being a value of 8 or about 8 pg / mL to 10 or about 10 pg / mL, and the threshold level for IL-16 being a value of 500 or about 500 pg / mL to 700 or about 700 pg / mL. In some of any of such embodiments, the thresholds can be any combination of the thresholds for each of TNF and IL-16 provided herein.

[0153] B. Exemplary Biomarkers, Analytes, or Parameters Associated with Response Outcomes In some embodiments, the analytes or biomarkers are associated with, correlated with, indicative of, and / or predict a particular outcome, e.g., a particular response outcome such as an objective response (OR), complete response (CR), or partial response (PR), or a durable response, e.g., an OR, CR, or PR that is sustained for 3, 6, 9 months, or more. In some embodiments, a decreased or reduced level or an increased level of one or more of such biomarkers (e.g., analytes), e.g., compared to a reference value or threshold level, can be associated with a response, e.g., an OR, CR, or PR, or any of the response outcomes described herein, e.g., in Section II.C. In some embodiments, criteria evaluated for effective treatment include overall response rate (ORR; sometimes known as response rate), complete response (CR; sometimes known as complete remission), complete response with incomplete bone marrow recovery (CRi), partial response (PR), or nodular partial remission (nPR). In some embodiments, relevant response outcomes include a durable response, eg, a response that is sustained for 3 months, 6 months, 9 months, 12 months or more after the initial response.

[0154] In some embodiments, the analytes or biomarkers are associated with, correlated with, indicative of, and / or predict a particular outcome, e.g., a particular response outcome or sustained response outcome, in a subject administered a cell therapy, e.g., a cell therapy with a composition containing genetically engineered cells. In some embodiments, the presence, expression, level, amount, or concentration of one or more biomarkers, e.g., analytes, in a biological sample obtained from a subject prior to administration of the cell therapy can be associated with, correlated with, indicative of, and / or predict a particular outcome, e.g., a particular response outcome or sustained response outcome. In some embodiments, the presence, expression, level, amount, or concentration of a particular biomarker can be correlated with a particular response outcome or sustained response outcome. In some embodiments, the response outcome can be any of the response outcomes described herein, e.g., in Section II.C.

[0155] In some embodiments, the analytes or biomarkers are associated with, correlated with, indicative of, and / or predict a particular outcome, e.g., a particular response outcome or sustained response outcome, in a subject administered a cell therapy, e.g., a cell therapy with a composition containing genetically engineered cells. In some embodiments, the presence, expression, level, amount, or concentration of one or more biomarkers, e.g., analytes, in a biological sample obtained from a subject prior to administration of the cell therapy can be associated with, correlated with, indicative of, and / or predict a particular outcome, e.g., a particular response outcome or sustained response outcome. In some embodiments, the presence, expression, level, amount, or concentration of a particular biomarker can be correlated with a particular response outcome or sustained response outcome. In some embodiments, the response outcome can be any of the response outcomes described herein, e.g., in Section II.C.

[0156] In some embodiments, the method includes individually comparing the level, amount, or concentration of the analyte in the sample with a threshold level, thereby determining the likelihood that the subject will achieve a response to the cell therapy. In some embodiments, the method includes selecting a subject who is likely to respond to the treatment based on the results of determining the likelihood that the subject will achieve a response to the cell therapy by individually comparing the level, amount, or concentration of the analyte in the sample with a threshold level. In some embodiments, the method also includes administering the cell therapy to the subject selected for treatment. In some embodiments, if it is determined that the subject is unlikely to achieve a response or sustained response, the method further includes administering an additional therapeutic agent to the subject.

[0157] In some embodiments, the biomarkers (e.g., analytes) include those associated with response outcomes and / or durable response. In some embodiments, the biomarkers (e.g., analytes) (including parameters thereof) include VEGFC or VEGFR1.

[0158] In some aspects, exemplary analytes or biomarkers that can be evaluated or analyzed for assessing the likelihood of a response after administration of a cell therapy include one or more analytes selected from VEGFC or VEGFR1. In some embodiments, if the level, amount, or concentration of one or more of the analytes is below a threshold level for any of the analytes or biomarkers, the subject is likely to achieve a response, and if the level, amount, or concentration of one or more of the analytes is above the threshold level, the subject is unlikely to achieve a response. In some embodiments, the response is or includes an objective response. In some embodiments, the objective response is or includes a complete response (CR) or partial response (PR). In some aspects, reduced VEGFC or VEGFR1 levels in a biological sample obtained from a subject prior to administration of a cell therapy (pre-treatment) can correlate with achieving an objective response, including a complete response (CR) or partial response (PR).

[0159] In some embodiments, the response comprises an objective response (OR). In some embodiments, the objective response comprises a complete response (CR; sometimes also known as a complete remission), a complete remission with incomplete bone marrow recovery (CRi), a complete remission (CR), a CR with incomplete bone marrow recovery (CRi), a nodular partial response (PR) (nPR), or a partial response (PR; sometimes also known as a partial remission).

[0160] Also provided herein is a method for assessing the likelihood of success of a cell therapy, comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and A step of individually comparing the level, amount or concentration of VEGFC and / or VEGFR1 in the sample with a threshold level, wherein (1) if the level, amount or concentration of VEGFC and / or VEGFR1 is below the respective threshold level, the subject is identified 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 equal to or greater than the respective threshold level, the subject is identified as having a low likelihood of achieving a response to the cell therapy.

[0161] Also provided herein is a method of selecting a subject for treatment with cell therapy, comprising the steps of: 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 derived from a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administering the cell therapy; and Selecting subjects who are likely to respond to treatment based on the results of determining the likelihood of the subject achieving a response to cell therapy by individually comparing the level, amount, or concentration of VEGFC and / or VEGFR1 in the sample with a respective threshold level, wherein (1) if the level, amount, or concentration of VEGFC and / or VEGFR1 is below the respective threshold level, the subject is identified as having a high likelihood of achieving a response to cell therapy, or (2) if the level, amount, or concentration of VEGFC and / or VEGFR1 is equal to or greater than the respective threshold level, the subject is identified as having a low likelihood of achieving a response to cell therapy. In some embodiments, the method also includes administering cell therapy to the subjects selected for treatment.

[0162] Also provided herein is a method for treatment, comprising the steps of: (a) selecting a subject likely to respond to treatment based on the results of determining the likelihood of the subject achieving a response to cell therapy by individually comparing 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 with a respective threshold level, wherein (1) the subject is identified as likely to achieve a response to the cell therapy if the level, amount, or concentration of VEGFC and / or VEGFR1 is below the respective threshold level, or (2) the subject is identified as unlikely to achieve a response to the cell therapy if the level, amount, or concentration of VEGFC and / or VEGFR1 is equal to or greater than the respective threshold level, wherein the biological sample is derived from a subject with CLL or SLL who is a candidate for cell therapy treatment, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds to cluster of differentiation 19 (CD19), and the biological sample is obtained from the subject prior to administration of the cell therapy and / or the subject does not comprise CAR-expressing T cells; and (b) administering the cell therapy to the subject selected for treatment.

[0163] In some embodiments, the threshold level is within 25%, within 20%, within 15%, within 10%, or within 5%, and / or within one standard deviation of the median or mean value of, or the median or mean level, amount, or concentration in, a biological sample of a parameter assessed from biological samples obtained from a group of subjects prior to receiving cell therapy, each of whom achieved a response after administration of a dose of engineered cells expressing a CAR to treat CLL or SLL.

[0164] In some embodiments, the threshold level is 1.25-fold or more higher, 1.3-fold or more higher, 1.4-fold or more higher, or 1.5-fold or more higher than the median or mean value of the parameter assessed from biological samples obtained from a group of subjects prior to receiving cell therapy, or the median or mean level, amount, or concentration in said biological samples, and each of the subjects in the group achieved a response after administration of a dose of engineered cells expressing a CAR to treat CLL or SLL.

[0165] In some embodiments, the threshold level is 1.25-fold or more higher, 1.3-fold or more higher, 1.4-fold or more higher, or 1.5-fold or more higher than the parameter assessed from the level, amount, or concentration in a biological sample obtained from a group of normal or healthy subjects who are not candidates for cell therapy treatment.

[0166] In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% below, and / or within one standard deviation of, the median or mean level, amount, or concentration of VEGFC or VEGFR1 in a biological sample obtained prior to receiving cell therapy from a group of subjects, each of whom achieved a response after administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition. In some embodiments, the threshold level is within 25%, 20%, 15%, 10%, or 5% above, and / or within one standard deviation of, the median or mean level, amount, or concentration of VEGFC or VEGFR1 in a biological sample obtained prior to receiving cell therapy from a group of subjects, each of whom achieved stable disease (SD) and / or progressive disease (PD) after administration of a recombinant receptor-expressing therapeutic cell composition to treat the same disease or condition.

[0167] In some aspects, exemplary analytes or biomarkers that can be evaluated or analyzed for assessing the likelihood of a sustained response after administration of a cell therapy include one or more analytes selected from VEGFC or VEGFR1. In some embodiments, if the level, amount, or concentration of one or more of the analytes is below a threshold level for any of the analytes or biomarkers, the subject is likely to achieve a sustained response, and if the level, amount, or concentration of one or more of the analytes is above the threshold level, the subject is unlikely to achieve a sustained response. In some embodiments, a sustained response is or includes a complete response (CR) or partial response (PR) that is sustained for 3, 4, 5, or 6 months or more. In some embodiments, a sustained response is or includes a CR or PR that is sustained for at least 3 months. In some aspects, reduced VEGFC or VEGFR1 levels in a biological sample obtained from a subject prior to administration of a cell therapy (pre-treatment) can be associated with achieving a sustained response, e.g., a CR or RR, that is sustained for at least 3 months.

[0168] In some embodiments, an exemplary biomarker or analyte is VEGFC. In some embodiments, the threshold level for VEGFC is a value of 60 or about 60 pg / mL to 70 or about 70 pg / mL. In some embodiments, the threshold level for VEGFC is 60 pg / mL, 61 pg / mL, 62 pg / mL, 63 pg / mL, 64 pg / mL, 65 pg / mL, 66 pg / mL, 67 pg / mL, 68 pg / mL, 69 pg / mL, or 70 pg / mL, or a value of about 60 pg / mL, 61 pg / mL, 62 pg / mL, 63 pg / mL, 64 pg / mL, 65 pg / mL, 66 pg / mL, 67 pg / mL, 68 pg / mL, 69 pg / mL, or 70 pg / mL, or a value between any of the foregoing. In some embodiments, the threshold level for VEGFC is 60 or about 60 pg / mL. In some embodiments, the threshold level for VEGFC is 61 or about 61 pg / mL. In some embodiments, the threshold level for VEGFC is 62 or about 62 pg / mL. In some embodiments, the threshold level for VEGFC is 63 or about 63 pg / mL. In some embodiments, the threshold level for VEGFC is 64 or about 64 pg / mL. In some embodiments, the threshold level for VEGFC is 65 or about 65 pg / mL. In some embodiments, the threshold level for VEGFC is 66 or about 66 pg / mL. In some embodiments, the threshold level for VEGFC is 67 or about 67 pg / mL. In some embodiments, the threshold level for VEGFC is 68 or about 68 pg / mL. In some embodiments, the threshold level for VEGFC is 69 or about 69 pg / mL. In some embodiments, the threshold level for VEGFC is 70 or about 70 pg / mL.

[0169] In some embodiments, the exemplary biomarker or analyte is VEGFR1. In some embodiments, the threshold level for VEGFR1 is a value of 80 or about 80 pg / mL to 120 or about 120 pg / mL. In some embodiments, the threshold level for VEGFR1 is 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, 100 pg / mL, 105 pg / mL, 110 pg / mL, 115 pg / mL, or 120 pg / mL, or a value of about 80 pg / mL, 85 pg / mL, 90 pg / mL, 95 pg / mL, 100 pg / mL, 105 pg / mL, 110 pg / mL, 115 pg / mL, or 120 pg / mL, or a value between any of the foregoing. In some embodiments, the threshold level for VEGFR1 is a value of 80 or about 80 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 85 or about 85 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 90 or about 90 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 95 or about 95 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 100 or about 100 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 105 or about 105 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 110 or about 110 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 115 or about 115 pg / mL. In some embodiments, the threshold level for VEGFR1 is a value of 120 or about 120 pg / mL.

[0170] In some embodiments, the levels, amounts, or concentrations of both VEGFC and VEGFR1 are assessed, with the threshold level for VEGFC being between or about 60 pg / mL and 70 pg / mL, and the threshold level for VEGFR1 being between or about 80 pg / mL and 120 pg / mL. In some of any such embodiments, the thresholds can be any combination of the thresholds for each of VEGFC and VEGFR1 provided herein.

[0171] II. Cellular Therapy Methods and Uses with Genetically Engineered Cells In some embodiments, the methods and uses provided herein, including determining the risk of toxicity and / or likelihood of success of cell therapy, relate to a treatment method involving administering to a subject, in an adoptive cell therapy setting, cells that express a genetically engineered (recombinant) cell surface receptor, typically a chimeric receptor such as a chimeric antigen receptor (CAR), that recognizes an antigen expressed by, associated with, and / or specific to the leukemia or lymphoma and / or the cell type from which it is derived. The methods and uses provided in Section I above are used together with, in conjunction with, or as part of, e.g., the cell therapies described in Section II, e.g., cell therapies involving administering engineered cells, such as modified T cells expressing a chimeric antigen receptor (CAR), and optionally, the administration of additional agents, e.g., those described in Section III.

[0172] In some aspects, the cells are generally administered as a composition formulated for administration, and the methods generally involve administering the cells to a subject one or more times, where one administration may include a specific or relative number of cells or engineered cells, and / or a predetermined ratio or composition of two or more subtypes, e.g., CD4 T cells and CD8 T cells, within the composition.

[0173] In some embodiments, the cells, populations, and compositions are administered to a subject with a particular disease or condition to be treated, e.g., by adoptive cell therapy, such as adoptive T cell therapy. In some embodiments, the methods involve treating a subject with a lymphoma or leukemia, such as chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), by administering antigen receptor-expressing cells (e.g., CAR-expressing cells).

[0174] In some aspects, the provided embodiments are based on the observation that the provided methods can be used to achieve high response rates with high durability compared to certain available cell therapy methods without increased risk of toxicity, for example, the observations described in the examples provided herein. In some embodiments, the provided methods allow for extended survival of cells adoptively transferred for cell therapy and / or a low incidence of toxicity in subjects. In some embodiments, the methods can be used to select subjects for cell therapy treatment who are likely or more likely to respond to cell therapy, and / or to determine appropriate doses or administration regimens for higher response rates and / or more durable responses while minimizing the risk of toxicity. Such methods can inform rational strategies to facilitate the safe and effective clinical application of adoptive cell therapy, such as CAR-T cell therapy.

[0175] In some embodiments, the provided methods achieve high response rates in a heavily pretreated population of subjects with high-risk CLL (or SLL), all of whom have received one or more previous therapies, including ibrutinib. In some embodiments, the subjects treated include those who have relapsed after initial remission with ibrutinib, or those who are resistant or intolerant to treatment with ibrutinib. In certain embodiments, the subjects treated include those who have relapsed after remission, or who are resistant or intolerant to one or more additional previous therapies in addition to ibrutinib, for example, 1, 2, 3, 4, 5, or more previous therapies. In some embodiments, the subjects have relapsed or are resistant to both ibrutinib and venetoclax pretreatment. In some embodiments, subjects who are resistant to such treatment have progressed after one or more previous therapies. In some embodiments, subjects to be treated, including those treated with one or more previous therapies (e.g., ibrutinib and / or venetoclax), include subjects with high-risk cytogenetic abnormalities, including TP53 mutations, complex karyotypes (i.e., at least three chromosomal alterations), and del17(p). In some embodiments, subjects for treatment according to embodiments provided herein include subjects who have failed both a BTK inhibitor (e.g., ibrutinib) and venetoclax. As disclosed herein, results from ongoing clinical trials show a high overall response rate (ORR) of over 65% of treated subjects across dose levels, including complete remission with recovery of incomplete blood counts (also known as complete response; CR) (CRi) in over 35% of treated subjects. Of these subjects, all had previously been treated with ibrutinib, and approximately half had previously been treated with ibrutinib and venetoclax.In some aspects, results are associated with achieving undetectable MRD (uMRD); achievement of uMRD has been reported to correlate with improved outcomes (Kovacs et al. (2016) J. Clin. Oncol., 34:3758-3765; Thompson and Wierda (2016) Blood, 127:279-286). In some embodiments, the provided methods result in a high percentage of durable responses that last for more than 1 month, more than 3 months, more than 6 months, or more without progression.

[0176] Such results achieved in high-risk subjects are superior compared to certain other alternative therapies.In particular, CLL is generally considered to be incurable, and patients often eventually relapse or become resistant to available treatments (Dighiero and Hamblin (2008) The Lancet, 371:1017-1029).In some cases, CR and uMRD are insufficient, and / or subjects progress after treatment with certain other active agents, such as ibrutinib as a single agent, venetoclax-rituximab, bendamustine-rituximab, or both ibrutinib and venetoclax, or have poor outcomes after treatment with them.In addition, multiple reports suggest that certain other CAR T cell therapies cannot achieve such sustained response rates.

[0177] In some embodiments, the methods and uses include administering cells that express genetically engineered (recombinant) cell surface receptors to a subject in adoptive cell therapy, and the receptors are generally chimeric receptors, such as chimeric antigen receptors (CARs), that recognize antigens that are expressed by, associated with, and / or specific to leukemia or lymphoma and / or cell types derived therefrom.In certain embodiments, the targeted antigen is CLL.The cells are generally administered in a composition formulated for administration; the methods generally involve administering one or more doses of cells to a subject, and the doses may contain a specific number or relative number of cells or engineered cells, and / or a defined ratio or composition of two or more subtypes, such as CD4 T cells:CD8 T cells, in the composition.

[0178] In certain embodiments, the method is carried out with a therapeutic T-cell product involving separate administration of a CD4+ CAR T-cell composition and a CD8+ CAR T-cell composition, in which the CD4+ CAR T cells and CD8+ CAR T cells are administered in specific or precise numbers as a flat dose and / or a defined ratio. In some cases, the method includes generating or manipulating the CAR T-cell composition by a process including separate isolation, selection, or enrichment of CD4+ T cells and CD8+ T cells from a biological sample. In some cases, methods for generating CAR-T cell compositions that include enrichment of CD4+ T cells and CD8+ T cells avoid the risk of including tumor cells in the CAR-T cell product or during manufacturing of the CAR-T cell product. Compared to other diseases, CLL is a cancer in which tumor cells are found in the periphery, which in some circumstances may interfere with and / or affect the efficacy of a CAR-T product that may contain such cells or may be derived from an initial composition containing such cells. In some aspects, the subject treated with the method has relapsed or refractory (r / r) CLL. In some aspects, the subject treated by the method has relapsed or refractory (r / r) SLL.

[0179] In some embodiments, provided methods involve assessing the risk of a subject developing toxicity associated with cell therapy, wherein the method involves assessing or detecting a biomarker (e.g., analyte) or parameter associated with toxicity, e.g., neurotoxicity, such as severe neurotoxicity, and / or CRS, e.g., severe CRS, in a particular group or subset of subjects, e.g., subjects identified as having high-risk disease, e.g., high-risk CLL. In some aspects, the method treats subjects with a form of high-grade and / or poor-prognosis CLL, e.g., CLL that has relapsed or is resistant to standard therapy (R / R) and has a poor prognosis. In some embodiments, the subject has failed one or more previous therapies. In some embodiments, the subject is ineligible for other previous therapies. In some embodiments, the subject has failed previous therapy with a Bruton's tyrosine kinase inhibitor (BTKi), such as ibrutinib. In some embodiments, the subject has failed ibrutinib and venetoclax. In some cases, the overall response rate (ORR; sometimes also known as the objective response rate) is less than 40% and / or the complete response (CR; sometimes also known as a complete remission) is less than 20% relative to available treatments, to the standard of care, or to a reference treatment for the disease and / or patient population for which the treatment is indicated.

[0180] In some embodiments, the methods, uses, and articles of manufacture involve or are used to select or identify specific groups or subsets of subjects, for example, based on a particular disease type, diagnostic criteria, previous treatment, and / or response to previous treatment, and assess the risk of developing toxicity associated with cell therapy in a subject by evaluating or detecting biomarkers (e.g., analytes) or parameters associated with toxicity, e.g., neurotoxicity, e.g., severe neurotoxicity and / or CRS, e.g., severe CRS, in the subject. In some embodiments, the methods involve treating a subject who has relapsed or become resistant to one or more previous therapies following remission after treatment with the previous therapies; or a subject who has relapsed or become resistant to one or more previous therapies, e.g., one or more lines of standard therapy (R / R). In some embodiments, the methods involve treating a subject with chronic lymphocytic leukemia. In some embodiments, the methods involve treating a subject with small lymphocytic lymphoma. In some embodiments, the methods involve treating subjects with an Eastern Cooperative Oncology Group Performance Status (ECOG) of 0 to 1. In some embodiments, the methods treat poor prognosis populations of CLL patients or subjects who have generally responded poorly to treatment or a specific reference treatment, such as populations with high-risk cytogenetic abnormalities (i.e., Del(17p), TP53 mutations, mutant IGHV, and complex karyotypes).

[0181] In some embodiments, the antigen receptor (e.g., CAR) specifically binds to a target antigen associated with a disease or condition, for example, CLL. In some embodiments, the antigen receptor binds to a target antigen associated with SLL. In some embodiments, the disease or disorder-associated antigen is CD19.

[0182] In some embodiments, the method includes administering a cell or a composition containing the cell to a subject, tissue, or cell, for example, having, at risk of, or suspected of having a disease, condition, or disorder. In some embodiments, the subject is an adult. In some embodiments, the subject is over 50, 60, or 70 years old, or about 50, 60, or 70 years old.

[0183] In some embodiments, the subject has previously been treated with a therapy or therapeutic agent targeting a disease or condition, such as CLL or SLL, before administering the cells expressing the recombinant receptor. In some embodiments, the subject has previously been treated with hematopoietic stem cell transplantation (HSCT), such as allogeneic HSCT or autologous HSCT. In some embodiments, the subject has had a poor prognosis after treatment with standard therapy and / or has failed one or more lines of previous therapy, for example, at least 1, 2, 3, 4 or more lines, or at least about 1, 2, 3, 4 or more lines of previous therapy. In some embodiments, the subject is being treated with or has previously received at least 1, 2, 3, or 4, or at least about 1, 2, 3, or 4 other therapies for treating CLL other than lymphodepleting therapy and / or a dose of cells expressing an antigen receptor. In some embodiments, the subject has previously been treated with chemotherapy or radiation therapy. In some aspects, the subject is resistant or non-responsive to other therapies or therapeutic agents. In some embodiments, the subject has persistent or recurrent disease after treatment with another therapy or intervention, including, for example, chemotherapy or radiation. In some embodiments, the subject has relapsed or resistant (R / R) chronic lymphocytic leukemia (CLL) and has failed or is ineligible for Bruton's tyrosine kinase inhibitor (BTKi) treatment.

[0184] In some embodiments, the subject has previously been treated with a therapy or therapeutic agent targeting a disease or condition, e.g., CLL, prior to administration of the cells expressing the recombinant antigen receptor. In some embodiments, the therapeutic agent is a kinase inhibitor, such as an inhibitor of Bruton's tyrosine kinase (Btk), e.g., ibrutinib. In some embodiments, the therapeutic agent is an inhibitor of B-cell lymphoma-2 (Bcl-2), e.g., venetoclax. In some embodiments, the therapeutic agent is an antibody (e.g., a monoclonal antibody) that specifically binds to an antigen expressed by CLL or NHL cells, e.g., an antigen from any one or more of CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igκ, Igλ, CD79a, CD79b, or CD30. In some embodiments, the therapeutic agent is an anti-CD20 antibody, e.g., rituximab. In some embodiments, the therapeutic agent is a depleting chemotherapy that is a combination therapy that includes rituximab, such as a combination therapy of fludarabine and rituximab or a combination therapy of anthracycline and rituximab. In some embodiments, the subject has previously been treated with hematopoietic stem cell transplantation (HSCT), such as allogeneic HSCT or autologous HSCT. In some embodiments, the subject has been treated with or previously received at least 1, 2, 3, or 4, or at least about 1, 2, 3, or 4, or about 1, 2, 3, or 4 other therapies for treating CLL other than lymphodepleting therapy and / or a dose of cells that express an antigen receptor. In some embodiments, the subject has previously been treated with chemotherapy or radiation therapy.

[0185] In some aspects, the subject is resistant or non-responsive to other therapies or therapeutic agents, hi some embodiments, the subject has persistent or recurrent disease after treatment with another therapy or intervention, including, for example, chemotherapy or radiation.

[0186] In some embodiments, the subject is a transplant-eligible subject, e.g., a subject eligible for hematopoietic stem cell transplantation (HSCT), e.g., allogeneic HSCT. In some such embodiments, the subject, despite being eligible, has not previously undergone a transplant prior to administration of the engineered cells (e.g., CAR-T cells) or compositions comprising the cells provided herein to the subject.

[0187] In some embodiments, the subject is a transplant-ineligible subject, e.g., a subject who is ineligible for hematopoietic stem cell transplantation (HSCT), e.g., allogeneic HSCT. In some embodiments, such a subject is administered engineered cells (e.g., CAR-T cells) or compositions comprising the cells according to the embodiments provided herein.

[0188] In some embodiments, the method includes administering cells to a subject selected or identified as having high-risk CLL. In some embodiments, the subject exhibits one or more cytogenetic abnormalities, e.g., associated with high-risk CLL. In some aspects, the treated population includes subjects with an Eastern Cooperative Oncology Group Performance Status (ECOG) of 0 to 1.

[0189] In some aspects of any embodiment, the subject being treated has failed two or more previous therapies. In some aspects of any embodiment, the subject being treated has failed three or more previous therapies. In some embodiments, the previous therapies include treatment with a Bruton's tyrosine kinase (BTK) inhibitor, such as ibrutinib; venetoclax; combination therapy including fludarabine and rituximab; radiation therapy; and hematopoietic stem cell transplantation (HSCT). In some embodiments, the subject or patient has previously received treatment with ibrutinib and / or venetoclax and has relapsed after remission, is resistant to the treatment, failed the treatment, and / or is intolerant to the treatment. In some embodiments, the subject or patient has previously received treatment with ibrutinib and venetoclax and has relapsed after remission, is resistant to the treatment, failed the treatment, and / or is intolerant to the treatment.

[0190] In some embodiments, methods are provided for assessing the risk of developing cell therapy-related toxicity and the likelihood of treatment success in a subject selected or identified as having relapsed after remission or being resistant to pretreatment with ibrutinib and venetoclax for treating CLL or SLL. In some aspects, the selected or identified subject is administered CAR T-cell therapy, e.g., anti-CD19 CAR-T-cell therapy, according to the provided methods.

[0191] In some embodiments, the subject has never achieved a complete response (CR), has never undergone autologous stem cell transplantation (ASCT), is refractory to one or more second-line therapies, has primary resistant disease, and / or has an ECOG performance score of 0-1.

[0192] In some aspects, subjects treated according to the provided embodiments include those with a diagnosis of CLL or SLL. In some embodiments, subjects with CLL are those who meet the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines and have clinically measurable disease (bone marrow infiltration with >30% lymphocytes, peripheral blood lymphocytosis >5x10 9 / L, and / or measurable lymph nodes and / or liver or splenomegaly. In some embodiments, subjects with CLL have lymphadenopathy and / or splenomegaly at the time of diagnosis with measurable disease, defined as at least one lesion >1.5 cm in greatest diameter, and <5×10 in peripheral blood. 9 Included are subjects with a diagnosis of SLL based on CD19+ CD5+ clonal B lymphocytes / L [<5000 / μL] and subjects with biopsy-diagnosed SLL.

[0193] In some aspects, a subject is ineligible for treatment with a Bruton's tyrosine kinase inhibitor (BTKi, e.g., ibrutinib) due to the requirement for full-dose anticoagulation or prior treatment or arrhythmia, or has previously failed treatment after receiving a BTKi as determined by stable disease (SD) or progressive disease (PD) as a best response, PD after a previous response, or discontinuation due to intolerance (e.g., unmanageable toxicity). In some aspects, a subject is treated according to provided embodiments if the subject has high-risk disease (determined by complex cytogenetic abnormalities (e.g., complex karyotype), del(17p), TP53 mutation, unmutated IGVH) and has failed (e.g., at least) two or more previous therapies; or if the subject has standard-risk disease and has failed (e.g., at least) three or more previous therapies. In some aspects, subjects treated according to provided embodiments exclude subjects with untreated active CNS disease, ECOG>1, or Richter transformation.

[0194] In some aspects, compositions, methods, and uses are provided for assessing the risk of developing toxicity associated with cell therapy in a subject by detecting toxicity-related biomarkers (e.g., analytes) or parameters in the subject, and for administering a cell therapy of a defined composition at a specific dose that correlates with a high response rate and / or durability of response, and a low toxicity level and / or incidence. In some embodiments, the administered composition or dose is a flat and / or fixed dose of cells and / or one or more cells having a specific phenotype, e.g., a strictly flat dose, e.g., a number within a specific range and / or degree of variability or dispersion compared to a specific number or target number of such cells. In some embodiments, the administered composition or dose is a ... number within a specific range and / or degree of variability compared to a specific number or target number of such cells. + cells and CD8 + cells (e.g., CD4 + CAR + T cells: CD8 + CAR + In some embodiments, the ratio of CD4 T cells is 1:1, and / or is within a certain degree of variation from such a ratio, e.g., within ±10%, e.g., within ±8%, e.g., the degree of variation or variance is ±10% or less, e.g., ±8% or less. + and CD8 +Cells are individually formulated and administered. In some embodiments, the administered cells exhibit consistent activity and / or function, e.g., cytokine production, apoptosis, and / or expansion. In some embodiments, the provided compositions exhibit highly consistent and defined activity and low variability between cells in the composition or between preparations, e.g., in terms of cell number, cell function, and / or cell activity. In some embodiments, consistency in activity and / or function, e.g., low variability between preparations of the composition, allows for improved efficacy and / or safety. In some embodiments, administration of a defined composition resulted in lower product variability and lower toxicity, e.g., CRS or neurotoxicity, compared to administration of a cell composition with high heterogeneity. In some embodiments, a defined, consistent composition also exhibits consistent cell expansion. Such consistency can facilitate dose determination, therapeutic window identification, dose-response assessment, and identification of target factors that may correlate with safety or toxicity outcomes.

[0195] In some embodiments, in a certain group of subjects who receive a single infusion of a specific dose level, some group of subjects can achieve an overall response rate (ORR, sometimes also known as objective response rate) of more than 80%, and a complete response (CR) rate of more than 50% at 3 months.In some embodiments, subjects who receive a specified dose show improved safety outcomes.In some aspects, the rate of severe CRS or severe NT is low.

[0196] In some embodiments, subject-specific factors, e.g., specific biomarkers or analytes (e.g., TNF, IL-16) and / or parameters (e.g., parameters related to tumor burden, such as lymph node tumor burden and / or blood tumor burden), can be used to predict the risk of toxicity. In some embodiments, subject-specific factors, e.g., specific biomarkers or analytes (e.g., VEGFC1 or VEGFR1), can be used to predict the likelihood of response. In several embodiments, provided embodiments can be used to achieve a high response rate with a low risk of toxicity.

[0197] In some embodiments, 25% or less, 20% or less, 15% or less, 10% or less, or 5% or less of subjects treated with the provided compositions, articles of manufacture, kits, methods, and uses are administered an agent that ameliorates, treats, or prevents toxicity (e.g., tocilizumab and / or dexamethasone) prior to or following administration of the cell therapy. In some embodiments, subjects are not administered any preventative treatment prior to receiving the engineered cells (e.g., CAR-T cells).

[0198] In some embodiments, the provided methods provide advantages, for example, allowing for the administration of cell therapy on an outpatient basis. In some embodiments, cell therapy, for example, the administration of a dose of T cells according to the provided embodiments, can be performed on an outpatient basis or does not require the subject to be hospitalized, for example, requiring an overnight stay. In some embodiments, such outpatient administration can increase access and reduce costs while maintaining a high and durable response rate with low toxicity. In some aspects, outpatient treatment can be advantageous for subjects who are already immunocompromised by previous treatments, for example, after lymphodepletion, and who are at higher risk of exposure during hospital stays or in hospitalization facilities. In some aspects, outpatient treatment also increases treatment options for subjects who may not have access to hospitalization, hospital facilities, or transplant centers, thereby expanding access to the treatment.

[0199] In some embodiments, the methods and uses result in or achieve a higher response rate and / or a more durable response or efficacy, and / or a reduced risk of toxicity or other side effects that may be associated with cell therapy, such as neurotoxicity (NT) or cytokine release syndrome (CRS). In some aspects, the provided observations suggested a low rate of severe NT (sNT) or severe CRS (sCRS), and a high rate of patients without any toxicity, such as NT or CRS.

[0200] In some embodiments, at least at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% or more of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve a complete response (CR). In some embodiments, at least 75%, at least 80%, or at least 90% of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve an objective response (OR). In some embodiments, at least 35%, at least 45%, at least 50%, at least 55%, or at least 60% or more of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve a CR or OR by 1 month, by 2 months, or by 3 months. In some embodiments, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% or more of subjects who have failed previous treatment with a Bruton's tyrosine kinase inhibitor (BTKi) and venetoclax treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve a complete response (CR). In some embodiments, at least 75%, at least 80%, or at least 90% of subjects who have failed previous treatment with a BTKi and venetoclax treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve an objective response (OR). In some embodiments, at least 35%, at least 45%, at least 50%, at least 55%, or at least 60% or more of subjects who have failed previous treatment with a BTKi and venetoclax treated according to the provided methods and / or with the provided articles of manufacture or compositions achieve a CR or OR by 1 month, by 2 months, or by 3 months. In some embodiments, in subjects treated by the method, more than 50%, more than 60%, or more than 70% had undetectable minimal residual disease (MRD) for at least 1 month, at least 2 months, at least 3 months, or at least 6 months after administration of a dose of cells.In some embodiments, among subjects who had failed previous treatment with BTKi and venetoclax who were treated according to the methods and / or with the provided articles of manufacture or compositions, more than 50%, more than 60%, or more than 70% had undetectable minimal residual disease (MRD) for at least 1 month, at least 2 months, at least 3 months, or at least 6 months after administration of a dose of cells.

[0201] In some embodiments, up to three months after initiation of administration of the cell therapy, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% or more of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions remain in response, e.g., remain in CR or OR and / or have undetectable MRD. In some embodiments, such response, e.g., CR or OR, is sustainable for at least three months. In some embodiments, up to three months after initiation of administration of the cell therapy, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% or more of subjects who have failed previous treatment with BTKi and venetoclax treated according to the provided methods and / or with the provided articles of manufacture or compositions remain in response, e.g., remain in CR or OR and / or have undetectable MRD. In some embodiments, such response, e.g., CR or OR, is sustainable for at least three months.

[0202] In some embodiments, the resulting responses observed in such subjects upon treatment with the provided methods and / or with the provided articles of manufacture or compositions are associated with or result in a low risk of any toxicity or a low risk of severe toxicity in the majority of treated subjects. In some embodiments, greater than or greater than about 30%, 35%, 40%, 50%, 55%, or 60% of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions do not exhibit CRS of any grade or neurotoxicity (NT) of any grade. In some embodiments, greater than or greater than about 50%, 60%, 70%, or 80% of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions do not exhibit severe CRS or Grade 3 or higher CRS. In some embodiments, greater than or about 50%, 60%, 70%, or 80% or more of subjects treated according to the provided methods and / or with the provided articles of manufacture or compositions do not exhibit severe neurotoxicity or Grade 3 or higher neurotoxicity, e.g., Grade 4 or 5 neurotoxicity.

[0203] In some embodiments, the resulting responses observed in such subjects who have failed previous treatment with BTKi and venetoclax upon treatment with a provided method and / or with a provided article of manufacture or composition are associated with or result in a low risk of any toxicity or a low risk of serious toxicity in the majority of treated subjects. In some embodiments, greater than or greater than about 30%, 35%, 40%, 50%, 55%, or 60% of subjects who have failed previous treatment with BTKi and venetoclax treated according to a provided method and / or with a provided article of manufacture or composition do not exhibit any grade of CRS or any grade of neurotoxicity (NT). In some embodiments, greater than or about 50%, 60%, 70%, or 80% or more of subjects who have failed previous treatment with a BTKi and venetoclax treated according to the provided methods and / or with the provided articles of manufacture or compositions do not exhibit severe CRS or Grade 3 or higher CRS. In some embodiments, greater than or about 50%, 60%, 70%, or 80% or more of subjects who have failed previous treatment with a BTKi and venetoclax treated according to the provided methods and / or with the provided articles of manufacture or compositions do not exhibit severe neurotoxicity or Grade 3 or higher neurotoxicity, e.g., Grade 4 or 5 neurotoxicity.

[0204] In some embodiments, at least or about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of subjects treated according to the methods and / or with the provided articles of manufacture or compositions do not exhibit early onset CRS or neurotoxicity, and / or do not exhibit onset of CRS earlier than 1, 2, 3, or 4 days after initiation of administration. In some embodiments, at least or about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of subjects treated according to the methods and / or with the provided articles of manufacture or compositions do not experience an onset of neurotoxicity earlier than 3, 4, 5, 6, or 7 days after initiation of administration. In some aspects, the median onset of neurotoxicity among subjects treated according to the methods and / or with the provided articles of manufacture or compositions is at or after the median peak of CRS or the median time to resolution of CRS among subjects treated by the methods. In some cases, the median onset of neurotoxicity among subjects treated by the methods is greater than or greater than about 8, 9, 10, or 11 days.

[0205] In some embodiments, at least or about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of subjects who have failed previous treatment with a BTKi and venetoclax treated according to the methods and / or with the provided articles of manufacture or compositions do not exhibit early onset CRS or neurotoxicity, and / or do not exhibit onset of CRS earlier than 1, 2, 3, or 4 days after initiation of administration. In some embodiments, at least or about 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of subjects who have failed previous treatment with a BTKi and venetoclax treated according to the methods and / or with a provided article of manufacture or composition exhibit no onset of neurotoxicity earlier than 3, 4, 5, 6, or 7 days after initiation of administration. In some aspects, the median onset of neurotoxicity among subjects who have failed previous treatment with a BTKi and venetoclax treated according to the methods and / or with a provided article of manufacture or composition is at or after the median peak of CRS or the median time to resolution of CRS in subjects treated according to the methods. In some cases, the median onset of neurotoxicity among subjects who had failed previous treatment with a BTKi and venetoclax treated with the method is greater than or greater than about 8, 9, 10, or 11 days.

[0206] In some embodiments, such results are as low as 2.5 x 10 7 or approximately 2.5 x 10 7 From 1.5 × 10 8 or about 1.5 x 10 8 pieces, for example, about 5 x 10 7 From 1×10 8 or about 1 x 10 8total recombinant receptor-expressing T cells (e.g., CAR+ T cells), e.g., at a defined ratio as described herein, e.g., at a ratio of 1:1 or about 1:1, and / or CAR + A precise or uniform or fixed number of T cells or CD4 + CAR + T cells and / or CD8 + CAR + Certain types of CARs, such as T cells + CD4 T cells administered in a precise, uniform, or fixed number, and / or any number of such cells within a specified degree of variance, e.g., + or - (plus or minus, in some cases denoted as ±) 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or less, relative to such precise, uniform, or fixed number. + and CD8 + In some embodiments, such a uniform or fixed number is greater than or equal to 2.5 x 10 7 Or about 2.5 x 10 7 Total CARs + T cells or CD8 + and / or CD4 + CAR + T cells, 5 x 10 7 Or about 5 x 10 7 Total CARs + T cells or CD8 + and / or CD4 + CAR + T cells, or 1 × 10 8 or about 1 x 10 8 Total CARs + T cells or CD8 + and / or CD4 + CAR + In some embodiments, the number of cells in the dose is 2.5 x 10 7 Cars + T cells (optional 1.25 x 10 7 CD4 + CAR + T cells and 1.25 × 107 CD8 + CAR + T cells); in some embodiments, it comprises, consists of, or consists essentially of 5×10 7 Cars + T cells (optional 2.5 x 10 7 CD4 + CAR + T cells and 2.5 × 10 7 CD8 + CAR + T cells); in some embodiments, it comprises, consists of, or consists essentially of 1 x 10 8 Cars + T cells (optional 0.5 x 10 8 CD4 + CAR + T cells and 0.5 × 10 8 CD8 + CAR + In some aspects, the number of cells administered is within a certain range of dispersion of such numbers in the above-described embodiments, e.g., within a range of plus or minus (±) 5, 6, 7, 8, 9, or 10%, e.g., within a range of plus or minus 8%, compared to the number of such cells. In some aspects, the dose is determined based on the number of such cells (e.g., total CAR T cells). + T cells or CD8 + and / or CD4 + CAR + Within this range, a correlation (optionally a linear relationship) is observed between the number of cells (e.g., T cells) and one or more outcomes indicative of the therapeutic response or its duration (e.g., remission, complete remission, and / or likelihood of achieving a particular duration of remission) and / or the duration of any of the foregoing. In some aspects, it is recognized that a higher dose of administered cells may result in a greater response without affecting or substantially affecting or affecting the incidence or risk of toxicity (e.g., CRS or neurotoxicity) or the degree of toxicity, e.g., severe CRS or severe neurotoxicity, in the subject.

[0207] In some aspects, subjects treated in accordance with provided embodiments have adequate organ function. For example, in some aspects, the subject exhibits one or more of the following: serum creatinine ≦1.5 × age-adjusted upper limit of normal (ULN) or estimated creatinine clearance (Cockcroft and Gault) >30 mL / min; alanine aminotransferase (ALT) ≦5 × ULN and total bilirubin <2.0 mg / dL (or <3.0 mg / dL for subjects with Gilbert syndrome or leukemic infiltration of the liver); adequate pulmonary function defined by ≦Common Terminology Criteria for Adverse Events (CTCAE) grade 1 dyspnea and oxygen saturation on room air (SaO2) ≧92%; and / or adequate cardiac function defined as a left ventricular ejection fraction (LVEF) ≧40% as assessed by an echocardiogram (ECHO) or multiple uptake gated acquisition (MUGA) scan performed within 30 days prior to evaluating the subject for administration of an engineered cell composition.

[0208] In some aspects, the provided methods provide for high or specific response rates (e.g., response rates in a population assessed after a certain period of time after administration, e.g., 1 month or 3 months), e.g., ORR of 75% or more, 80% or more, 85% or more, or about 75% or more, 80% or more, 85% or more (e.g., 1-month ORR or 3-month ORR), and 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, CR rates (e.g., 1-month or 3-month CR rates) of 60% or more, 65% or more, 70% or more, 71% or more, 72% or more, 73% or more, 74% or more, or approximately 75% or more, or about 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 71% or more, 72% or more, 73% or more, 74% or more, or approximately 75% or more can be achieved. In some embodiments, such response rates and durability are achieved only after a single administration or dose of such therapy. Treatment of such subjects with the provided methods and / or with the provided articles of manufacture or compositions also, in some embodiments, results in subjects achieving high response rates but not exhibiting higher incidences of toxicity, such as neurotoxicity or CRS, even with higher cell doses.

[0209] Thus, in some embodiments, the provided methods, articles of manufacture, and / or compositions may offer advantages over other available methods, solutions, or approaches for treatment, e.g., adoptive cell therapy. In particular, some provided embodiments offer advantages to subjects with high-risk CLL by achieving high rates of durable responses while reducing the incidence of toxicity or side effects.

[0210] In some embodiments, one or more inflammatory cytokines, chemokines or growth factors or receptors are monitored before, during or after CAR treatment.In some embodiments, TNF or IL-16 is evaluated or monitored in subjects, for example, according to the methods herein.In some embodiments, VEGFC or VEGFR1 is evaluated or monitored in subjects, for example, according to the methods herein.

[0211] In some aspects, the provided methods also involve administering T cell therapy, such as a composition comprising cells for adoptive cell therapy, e.g., CAR-expressing T cells, e.g., anti-CD19 CAR+ T cells. In some embodiments, the methods also include lymphodepletion therapy, such as cyclophosphamide, fludarabine, or a combination thereof, prior to the T cell therapy.

[0212] A. Treatment Methods Provided herein are methods for assessing the risk of developing toxicity associated with cell therapy in a subject, involving evaluating or detecting a toxicity-related biomarker (e.g., analyte) or parameter, and administering engineered cells, such as engineered T cells, or a composition comprising the engineered cells. Also provided are methods and uses of engineered cells (e.g., T cells) and / or compositions thereof, including methods and uses for treating subjects with a disease or condition, such as leukemia or lymphoma, e.g., chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), involving administration of the engineered cells and / or compositions thereof. In some embodiments, the provided methods and uses can achieve improved response and / or more durable response or efficacy and / or a reduced risk of toxicity or other side effects, for example, in certain groups of treated subjects, compared with certain alternative methods. Also provided in some aspects are methods of administering engineered cells, such as engineered T cells, or a composition comprising the engineered cells to a subject, e.g., a subject with a disease or disorder. In some aspects, the use of engineered cells, such as engineered T cells, or compositions comprising engineered cells for the treatment of disease or disorders is also provided. In some aspects, the use of engineered cells, such as engineered T cells, or compositions comprising engineered cells for the manufacture of a medicament for the treatment of disease or disorders is also provided. In some aspects, a method of administering engineered cells, such as engineered T cells, or compositions comprising engineered cells for use in the treatment of disease or disorders or for administration to a subject with a disease or disorder is also provided. In some aspects, the use of engineered cells, such as engineered T cells, or compositions comprising engineered cells is according to any of the methods described herein.

[0213] Engineered cells expressing recombinant receptors, such as the chimeric antigen receptors (CARs) described herein, or compositions comprising the same, are useful in a variety of therapeutic, diagnostic, and prophylactic applications. For example, the engineered cells or compositions comprising the engineered cells are useful for treating various diseases and disorders in a subject. Such methods and uses include therapeutic methods and uses involving administration of the engineered cells or compositions comprising the same to a subject having a disease, condition, or disorder, such as a tumor or cancer. In some embodiments, the engineered cells or compositions comprising the same are administered in an amount effective to provide treatment for the disease or disorder. Uses include the use of the engineered cells or compositions in such methods and treatments, as well as in the preparation of medicaments for carrying out such therapeutic methods. In some embodiments, the engineered cells or compositions comprising the engineered cells are for use in treating various diseases and disorders in a subject, e.g., according to therapeutic methods. In some embodiments, the methods are carried out by administering the engineered cells or compositions comprising the same to a subject having or suspected of having a disease or condition. In some embodiments, the methods thereby treat the disease, condition, or disorder in the subject.

[0214] The general method for administering cells for adoptive cell therapy is known and can be used in connection with the provided methods and compositions.For example, adoptive T cell therapy methods are described in, for example, U.S. Patent Application Publication No. 2003 / 0170238 to Gruenberg et al.; U.S. Patent No. 4,690,915 to Rosenberg; Rosenberg (2011) Nat Rev Clin Oncol. 8(10):577-85).See, for example, Themeli et al. (2013) Nat Biotechnol. 31(10):928-933; Tsukahara et al. (2013) Biochem Biophys Res Commun 438(1):84-9; Davila et al. (2013) PLoS ONE 8(4):e61338.

[0215] The disease or condition to be treated can be any in which the expression of an antigen is associated with and / or involved in the pathogenesis of the disease, condition, or disorder, e.g., causes, exacerbates, or is otherwise involved in such a disease, condition, or disorder. Exemplary diseases and conditions can include diseases or conditions associated with malignant tumors or cellular transformation (e.g., cancer), autoimmune or inflammatory diseases, or infectious diseases caused, for example, by bacterial, viral, or other pathogens. Exemplary antigens, including antigens associated with various diseases and conditions that can be treated, are described above. In certain embodiments, the chimeric antigen receptor or transgenic TCR specifically binds to an antigen associated with the disease or condition.

[0216] Among the diseases, conditions, and disorders are tumors, including solid tumors, hematological malignancies, and melanomas, and including localized and metastatic tumors; infectious diseases, such as infections with viral or other pathogens, such as HIV, HCV, HBV, CMV, and HPV; and parasitic diseases, as well as autoimmune and inflammatory diseases. In some embodiments, the disease, disorder, or condition is tumor, cancer, malignancy, neoplasm, or other proliferative disease or disorder. Such diseases for treatment by the methods provided herein include, but are not limited to, leukemia, lymphoma, such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

[0217] In some embodiments, the Eastern Cooperative Oncology Group (ECOG) performance status index can be used to evaluate or select subjects for treatment, for example, subjects who have had poor outcomes with previous therapies (see, e.g., Oken et al. (1982) Am J Clin Oncol. 5:649-655). The performance status of the ECOG scale describes a patient's level of functionality in terms of their ability to care for themselves, their daily activities, and their physical abilities (e.g., walking, working, etc.). In some embodiments, an ECOG performance status of 0 indicates that a patient is able to carry out normal activities. In some aspects, a subject with an ECOG performance status of 1 exhibits some limitations in physical activity, but the subject is fully ambulatory. In some aspects, a patient with an ECOG performance status of 2 is more than 50% ambulatory. In some cases, a subject with an ECOG performance status of 2 is also able to care for themselves; see, e.g., Sorensen et al., (1993) Br J Cancer 67(4) 773-775. The criteria reflecting ECOG performance status are listed in Table 1 below:

[0218] Table 1: ECOG Performance Status Criteria TIFF0007605840000001.tif47167

[0219] In some embodiments, the antigen targeted by the receptor (e.g., CAR) includes an antigen associated with B cell malignancies, such as any of several known B cell markers. In some embodiments, the antigen is or includes CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igκ, Igλ, CD79a, CD79b, or CD30. In some embodiments, the antigen is CD19.

[0220] In some embodiments, cell therapy, e.g., adoptive T cell therapy, is performed by autologous transfer, in which cells are isolated and / or otherwise prepared from the subject to be treated or from a sample derived from such a subject. Thus, in some aspects, the cells are derived from a subject, e.g., a patient, in need of treatment, and the cells, after isolation and processing, are administered to the same subject.

[0221] In some embodiments, cell therapy, such as adoptive T cell therapy, is carried out by allogeneic transfer, in which cells are isolated and / or otherwise prepared from a subject other than the subject who will receive cell therapy or who will ultimately receive cell therapy, such as a first subject.In such embodiments, the cells are then administered to a different subject of the same species, such as a second subject.In some embodiments, the first subject and the second subject are genetically identical.In some embodiments, the first subject and the second subject are genetically similar.In some embodiments, the second subject expresses the same HLA class or supertype as the first subject.

[0222] The cells can be administered by any suitable means, for example, by bolus injection, injection, for example, intravenous or subcutaneous injection, intraocular injection, periocular injection, subretinal injection, intravitreal injection, transseptal injection, subscleral injection, intrachoroidal injection, intracameral injection, subconjectval injection, subconjunctival injection, subtenon injection, retrobulbar injection, periocular injection, or posterior juxtascleral delivery. In some embodiments, they are administered parenterally, intrapulmonary, and intranasally, and, if local treatment is desired, intralesional administration. Parenteral injections include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In some embodiments, a certain dose is administered by a single bolus of cells. In some embodiments, it is administered by multiple bolus administration of cells or by continuous infusion of cells, for example, over a period of 3 days or less. In some embodiments, administration of the cell dose or any additional therapy, eg, lymphodepleting therapy, interventional therapy, and / or combination therapy, is via outpatient delivery.

[0223] For the prevention or treatment of disease, the appropriate dosage can be determined by the type of disease being treated, the type of cells or recombinant receptor, the severity and course of the disease, whether the cells are being administered for prophylactic or therapeutic purposes, previous treatments, the ...

Claims

1. 1. A method for aiding in determining a risk of developing toxicity following administration of a cell therapy, comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and a ratio of blood tumor burden to lymph node tumor burden in a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), the one or more parameters being assessed in the subject prior to administration of the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually, (1) if (a) the lymph node tumor burden is equal to or greater than a threshold level for lymph node tumor burden, (b) the blood tumor burden is less than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is less than a threshold level for the ratio, the subject is indicated to be at risk for developing neurotoxicity following administration of the cell therapy; or (2) if (a) the lymph node tumor burden is below a threshold level for tumor burden, (b) the blood tumor burden is equal to or greater than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is above a threshold level for the ratio, the subject is indicated as not being at risk for developing neurotoxicity following administration of the cell therapy; Process.

2. 1. A medicament comprising a cell therapy for use in a method of treating a subject having chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL), the method comprising the steps of: (a) assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and a ratio of blood tumor burden to lymph node tumor burden, wherein the cell therapy comprises a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), and wherein the one or more parameters are assessed in the subject prior to administration of the cell therapy; (b) comparing the value of the one or more parameters to a threshold level for each parameter individually, (1) identifying a subject as at risk for developing neurotoxicity following administration of a cell therapy if (a) the lymph node tumor burden is equal to or greater than a threshold level for lymph node tumor burden, (b) the blood tumor burden is less than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is less than a threshold level for the ratio; or (2) identifying the subject as not at risk for developing neurotoxicity following administration of the cell therapy if (a) the lymph node tumor burden is below a threshold level for tumor burden, (b) the blood tumor burden is equal to or greater than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is above a threshold level for the ratio; process; and (c) if the subject is not at risk for developing neurotoxicity, administering the cell therapy to the subject.

3. 1. A medicament comprising a cell therapy for use in a method of treating a subject having chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL), comprising: The method includes determining a risk of developing toxicity following administration of the cell therapy of claim 1, If the subject is indicated to be at risk for developing neurotoxicity, the method further comprises administering to the subject a reduced dose of the cell therapy; The cell therapy is as claimed in claim 1, (a) the method further comprises administering to the subject an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the manifestation of neurotoxicity or the risk of the manifestation of neurotoxicity; and / or (b) administration of the cellular therapy to the subject is performed or designated to be performed in an inpatient setting and / or involving one or more days of hospitalization; Medicine.

4. If the subject is identified as being at risk for developing neurotoxicity, the method further comprises: (i) administering to a subject a cell therapy at a reduced dose, wherein: (a) the method further comprises administering to the subject an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the manifestation of neurotoxicity or the risk of the manifestation of neurotoxicity; and / or (b) administration of the cellular therapy to the subject is performed or designated to be performed in an inpatient setting and / or involving one or more days of hospitalization; process; or (ii) administering to the subject an alternative treatment other than a cell therapy for treating CLL or SLL. The pharmaceutical composition of claim 2, further comprising:

5. If the subject is identified as not at risk for developing neurotoxicity, the method further comprises: (i) administering a cell therapy to a subject, wherein: (a) at or after the subject presents with a persistent fever or a fever that has not decreased by more than 1° C. following treatment with an antipyretic agent, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents or other treatments that may treat, prevent, delay, reduce, or attenuate the manifestation of toxicity or the risk of the manifestation of toxicity; and / or (b) the administration and follow-up of the cellular therapy is performed on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject exhibits persistent fever or a fever that does not decrease by more than 1° C. following treatment with antipyretics; Process The pharmaceutical composition according to claim 2 or claim 3, further comprising:

6. A method of selecting a subject for treatment with a cell therapy, comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and a ratio of blood tumor burden to lymph node tumor burden in a subject with chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL) who is a candidate for treatment with a cell therapy, the cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), the parameters being assessed in the subject prior to administration of the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually, (1) If (a) the lymph node tumor burden is equal to or greater than a threshold level for lymph node tumor burden, (b) the blood tumor burden is less than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is less than a threshold level for that ratio, (i) administration of the cell therapy at a reduced dose; (ii) administration of an agent or other treatment that can treat, prevent, delay, reduce or attenuate the manifestation of neurotoxicity or the risk of the manifestation of neurotoxicity; (iii) administration of a cellular therapy that is performed or designated to be performed in an inpatient setting and / or involving one or more days of hospitalization; and / or (iv) Administration of an alternative treatment other than a cell therapy to treat CLL or SLL Select for; or (2) If (a) the lymph node tumor burden is below a threshold level for tumor burden, (b) the blood tumor burden is equal to or greater than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is above a threshold level for that ratio, (i) selected for administration of a cellular therapy, wherein: (a) at or after the subject presents with a persistent fever or a fever that has not decreased by more than 1° C. following treatment with an antipyretic agent, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents or other treatments that may treat, prevent, delay, reduce, or attenuate the manifestation of toxicity or the risk of the manifestation of toxicity; and / or (b) the administration and follow-up of the cellular therapy is performed on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject exhibits persistent fever or a fever that does not decrease by more than 1° C. following treatment with antipyretics; Process.

7. 1. A medicament comprising a cell therapy for use in a method of treating a subject having chronic lymphoblastic leukemia (CLL) or small lymphocytic lymphoma (SLL), the method comprising the steps of: assessing one or more disease burden parameters selected from lymph node tumor burden, blood tumor burden, and a ratio of blood tumor burden to lymph node tumor burden, wherein the subject is a candidate for treatment with a cell therapy comprising a dose of engineered cells comprising T cells expressing a chimeric antigen receptor (CAR) that binds cluster of differentiation 19 (CD19), and wherein the parameters are assessed in the subject prior to administration of the cell therapy; and comparing the value of the one or more parameters to a threshold level for each parameter individually, (1) If (a) the lymph node tumor burden is equal to or greater than a threshold level for lymph node tumor burden, (b) the blood tumor burden is less than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is less than a threshold level for that ratio, (i) reduced doses of cell therapy; (ii) an agent or other treatment that can treat, prevent, delay, reduce or attenuate the manifestation of neurotoxicity or the risk of the manifestation of neurotoxicity; (iii) a cellular therapy that is performed or designated to be performed in an inpatient setting and / or involving a one or more day hospital stay; and / or (iv) Alternative treatments other than cell therapy for treating CLL or SLL or (2) administering to the subject a cell therapy if (a) the lymph node tumor burden is below a threshold level for tumor burden, (b) the blood tumor burden is equal to or greater than a threshold level for blood tumor burden, and / or (c) the ratio of blood tumor burden to lymph node tumor burden is above a threshold level for the ratio, wherein (i) at or after the subject presents with a persistent fever or a fever that has not decreased by more than 1° C. following treatment with an antipyretic agent, unless or until the subject exhibits signs or symptoms of toxicity, the subject is not administered agents or other treatments that may treat, prevent, delay, reduce, or attenuate the manifestation of toxicity or the risk of the manifestation of toxicity; and / or (ii) the administration and follow-up of the cell therapy is performed on an outpatient basis and / or without hospitalizing the subject and / or without requiring an overnight stay in the hospital and / or without requiring hospitalization or an overnight stay in the hospital, unless or until the subject exhibits persistent fever or a fever that does not decrease by more than 1° C. following treatment with antipyretics; Process.

8. 10. The method of claim 1 or claim 6, wherein assessing blood tumor burden comprises determining a lymphocyte concentration in the subject's blood, the concentration being lymphocytes per microliter (μL) of blood.

9. A threshold level for blood tumor burden is a value between 800 or about 800 lymphocytes / μL and 3000 or about 3000 lymphocytes / μL, or between 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL or 3000 lymphocytes / μL.

9. The method of any one of claims 1, 6, and 8, wherein the lymphocyte count is about 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL or 3000 lymphocytes / μL, or a value between any of the foregoing.

10. 10. The method of any one of claims 1, 6, 8, and 9, wherein assessing lymph node tumor burden comprises determining largest lymph node diameter, wherein largest lymph node diameter is measured in centimeters (cm).

11. 11. The method of claim 10, wherein the threshold level for maximum lymph node diameter as lymph node tumor burden is a value between 4 or about 4 cm and 7 or about 7 cm.

12. 12. The method of claim 10 or claim 11, wherein the threshold level for maximum lymph node diameter as lymph node tumor burden is at or about a value of 4cm, 4.25cm, 4.5cm, 4.75cm, 5cm, 5.25cm, 5.5cm, 5.75cm, 6cm, 6.25cm, 6.5cm, 6.75cm or 7cm, or any value therebetween.

13. 10. The method of any one of claims 1, 6, 8, and 9, wherein assessing the ratio of lymph node tumor burden to blood tumor burden comprises determining the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm), and wherein the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as the ratio of lymph node tumor burden to blood tumor burden is a value of at or about 300 to at or about 1000.

14. 14. The method of claim 13, wherein the threshold level for the ratio of lymphocyte count per microliter (μL) of blood to largest lymph node diameter in centimeters (cm) as a ratio of blood tumor burden to lymph node tumor burden is at or about a value of 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000, or any value therebetween.

15. 10. The method of any one of claims 1, 6, 8, and 9, wherein assessing lymph node tumor burden comprises determining the sum of two-way products (SPD).

16. SPD is in square centimeters (cm 2 16. The method of claim 15, wherein the concentration is measured in units of 100 μg / kg.

17. The threshold level for SPD as lymph node tumor burden is 10 or approximately 10 cm 2 ~40 or about 40cm 2 17. The method of claim 15 or claim 16, wherein the value of

18. The threshold level for SPD as lymph node tumor burden was 10 cm 2 , 12.5cm 2 , 15cm 2 , 17.5cm 2 , 20cm 2 , 22.5cm 2 , 25cm 2 , 27.5cm 2 , 30cm 2 , 32.5cm 2 , 35cm 2 , 37.5cm 2 Or 40cm 2 , or about 10 cm 2 , 12.5cm 2 , 15cm 2 , 17.5cm 2 , 20cm 2 , 22.5cm 2 , 25cm 2 , 27.5cm 2 , 30cm 2 , 32.5cm 2 , 35cm 2 , 37.5cm 2 Or 40cm 2 or any value therebetween.

19. The step of assessing the ratio of blood tumor burden to lymph node tumor burden comprises measuring the ratio of blood tumor burden to lymph node tumor burden in square centimeters (cm 2 10. The method of any one of claims 1, 6, 8, and 9, comprising determining a ratio of lymphocytes per microliter (μL) of blood to sum of two-way products (SPD) in units of 100 / μL, wherein the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is a value at or about 25 to 500 or about 500.

20. 20. The method of claim 19, wherein the threshold level for the ratio of lymphocytes per microliter (μL) of blood to SPD as a ratio of blood tumor burden to lymph node tumor burden is at or about a value of 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450 or 500, or any value therebetween.

21. The method of any one of claims 1, 6, and 8-20, wherein the value of the one or more disease burden parameters is the value of said one or more disease burden parameters before administering lymphodepleting therapy to the subject.

22. A pharmaceutical composition described in any one of claims 2 to 5, and 7, wherein the step of assessing blood tumor burden includes a step of determining lymphocyte concentration in the subject's blood, the concentration being the number of lymphocytes per microliter (μL) of blood.

23. The method of claim 22, wherein the threshold level for blood tumor burden is a value between 800 or about 800 lymphocytes / μL and 3000 or about 3000 lymphocytes / μL, or between 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL or 3000 lymphocytes / μL.

23. The medicament of any one of claims 2 to 5, 7 and 22, wherein the lymphocytes / μL is at or near 800 lymphocytes / μL, 900 lymphocytes / μL, 1000 lymphocytes / μL, 1250 lymphocytes / μL, 1500 lymphocytes / μL, 1750 lymphocytes / μL, 2000 lymphocytes / μL, 2250 lymphocytes / μL, 2500 lymphocytes / μL, 2750 lymphocytes / μL or 3000 lymphocytes / μL, or any value therebetween.

24. The pharmaceutical composition of any one of claims 2 to 5, 7, 22 and 23, wherein the step of assessing lymph node tumor burden includes a step of determining maximum lymph node diameter, wherein maximum lymph node diameter is measured in centimeters (cm).

25. The pharmaceutical composition of claim 24, wherein the threshold level for maximum lymph node diameter as lymph node tumor burden is a value between 4 or about 4 cm and 7 or about 7 cm.

26. The pharmaceutical composition of claim 24 or claim 25, wherein the threshold level for maximum lymph node diameter as lymph node tumour burden is 4cm, 4.25cm, 4.5cm, 4.75cm, 5cm, 5.25cm, 5.5cm, 5.75cm, 6cm, 6.25cm, 6.5cm, 6.75cm or 7cm, or a value of about 4cm, 4.25cm, 4.5cm, 4.75cm, 5cm, 5.25cm, 5.5cm, 5.75cm, 6cm, 6.25cm, 6.5cm, 6.75cm or 7cm, or a value between any of the above.

27. ​​A pharmaceutical composition according to any one of claims 2 to 5 and 7, wherein the step of assessing the ratio of blood tumor burden to lymph node tumor burden comprises a step of determining the ratio of lymphocyte counts per microliter (μL) of blood to maximum lymph node diameter in centimeters (cm), and the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to maximum lymph node diameter in centimeters (cm) as the ratio of blood tumor burden to lymph node tumor burden is a value from at or about 300 to at or about 1000.

28. The pharmaceutical composition of claim 27, wherein the threshold level for the ratio of lymphocyte count per microliter (μL) of blood to maximum lymph node diameter in centimeters (cm) as the ratio of blood tumor burden to lymph node tumor burden is 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000, or a value of about 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000, or a value between any of the above.

29. A pharmaceutical agent described in any one of claims 2 to 5 and 7, wherein the step of assessing lymph node tumor burden includes a step of determining the sum of two-way products (SPD).

30. The method of claim 29, wherein SPD is measured in units of square centimeters (cm2).

31. The method of claim 29 or 30, wherein the threshold level for SPD as lymph node tumor burden is a value between 10 or about 10 cm 2 and 40 or about 40 cm 2 .

32. The method of claim 31, wherein the threshold level for SPD as lymph node tumour burden is 10cm2, 12.5cm2, 15cm2, 17.5cm2, 20cm2, 22.5cm2, 25cm2, 27.5cm2, 30cm2, 32.5cm2, 35cm2, 37.5cm2 or 40cm2, or about 10cm2, 12.5cm2, 15cm2, 17.5cm2, 20cm2, 22.5cm2, 25cm2, 27.5cm2, 30cm2, 32.5cm2, 35cm2, 37.5cm2 or 40cm2.

32. The pharmaceutical composition of claim 29, wherein the value is a value between any of the above.

33. A pharmaceutical agent according to any one of claims 2 to 5 and 7, wherein the step of assessing the ratio of blood tumor burden to lymph node tumor burden comprises determining the ratio of lymphocyte counts per microliter (μL) of blood to sum of two-way products (SPD) in units of square centimeters (cm2), and the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is a value from at or about 25 to at or about 500.

34. The pharmaceutical composition of claim 33, wherein the threshold level for the ratio of lymphocyte counts per microliter (μL) of blood to SPD as the ratio of blood tumor burden to lymph node tumor burden is 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450 or 500, or a value of about 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450 or 500, or a value between any of the above.

35. A pharmaceutical described in any one of claims 2 to 5, 7, and 22 to 34, wherein the value of one or more disease burden parameters is the value of the one or more disease burden parameters before administering lymphodepletion therapy to the subject.

36. The pharmaceutical agent of any one of claims 2 to 5, 7, and 22 to 35, further comprising administering to the subject a lymphodepletion therapy prior to administration of the cell therapy.

37. The pharmaceutical composition of any one of claims 2 to 5, 7, and 22 to 36, further comprising administering to the subject a Bruton's tyrosine kinase inhibitor (BTKi), wherein the BTKi is ibrutinib.

38. The pharmaceutical agent of claim 37, wherein administration of BTKi is initiated prior to initiation of administration of cell therapy.

39. Ibrutinib is administered at a dose of 140 or about 140 mg to 840 or about 840 mg per day; ibrutinib is administered at a dose of 280 or about 280 mg to 560 or about 560 mg per day; or Ibrutinib is administered at a dose of 420 or about 420 mg per day, A pharmaceutical agent according to claim 37 or claim 38.

40. The medicament according to any one of claims 2 to 5, 7 and 22 to 35, wherein the disease is relapsed or refractory (r / r) CLL and / or the disease is relapsed or refractory (r / r) SLL.

41. The dose of engineered cells is ＋ Cells vs. CAR-expressing CD8 ＋ The medicament of any one of claims 2 to 5, 7, and 22 to 40, comprising a predetermined ratio of cells, said ratio being from about 1:3 to about 3:

1.

42. The dose of engineered cells is 2.5×10 7 or about 2.5 x 10 7 Total CAR-expressing cells ~1.0 x 10 8 or about 1.0 x 10 8 The pharmaceutical agent of any one of claims 2 to 5, 7, and 22 to 41, comprising a total of CAR-expressing cells.

43. Prior to administration of cell therapy, The subject has been treated with one or more prior therapies for CLL or SLL in addition to another dose of CAR-expressing cells and lymphodepleting therapy; and / or The subject has relapsed following remission after treatment with two or more prior therapies or has become resistant to treatment with two or more prior therapies, has failed treatment with two or more prior therapies, and / or is intolerant to treatment with two or more prior therapies. The pharmaceutical composition according to any one of claims 2 to 5, 7, and 22 to 42.

44. The pharmaceutical composition of claim 43, wherein the one or more prior treatments are at least two prior treatments.

45. The pharmaceutical agent of claim 43, wherein the one or more prior therapies are selected from kinase inhibitors, inhibitors of Bruton's tyrosine kinase (BTK), ibrutinib; venetoclax; combination therapy including fludarabine and rituximab; radiation therapy; and hematopoietic stem cell transplantation (HSCT).

46. The pharmaceutical agent of any one of claims 43 to 45, wherein the subject has relapsed following remission after treatment with ibrutinib and venetoclax, has become resistant to treatment with ibrutinib and venetoclax, has failed treatment with ibrutinib and venetoclax, and / or is intolerant to ibrutinib and venetoclax.

47. The pharmaceutical agent of any one of claims 2 to 5, 7, and 22 to 46, wherein the engineered cells are primary T cells obtained from the subject.

48. The pharmaceutical of any one of claims 2-5, 7 and 22-47, wherein the engineered cells are autologous to the subject.

49. and / or the CAR comprises an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, 4-1BB, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule, CD3 zeta. CARs, in turn, contain an extracellular antigen-binding domain specific for CD19, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, and a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule. A pharmaceutical agent according to any one of claims 2 to 5, 7 and 22 to 48.

50. The pharmaceutical of claim 49, wherein the antigen-binding domain is an scFv.

51. the scFv comprises a CDRL1 sequence of RASQDISKYLN (SEQ ID NO:35), a CDRL2 sequence of SRLHSGV (SEQ ID NO:36), and / or a CDRL3 sequence of GNTLPYTFG (SEQ ID NO:37), and / or a CDRH1 sequence of DYGVS (SEQ ID NO:38), a CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO:39), and / or a CDRH3 sequence of YAMDYWG (SEQ ID NO:40); the scFv comprises the variable heavy chain region of FMC63 and the variable light chain region of FMC63, and / or the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63, or binds to the same epitope as any of the foregoing or competes for binding with any of the foregoing; The scFv is V as shown in SEQ ID NO:41 H and V as shown in SEQ ID NO:42 L Including said V H and the V L and separated by a flexible linker, said flexible linker being or comprising the sequence shown in SEQ ID NO:24; and / or The scFv has or comprises the sequence shown in SEQ ID NO: 43; The pharmaceutical composition of claim 50.

52. An article of manufacture comprising a composition for cell therapy, or one of a plurality of compositions for cell therapy, comprising T cells that express a CAR that binds to CD19, and instructions for administering the cell therapy, specifying administering the T cell composition in accordance with the medicament of any one of claims 2-5, 7, and 22-51.

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