Provided herein are methods and articles of manufacture for use with cell therapy for the treatment of diseases or conditions, e.g., cancer, including for predicting and treating a toxicity. In some embodiments, the toxicity is related to cytokine release syndrome (CRS). The methods generally involve assessing a change in a factor indicative of tumor burden prior to administration of a cell therapy in a subject that is associated with and/or correlate to a risk of developing toxicity. In some aspects, the methods can be used to determine if the subject is at risk or likely at risk for developing a toxicity following administration of the cell therapy. Also provided are methods for treating a subject having a disease or condition, in some cases involving administration of the cell therapy, based on assessment of risk of developing a toxicity following administration of the therapy. Also provided herein are reagents and kits for performing the methods.

CROSS-REFERENCE TO RELATED APPLICATIONS

(1) This application is a National Stage application under 35 U.S.C. § 371 of International Application No. PCT/US2018/058579, filed on Oct. 31, 2018 which claims priority from U.S. provisional patent application 62/580,417, filed Nov. 1, 2017, entitled “METHODS ASSOCIATED WITH TUMOR BURDEN FOR ASSESSING RESPONSE TO A CELL THERAPY,” the contents of which are incorporated by reference in their entirety.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

(1) The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 73504201300SeqList.txt, created Apr. 22, 2020, which is 35,579 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.

FIELD

(2) The present disclosure provides methods and articles of manufacture for use with cell therapy for the treatment of diseases or conditions, e.g., cancer, including for predicting and treating a toxicity. In some embodiments, the toxicity is related to cytokine release syndrome (CRS). The methods generally involve assessing a change in a factor indicative of tumor burden in a subject, which is associated with and/or correlates to a risk of developing toxicity following administration of the cell therapy. In some aspects, the methods can be used to determine if the subject is at risk or likely at risk for developing a toxicity following administration of the cell therapy. The present disclosure also provides methods for treating a subject having a disease or condition according to a particular treatment regimen, in some cases involving administration of the cell therapy, based on assessment of risk of developing a toxicity following administration of the therapy. Also provided herein are reagents and kits for performing the methods.

BACKGROUND

(3) Various methods are available for adoptive cell therapy using engineered cells expressing recombinant receptors, such as chimeric antigen receptor (CARs). Improved methods are needed, for example, to increase safety and/or reduce the risk of toxicity in a subject to the administered cells. Provided are methods, kits and articles of manufacture that meet such needs.

SUMMARY

(4) Provided herein is a method of assessing a risk of a toxicity or a toxicity-related outcome, following administration of a cell therapy, the method including assessing a factor indicative of disease burden at two time points prior to receiving a cell therapy from a subject that is a candidate for receiving a cell therapy for treatment of a disease or condition; and determining a fold change in the factor indicative of disease burden between the two time points, wherein the fold change indicates the risk or likely risk of the subject developing a toxicity following administration of the therapy to the subject. In some embodiments, the factor indicative of disease burden is a volumetric measure of a tumor or is an inflammatory marker in a sample from a subject. In some cases, the factor indicative of disease burden is a volumetric measure and the volumetric measure is a sum of the products of diameters (SPD), longest tumor diameters (LD), sum of longest tumor diameters (SLD), tumor volume, necrosis volume, necrosis-tumor ratio (NTR), peritumoral edema (PTE), and edema-tumor ratio (ETR). In some aspects, the volumetric measure is measured using computed tomography (CT), positron emission tomography (PET), and/or magnetic resonance imaging (MRI) of the subject.

(5) In some aspects, the factor indicative of disease burden is an inflammatory marker and the inflammatory marker is C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, ferritin, β2 microglobulin (β2-M), or lactate dehydrogenase (LDH). In some embodiments, the sample is or contains a blood sample, plasma sample, or serum sample. In some cases, the inflammatory marker is assessed using a colorimetric assay or an immunoassay. In some examples, the inflammatory marker is assessed using an immunoassay and the immunoassay is selected from enzyme-linked immunosorbent assay (ELISA), enzyme immunoassay (EIA), radioimmunoassay (RIA), surface plasmon resonance (SPR), Western Blot, Lateral flow assay, immunohistochemistry, protein array or immuno-PCR (iPCR).

(6) In some of any such embodiments, the subject is a human.

(7) In some of any such embodiments, the two time points includes a first time point and a second time point, and wherein the fold change is a ratio of the factor indicative of disease burden at the first time point and the second time point. In some aspects, the two time points are both no more than one month or two months prior to receiving the cell therapy. In some cases, the two time points are not less than one week, two weeks, three weeks, four weeks, or five weeks apart. In some embodiments, the two time points are not less than three weeks apart. In some embodiments, the two time points are not more than four weeks apart, five weeks, or six weeks apart. In some instances, the second time point is more than 1, 2, 3, 4, 5, 6, or 7 days before administration of the cell therapy.

(8) In some of any such embodiments, the cell therapy contains cells engineered to express a recombinant receptor. In some embodiments, the toxicity is neurotoxicity and/or cytokine release syndrome (CRS). In some aspects, the toxicity is early toxicity that develops within 7 days of administration of the cell therapy. In some examples, the toxicity develops within 3, 4, 5, 6, or 7 days of administration of the cell therapy. In some instances, the toxicity is a first sign of a fever or is a sustained fever following administration of the cell therapy.

(9) In some embodiments, the subject is or is likely at risk of developing toxicity if the fold change is at or above a threshold value; or the subject is not or is likely not at risk of developing toxicity if the fold change is below a threshold value. In some aspects, the threshold value is a value that: i) is within 25%, within 20%, within 15%, within 10%, or within 5% above the average fold change of the factor indicative of disease burden and/or is within a standard deviation above the average fold change of the factor indicative of disease burden in a plurality of control subjects; ii) is above the highest fold change of the factor indicative of disease burden, optionally within 50%, within 25%, within 20%, within 15%, within 10%, or within 5% above such highest fold change, measured in at least one subject from among a plurality of control subjects; and/or iii) is above the highest fold change as measured among more than 75%, 80%, 85%, 90%, or 95%, or 98% of subjects from a plurality of control subjects.

(10) In some embodiments, the plurality of control subjects are a group of subjects prior to receiving a cell therapy for treating a disease or condition, said cell therapy containing cells genetically engineered to express a recombinant receptor, wherein each of the subjects of the group went on to develop toxicity, optionally early toxicity, optionally a fever or a sustained fever, within 7 days after receiving the cell therapy for treating the same disease or condition.

(11) In some embodiments, if the subject is indicated as likely to develop toxicity, selecting the subject for administration of a therapeutic regimen, the therapeutic regimen comprising administering to the subject: i. an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of a toxicity and the cell therapy, wherein administration of the agent is to be administered (i) prior to, (ii) within one, two, or three days of, (iii) concurrently with and/or (iv) at first fever following, the initiation of administration of the cell therapy to the subject; ii. the cell therapy at a reduced dose or at a dose that is not associated with risk of developing toxicity or severe toxicity, or is not associated with a risk of developing a toxicity or severe toxicity in a majority of subjects, and/or a majority of subjects having a disease or condition that the subject has or is suspected of having, following administration of the cell therapy; and/or iii. the cell therapy in an in-patient setting and/or with admission to the hospital for one or more days, optionally wherein the cell therapy is otherwise to be administered to subjects on an outpatient basis or without admission to the hospital for one or more days; or iv. an alternative therapeutic treatment other than the cell therapy.

(12) In some embodiments, if subject is indicated as likely not at risk of developing toxicity, selecting the subject for administration of a therapeutic regimen, the therapeutic regimen comprising administering to the subject: i. the cell therapy, optionally at a non-reduced dose, optionally on an outpatient basis or without admission to the hospital for one or more days; ii. the cell therapy, wherein administration of the cell therapy does not include administering, prior to or concurrently with administering the cell therapy and/or prior to the development of a sign or symptom of toxicity other than fever, an agent or treatment capable of treating, preventing, delaying, or attenuating the development of the toxicity; or iii. the cell therapy in an outpatient setting and/or without admission of the subject to the hospital overnight or for one or more consecutive days and/or is without admission of the subject to the hospital for one or more days.

(13) In some embodiments, if the subject is indicated as likely to develop toxicity following administration of the cell therapy, the cell therapy is not administered to the subject.

(14) In some embodiments, the method further includes administering the therapeutic regimen to the selected subject.

(15) Provided herein is a method of treatment including administering a therapeutic regimen to a subject that is a candidate for receiving a cell therapy for treatment of a disease or condition, wherein the administration is carried out following or based on the results of assessing the subject for a fold change in a factor indicative of disease burden between two time points prior to receiving a cell therapy. In some aspects, the factor indicative of disease burden is a volumetric measure of a tumor or is an inflammatory marker in a sample from a subject. In some examples, the factor indicative of disease burden is a volumetric measure and the volumetric measure is a sum of the products of diameters (SPD), longest tumor diameters (LD), sum of longest tumor diameters (SLD), necrosis, tumor volume, necrosis volume, necrosis-tumor ratio (NTR), peritumoral edema (PTE), and edema-tumor ratio (ETR). In some cases, the volumetric measure is measured using computed tomography (CT), positron emission tomography (PET), and/or magnetic resonance imaging (MRI) of the subject.

(16) In some embodiments, the factor indicative of disease burden is an inflammatory marker and the inflammatory marker is C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, ferritin, β2 microglobulin (β2-M), or lactate dehydrogenase (LDH). In some aspects, the sample is or contains a blood sample, plasma sample, or serum sample. In some cases, the inflammatory marker is assessed using a colorimetric assay or an immunoassay. In some examples, the inflammatory marker is assessed using an immunoassay and the immunoassay is selected from enzyme-linked immunosorbent assay (ELISA), enzyme immunoassay (EIA), radioimmunoassay (RIA), surface plasmon resonance (SPR), Western Blot, Lateral flow assay, immunohistochemistry, protein array or immuno-PCR (iPCR).

(17) In some of any such embodiments, the subject is a human.

(18) In some of any such embodiments, the two time points includes a first time point and a second time point, and wherein the fold change is a ratio of the factor indicative of disease burden at the first time point and the second time point. In some embodiments, the two time points are both no more than one month or two months prior to receiving the cell therapy. In some cases, the two time points are not less than one week, two weeks, three weeks, four weeks, or five weeks apart. In some instances, the two time points are not less than three weeks apart. In some cases, the two time points are not more than four weeks apart, five weeks, or six weeks apart. In some instances, the second time point is more than 1, 2, 3, 4, 5, 6, or 7 days before administration of the cell therapy.

(19) In some of any such embodiments, the cell therapy contains cells engineered to express a recombinant receptor. In some embodiments, the fold change in the factor indicative of disease burden is associated with a risk of developing toxicity following administration of the cell therapy.

(20) In some of any such embodiments, the toxicity is neurotoxicity and/or cytokine release syndrome (CRS). In some cases, the toxicity is early toxicity that develops within 7 days of administration of the cell therapy. In some aspects, the toxicity develops within 3, 4, 5, 6, or 7 days of administration of the cell therapy. In some instances, the toxicity is a first sign of a fever or is a sustained fever following administration of the cell therapy.

(21) In some of any such embodiments, the assessing of the fold change in a factor indicative of disease burden between two time points includes a comparison to a threshold value, wherein the comparison indicates the risk or likely risk of the subject developing toxicity following administration of the cell therapy to the subject. In some of any such embodiments, the fold change in the factor indicative of disease burden correlates to a risk that the subject is or is likely to develop toxicity following administration of the cell therapy when it is administered. In some of any such embodiments, the subject is or is likely at risk of developing toxicity if the fold change is at or above a threshold value; or the subject is not or is likely not at risk of developing toxicity if the fold change is below a threshold value. In some examples, the threshold value is a value that: i) is within 25%, within 20%, within 15%, within 10%, or within 5% above the average fold change of the factor indicative of disease burden and/or is within a standard deviation above the average fold change of the factor indicative of disease burden in a plurality of control subjects; ii) is above the highest fold change of the factor indicative of disease burden, optionally within 50%, within 25%, within 20%, within 15%, within 10%, or within 5% above such highest fold change, measured in at least one subject from among a plurality of control subjects; and/or iii) is above the highest fold change as measured among more than 75%, 80%, 85%, 90%, or 95%, or 98% of subjects from a plurality of control subjects.

(22) In some cases, the plurality of control subjects are a group of subjects prior to receiving a cell therapy for treating a disease or condition, said cell therapy containing cells genetically engineered to express a recombinant receptor, wherein each of the subjects of the group went on to develop toxicity, optionally early toxicity, optionally a fever or a sustained fever, within 7 days after receiving the cell therapy for treating the same disease or condition.

(23) In some of any such embodiments, if the assessing indicates the subject is or is likely to develop toxicity following administration of the cell therapy, the therapeutic regimen includes administering to the subject: i. an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of a toxicity and the cell therapy, wherein administration of the agent is to be administered (i) prior to, (ii) within one, two, or three days of, (iii) concurrently with and/or (iv) at first fever following, the initiation of administration of the cell therapy to the subject; ii. the cell therapy at a reduced dose or at a dose that is not associated with risk of developing toxicity or severe toxicity, or is not associated with a risk of developing a toxicity or severe toxicity in a majority of subjects, and/or a majority of subjects having a disease or condition that the subject has or is suspected of having, following administration of the cell therapy; and/or iii. the cell therapy in an in-patient setting and/or with admission to the hospital for one or more days, optionally wherein the cell therapy is otherwise to be administered to subjects on an outpatient basis or without admission to the hospital for one or more days; or iv. an alternative therapeutic treatment other than the cell therapy.

(24) In some of any such embodiments, if the assessing indicates the subject is not or is likely not to develop toxicity following administration of the cell therapy, the therapeutic regimen includes administering to the subject: i. the cell therapy, optionally at a non-reduced dose, optionally on an outpatient basis or without admission to the hospital for one or more days; ii. the cell therapy, wherein administration of the cell therapy does not include administering, prior to or concurrently with administering the cell therapy and/or prior to the development of a sign or symptom of toxicity other than fever, an agent or treatment capable of treating, preventing, delaying, or attenuating the development of the toxicity; or iii. the cell therapy in an outpatient setting and/or without admission of the subject to the hospital overnight or for one or more consecutive days and/or is without admission of the subject to the hospital for one or more days.

(25) In some of any such embodiments, if the assessing indicates the subject is or is likely to develop toxicity following administration of the cell therapy, the cell therapy is not administered to the subject.

(26) In some of any such embodiments, the disease or condition is a cancer. In some examples, the cancer is a myeloma, lymphoma or leukemia. In some cases, the disease or condition is a B cell malignancy. In some instances, the B cell malignancy is selected from acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), non-Hodgkin lymphoma (NHL), or Diffuse Large B-Cell Lymphoma (DLBCL), or a subtype of any of the foregoing.

(27) In some of any such embodiments, greater than or greater than about 30%, 35%, 40%, or 50% of the subjects treated according to the method do not exhibit any grade of cytokine release syndrome (CRS) or neurotoxicity; and/or at least at or about 45, 50, 60, 65, 70, 75, 80, 85, 90, 95% or about 100% of subjects treated according to the method do not exhibit severe CRS, optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 CRS; and/or at least at or about 45, 50, 60, 65, 70, 75, 80, 85, 90, 95% or about 100% of subjects treated according to the method do not exhibit severe neurotoxicity, optionally grade 3 or higher, prolonged grade 3 or higher or grade 4 or 5 neurotoxicity; and/or at least at or about 45, 50, 60, 65, 70, 75, 80, 85, 90, 95% or about 100% of subjects treated according to the method do not exhibit cerebral edema.

(28) In some of any such embodiments, prior to initiation of administration of the dose of cells, the subject has not been administered an agent or treatment capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of a toxicity; and/or the subject is not administered an agent or treatment for the treatment or prevention or reduction or attenuation of a neurotoxicity and/or a cytokine release syndrome or risk thereof, within a period of time following administration of the dose, which period of time is optionally at or about 1, 2, 3, 4, 5 days or is optionally at or about 6, 7, 8, 9, 10, 11 days or is optionally 1 or 2 or 3 or 4 weeks; and/or the subject is not administered an agent or treatment for the treatment or prevention or reduction or attenuation of a neurotoxicity and/or a cytokine release syndrome or risk thereof, following administration of the dose, prior to or unless the subject exhibits a sign or symptom of the toxicity and/or prior to or unless the subject exhibits a sign or symptom of the toxicity other than a fever, optionally wherein the fever is not a sustained fever or the fever is or has been reduced or reduced by more than 1° C. after treatment with an antipyretic; and/or the administration and any follow-up is carried out on an outpatient basis and/or without admitting the subject to a hospital and/or without an overnight stay at a hospital and/or without requiring admission to or an overnight stay at a hospital, optionally unless or until the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic.

(29) In some of any such embodiments, prior to initiation of administration of the dose of cells, the subject has not been administered an anti-IL-6 or anti-IL-6R antibody, optionally tocilizumab or siltuximab, and/or has not been administered a steroid, optionally dexamethasone, the subject is not administered an anti-IL-6 or anti-IL-6R antibody, optionally tocilizumab or siltuximab, and/or has not been administered a steroid, optionally dexamethasone, within a period of time following administration of the dose, which period of time is optionally at or about 1, 2, 3, 4, 5 days or is optionally at or about 6, 7, 8, 9, 10, 11 days or is optionally 1 or 2 or 3 or 4 weeks; and/or the subject is not administered an anti-IL-6 or anti-IL-6R antibody, optionally tocilizumab or siltuximab, and/or has not been administered a steroid, optionally dexamethasone, following administration of the cell dose, prior to, or unless, the subject exhibits a sign or symptom of a toxicity, optionally a neurotoxicity or CRS, and/or prior to, or unless, the subject exhibits a sign or symptom of a toxicity, optionally a neurotoxicity or CRS, other than a fever, optionally wherein the fever is not a sustained fever or the fever is or has been reduced or reduced by more than 1° C. after treatment with an antipyretic; and/or the administration and any follow-up is carried out on an outpatient basis and/or without admitting the subject to a hospital and/or without an overnight stay at a hospital and/or without requiring admission to or an overnight stay at a hospital, optionally unless or until the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic.

(30) In some of any such embodiments, the administration is carried out on an outpatient basis and/or without requiring admission to or an overnight stay at a hospital; and if the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic, the subject is admitted to the hospital or to an overnight stay at a hospital and/or is administered an agent or treatment for the treatment or prevention or reduction or attenuation of a neurotoxicity and/or a cytokine release syndrome or risk thereof.

(31) In some of any such embodiments, the cell therapy is or contains tumor infiltrating lymphocytic (TIL) therapy. In some of any such embodiments, the cell therapy contains cells engineered to express a recombinant receptor that specifically binds to an antigen associated with a disease or condition and/or expressed in cells associated with the disease or condition. In some of any such embodiments, the cell therapy is an adoptive cell therapy. In some cases, the cells contain immune cells. In some examples, the immune cells are or contains T cells or NK cells. In some aspects, the immune cells are or contains T cells and the T cells contain CD4+ and/or CD8+ T cells.

(32) In some of any such embodiments, the cell therapy is a T cell therapy comprising genetically engineered cells expressing a recombinant receptor. In some cases, the recombinant receptor is a T cell receptor or a functional non-T cell receptor. In some examples, the recombinant receptor specifically binds to an antigen associated with a disease or condition and/or expressed in cells associated with the disease or condition. In some examples, the antigen is selected from among 5T4, 8H9, avb6 integrin, B7-H6, B cell maturation antigen (BCMA), CA9, a cancer-testes antigen, carbonic anhydrase 9 (CAIX), CCL-1, CD19, CD20, CD22, CEA, hepatitis B surface antigen, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7/8, CD123, CD138, CD171, carcinoembryonic antigen (CEA), CE7, a cyclin, cyclin A2, c-Met, dual antigen, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, ephrinB2, erb-B2, erb-B3, erb-B4, erbB dimers, EGFR VIII, estrogen receptor, Fetal AchR, folate receptor alpha, folate binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, G250/CAIX, GD2, GD3, gp100, Her2/neu (receptor tyrosine kinase erbB2), HMW-MAA, IL-22R-alpha, IL-13 receptor alpha 2 (IL-13Ra2), kinase insert domain receptor (kdr), kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MART-1, mesothelin, murine CMV, mucin 1 (MUC1), MUC16, NCAM, NKG2D, NKG2D ligands, NY-ESO-1, O-acetylated GD2 (OGD2), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), PSCA, progesterone receptor, survivin, ROR1, TAG72, VEGF receptors, VEGF-R2, Wilms Tumor 1 (WT-1), a pathogen-specific antigen.

(33) In some embodiments, the antigen is or includes αvβ6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer/testis antigen 1B (CTAG, also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7/8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPRC5D), Her2/neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen A1 (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Ra2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-1), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and/or biotinylated molecules, and/or molecules expressed by HIV, HCV, HBV or other pathogens. Antigens targeted by the receptors in some embodiments include antigens associated with a B cell malignancy, such as any of a number of known B cell marker. In some embodiments, the antigen is or includes CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda, CD79a, CD79b or CD30.

(34) In some embodiments, the antigen is or includes a pathogen-specific or pathogen-expressed antigen. In some embodiments, the antigen is a viral antigen (such as a viral antigen from HIV, HCV, HBV, etc.), bacterial antigens, and/or parasitic antigens.

(35) In some embodiments, the CAR contains an extracellular antigen-recognition domain that specifically binds to the antigen and an intracellular signaling domain comprising an ITAM, wherein optionally, the intracellular signaling domain contains an intracellular domain of a CD3-zeta (CD3ζ) chain; and/or wherein the CAR further contains a costimulatory signaling region, which optionally contains a signaling domain of CD28 or 4-1BB. In some aspects, the genetically engineered cells contain T cells or NK cells. In some of any such embodiments, the genetically engineered cells contain T cells, and the T cells contain CD4+ and/or CD8+ T cells. In some cases, the T cells are primary T cells obtained from a subject. In some of any such embodiments, the cells of the cell therapy are autologous to the subject. In some of any such embodiments, the cells are allogeneic to the subject. In some of any such embodiments, the threshold fold change for SPD is about 5 fold, 6 fold, 7 fold, 8 fold, or 9 fold. In some of any such embodiments, the threshold value is a threshold value for fold change of a volumetric measure of disease burden that is SPD, wherein the fold change is at least about or is about or is 5 fold, 6 fold, 7 fold, 8 fold, or 9 fold.

(36) In some of any such embodiments, the cell therapy includes the administration of from or from about 1×10.sup.5 to 1×10.sup.8 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), from or from about 5×10.sup.5 to 1×10.sup.7 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs) or from or from about 1×10.sup.6 to 1×10.sup.7 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), each inclusive. In some of any such embodiments, the cell therapy includes the administration of no more than 1×10.sup.8 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), no more than 1×10.sup.7 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), no more than 0.5×10.sup.7 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), no more than 1×10.sup.6 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs), no more than 0.5×10.sup.6 total recombinant receptor-expressing cells, total T cells, or total peripheral blood mononuclear cells (PBMCs).

(37) Provided is a kit containing a cell therapy, said cell therapy comprising cells genetically engineered to express a recombinant receptor; and instructions for administering the cell therapy to a subject, wherein the instructions specify: (1) assessing one or more factors indicative of tumor burden in a subject that is a candidate for treatment with the cell therapy, wherein the assessing is performed at two time points prior to the subject receiving the cell therapy, and the factor indicative of tumor burden is a volumetric measure of the tumor or is an inflammatory marker in a sample from a subject; and (2) administering the cell therapy to the subject based on the fold change in the factor indicative of disease burden between the two time points, wherein the fold change indicates the risk or likely risk of the subject developing toxicity following administration of the cell therapy to the subject.

(38) Also provided is a kit containing a cell therapy, said cell therapy comprising cells genetically engineered to express a recombinant receptor; and instructions for administering the cell therapy to a subject having or suspected of having a tumor, wherein the instructions specify: (1) assessing, at two different time points, one or more factors indicative of disease burden in a subject that is a candidate for treatment with the cell therapy, wherein, at each of the two time points, the subject has not yet been administered the cell therapy and the factors indicative of disease burden comprises a volumetric measure of the tumor or a level or amount of an inflammatory marker in a sample from the subject, wherein the fold change in the factor assessed at the two different time points indicates the degree of risk or likely risk of the subject developing toxicity following administration of the cell therapy to the subject; and (2) (i) if the fold change is at or below a threshold value, administering the cell therapy to the subject, or (ii) administering the cell therapy to the subject, or (iii) administering the cell therapy to the subject at an amount, dose, setting, time or frequency that is based on the fold change. In some embodiments, the kit further comprises instructions for assessing the presence, level or amount of at least one of the inflammatory marker in two or more samples obtained at two or more time points from a subject that is a candidate for treatment with the cell therapy and determining a fold-change in the level or amount of the marker assessed at two of the two or more time points, wherein the fold change indicates the degree of risk or likely risk of the subject developing toxicity following administration of the cell therapy to the subject. In some embodiments, the kit further comprises instructions for (i) administering a therapeutic regimen comprising the cell therapy to the subject if the fold change is at or below a threshold value, (ii) administering the cell therapy to the subject, or (iii) administering the therapeutic regimen to the subject at an amount, dose, setting, time or frequency based on the fold change of the at least one inflammatory marker.

(39) Also provided is a kit containing a cell therapy, said cell therapy comprising cells genetically engineered to express a recombinant receptor; and one or more reagents for assaying one or more factor indicative of disease burden, wherein the factor indicative of disease burden is an inflammatory marker selected from C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, ferritin, β2 microglobulin (β2-M), or lactate dehydrogenase (LDH). In some embodiments, the kit further includes instructions for assessing the presence, level or amount of at least one of the inflammatory marker in two or more samples obtained at two time points from a subject that is a candidate for treatment with the cell therapy and determining the fold-change in the factor between the two time points, wherein the fold change indicates the risk or likely risk of the subject developing toxicity following administration of the cell therapy to the subject. In some cases, the kit further contains instructions for administering a therapeutic regimen comprising the cell therapy to the subject following or based on the fold change of the at least one inflammatory marker.

(40) Provided is a kit containing a cell therapy, said cell therapy comprising cells genetically engineered to express a recombinant receptor; and instructions for administering a therapeutic regimen comprising the cell therapy following or based on the results of assessing the subject for a fold change in a factor indicative of disease burden between two time points prior to receiving a cell therapy, wherein the subject is a candidate for treatment with the cell therapy. Also provided is a kit containing a cell therapy, said cell therapy comprising cells genetically engineered to express a recombinant receptor; and (b) instructions for administering a therapeutic regimen comprising the cell therapy based on the results of assessing the subject for a fold change in a factor indicative of disease burden between two time points prior to receiving a cell therapy, wherein the instructions specify (i) administering the cell therapy to the subject if the fold change is at or below a threshold value, (ii) administering the cell therapy to the subject, or (iii) administering the therapeutic regimen to the subject at an amount, dose, setting, time or frequency based on the fold change, and wherein the subject is a candidate for treatment with the cell therapy. In some aspects, the factor indicative of disease burden is a volumetric measure of a tumor or is an inflammatory marker in a sample from a subject. In some embodiments, the factor indicative of disease burden is a volumetric measure and the volumetric measure is a sum of the products of diameters (SPD), longest tumor diameters (LD), sum of longest tumor diameters (SLD), necrosis, tumor volume, necrosis volume, necrosis-tumor ratio (NTR), peritumoral edema (PTE), and edema-tumor ratio (ETR). In some cases, the volumetric measure is measured using computed tomography (CT), positron emission tomography (PET), and/or magnetic resonance imaging (MRI) of the subject.

(41) In some embodiments, the kit contains reagents for detecting C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, ferritin, β2 microglobulin (β2-M), or lactate dehydrogenase (LDH). In some aspects, the inflammatory marker is assessed using a colorimetric assay or an immunoassay. In some examples, the inflammatory marker is assessed using an immunoassay and the immunoassay is selected from enzyme-linked immunosorbent assay (ELISA), enzyme immunoassay (EIA), radioimmunoassay (RIA), surface plasmon resonance (SPR), Western Blot, Lateral flow assay, immunohistochemistry, protein array or immuno-PCR (iPCR).

(42) In some of any such embodiments, the sample is or contains a blood sample, plasma sample, or serum sample. In some of any such embodiments, the subject is a human.

(43) In some of any such embodiments, the two time points includes a first time point and a second time point, and wherein the fold change is a ratio of the factor indicative of disease burden at the a first time point and a second time point. In some of any such embodiments, the two time points comprises a first time point and a second time point, and wherein the fold change is a ratio of the factor indicative of disease burden at the first time point and the factor indicative of disease burden at the second time point. In some cases, if the cell therapy is to be administered to the subject, the two time points are both no more than one month or two months prior to the subject receiving the cell therapy. In some cases, the two time points are both no more than one month or two months prior to receiving the cell therapy. In some aspects, the two time points are not less than one week, two weeks, three weeks, four weeks, or five weeks apart. In some examples, the two time points are not less than three weeks apart. In some examples, the two time points are not more than four weeks apart, five weeks, or six weeks apart. In some cases, the second time point is more than 1, 2, 3, 4, 5, 6, or 7 days before administration of the cell therapy. In some cases, if the cell therapy is to be administered to the subject, the second time point is more than 1, 2, 3, 4, 5, 6, or 7 days before administration of the cell therapy.

(44) In some of any such embodiments, the instructions specify that the fold change in the factor indicative of disease burden indicates the subject is or is likely at risk of developing toxicity if the fold change is at or above a threshold value; or the instructions specify that the fold change in the factor indicative of disease burden indicates the subject is not or is likely not at risk of developing toxicity if the fold change is below a threshold value.

(45) In some embodiments, the threshold value is a value that i) is within 25%, within 20%, within 15%, within 10%, or within 5% above the average fold change of the factor indicative of disease burden and/or is within a standard deviation above the average fold change of the factor indicative of disease burden in a plurality of control subjects; ii) is above the highest fold change of the factor indicative of disease burden, optionally within 50%, within 25%, within 20%, within 15%, within 10%, or within 5% above such highest fold change, measured in at least one subject from among a plurality of control subjects; and/or iii) is above the highest fold change as measured among more than 75%, 80%, 85%, 90%, or 95%, or 98% of subjects from a plurality of control subjects. In some cases, the plurality of control subjects are a group of subjects prior to receiving a cell therapy for treating a disease or condition, said cell therapy containing cells genetically engineered to express a recombinant receptor, wherein each of the subjects of the group went on to develop toxicity, optionally early toxicity, optionally a fever or a sustained fever, within 7 days after receiving the cell therapy for treating the same disease or condition. In some cases, the plurality of control subjects is a group of subjects having been administered a cell therapy for treating a disease or condition and having had the fold change of the factor indicative of disease burden assessed, wherein each of the subjects of the group went on to develop toxicity, optionally early toxicity, optionally a fever or a sustained fever, within 7 days after receiving the cell therapy for treating the same disease or condition.

(46) In some of any such embodiments, the instructions specify if the fold change indicates the subject is or is likely to develop toxicity, selecting the subject for administration of a therapeutic regimen, the therapeutic regimen comprising administering to the subject: i. an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of a toxicity and the cell therapy, wherein administration of the agent is to be administered (i) prior to, (ii) within one, two, or three days of, (iii) concurrently with and/or (iv) at first fever following, the initiation of administration of the cell therapy to the subject, ii. the cell therapy at a reduced dose or at a dose that is not associated with risk of developing toxicity or severe toxicity, or is not associated with a risk of developing a toxicity or severe toxicity in a majority of subjects, and/or a majority of subjects having a disease or condition that the subject has or is suspected of having, following administration of the cell therapy; and/or iii. the cell therapy in an in-patient setting and/or with admission to the hospital for one or more days, optionally wherein the cell therapy is otherwise to be administered to subjects on an outpatient basis or without admission to the hospital for one or more days; or iv. an alternative therapeutic treatment other than the cell therapy.

(47) In some of any such embodiments, the instructions specify if the fold change indicates the subject is not or is likely not at risk of developing toxicity, selecting the subject for administration of a therapeutic regimen, the therapeutic regimen comprising administering to the subject: i. the cell therapy, optionally at a non-reduced dose, optionally on an outpatient basis or without admission to the hospital for one or more days; ii. the cell therapy, wherein administration of the cell therapy does not include administering, prior to or concurrently with administering the cell therapy and/or prior to the development of a sign or symptom of toxicity other than fever, an agent or treatment capable of treating, preventing, delaying, or attenuating the development of the toxicity; or iii. the cell therapy in an outpatient setting and/or without admission of the subject to the hospital overnight or for one or more consecutive days and/or is without admission of the subject to the hospital for one or more days.

(48) In some of any such embodiments, the instructions specify if the fold change indicates the subject is or is likely to develop toxicity, the therapeutic regimen is not administered to the subject.

(49) In some cases, the instructions specify the administration is carried out on an outpatient basis and/or without requiring admission to or an overnight stay at a hospital; and if the subject exhibits a sustained fever or a fever that is or has not been reduced or not reduced by more than 1° C. after treatment with an antipyretic, the subject is admitted to the hospital or to an overnight stay at a hospital and/or is administered an agent or treatment for the treatment or prevention or reduction or attenuation of a neurotoxicity and/or a cytokine release syndrome or risk thereof.

(50) In some of any such embodiments, the toxicity is neurotoxicity and/or cytokine release syndrome (CRS). In some cases, the toxicity is early toxicity, and in some aspects is early toxicity that develops within a certain number of days, such as within 7 days, of administration of the cell therapy. In some examples, the toxicity develops within 3, 4, 5, 6, or 7 days of administration of the cell therapy. In some instances, the toxicity is a first sign of a fever or is a sustained fever following administration of the cell therapy.

(51) In some of any such embodiments, the cell therapy is or includes tumor infiltrating lymphocytic (TIL) therapy. In some of any such embodiments, the cell therapy contains cells engineered to express a recombinant receptor that specifically binds to an antigen associated with a disease or condition and/or expressed in cells associated with the disease or condition. In some cases, the cell therapy is an adoptive cell therapy. In some aspects, the cells contain immune cells. In some instances, the immune cells are or contain T cells or NK cells. In some examples, the immune cells are or contain T cells and the T cells contain CD4+ and/or CD8+ T cells. In some instances, the cell therapy is a T cell therapy comprising genetically engineered cells expressing a recombinant receptor.

(52) In some embodiments, the disease or condition is a cancer. In some instances, the cancer is a myeloma, leukemia or lymphoma. In some aspects, the disease or condition is a B cell malignancy. In some examples, the B cell malignancy is selected from acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), non-Hodgkin lymphoma (NHL), or Diffuse Large B-Cell Lymphoma (DLBCL), or a subtype of any of the foregoing.

(53) In some embodiments, the antigen is selected from among 5T4, 8H9, avb6 integrin, B7-H6, B cell maturation antigen (BCMA), CA9, a cancer-testes antigen, carbonic anhydrase 9 (CAIX), CCL-1, CD19, CD20, CD22, CEA, hepatitis B surface antigen, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7/8, CD123, CD138, CD171, carcinoembryonic antigen (CEA), CE7, a cyclin, cyclin A2, c-Met, dual antigen, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, ephrinB2, erb-B2, erb-B3, erb-B4, erbB dimers, EGFR vIII, estrogen receptor, Fetal AchR, folate receptor alpha, folate binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, G250/CAIX, GD2, GD3, gp100, Her2/neu (receptor tyrosine kinase erbB2), HMW-MAA, IL-22R-alpha, IL-13 receptor alpha 2 (IL-13Ra2), kinase insert domain receptor (kdr), kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MART-1, mesothelin, murine CMV, mucin 1 (MUC1), MUC16, NCAM, NKG2D, NKG2D ligands, NY-ESO-1, O-acetylated GD2 (OGD2), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), PSCA, progesterone receptor, survivin, ROR1, TAG72, VEGF receptors, VEGF-R2, Wilms Tumor 1 (WT-1), a pathogen-specific antigen.

(54) In some embodiments, the antigen is selected from among αvβ6 integrin (avb6 integrin), B cell maturation antigen (BCMA), B7-H3, B7-H6, carbonic anhydrase 9 (CA9, also known as CAIX or G250), a cancer-testis antigen, cancer/testis antigen 1B (CTAG, also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), a cyclin, cyclin A2, C-C Motif Chemokine Ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7/8, CD123, CD133, CD138, CD171, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), type III epidermal growth factor receptor mutation (EGFR vIII), epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), ephrinB2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), a folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G Protein Coupled Receptor 5D (GPRC5D), Her2/neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimers, Human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigen, Human leukocyte antigen A1 (HLA-A1), Human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22Ra), IL-13 receptor alpha 2 (IL-13Ra2), kinase insert domain receptor (kdr), kappa light chain, Li cell adhesion molecule (L1-CAM), CE7 epitope of Li-CAM, Leucine Rich Repeat Containing 8 Family Member A (LRRC8A), Lewis Y, Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, murine cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligands, melan A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, Preferentially expressed antigen of melanoma (PRAME), progesterone receptor, a prostate specific antigen, prostate stem cell antigen (PSCA), prostate specific membrane antigen (PSMA), Receptor Tyrosine Kinase Like Orphan Receptor 1 (ROR1), survivin, Trophoblast glycoprotein (TPBG also known as 5T4), tumor-associated glycoprotein 72 (TAG72), Tyrosinase related protein 1 (TRP1, also known as TYRP1 or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautomerase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-1), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and/or biotinylated molecules, and/or molecules expressed by HIV, HCV, HBV or other pathogens. Antigens targeted by the receptors in some embodiments include antigens associated with a B cell malignancy, such as any of a number of known B cell marker. In some embodiments, the antigen is or includes CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Igkappa, Iglambda, CD79a, CD79b or CD30.

(55) In some embodiments, the antigen is or includes a pathogen-specific or pathogen-expressed antigen. In some embodiments, the antigen is a viral antigen (such as a viral antigen from HIV, HCV, HBV, etc.), bacterial antigens, and/or parasitic antigens.

(56) In some of any such embodiments, the recombinant receptor is a T cell receptor or a functional non-T cell receptor. In some embodiments, the recombinant receptor is a chimeric antigen receptor (CAR). In some cases, the CAR contains an extracellular antigen-recognition domain that specifically binds to the antigen and an intracellular signaling domain comprising an ITAM, wherein optionally, the intracellular signaling domain contains an intracellular domain of a CD3-zeta (CD3ζ) chain; and/or wherein the CAR further contains a costimulatory signaling region, which optionally contains a signaling domain of CD28 or 4-1BB.

(57) In some of any such embodiments, the kit further contains an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of a toxicity. In some embodiments, the agent or other treatment is or includes one or more of a steroid; an antagonist or inhibitor of a cytokine receptor or cytokine selected from among IL-10, IL-10R, IL-6, IL-6 receptor, IFNγ, IFNGR, IL-2, IL-2R/CD25, MCP-1, CCR2, CCR4, MIP1β, CCR5, TNFalpha, TNFR1, IL-1, and IL-1Ralpha/IL-1beta; or an agent capable of preventing, blocking or reducing microglial cell activity or function. In some examples, the antagonist or inhibitor is or includes an agent selected from among an antibody or antigen-binding fragment, a small molecule, a protein or peptide and a nucleic acid. In some cases, the agent or other treatment is an anti-IL-6 antibody or an anti-IL6 receptor antibody. In some examples, the agent or other treatment is or includes an agent selected from among tocilizumab, siltuximab, clazakizumab, sarilumab, olokizumab (CDP6038), elsilimomab, ALD518/BMS-945429, sirukumab (CNTO 136), CPSI-2634, ARGX-109, FE301 and FM101. In some instances, the agent or other treatment is or includes tocilizumab. In some cases, the agent or other treatment is or includes siltuximab. In some of any such embodiments, the steroid is or includes dexamethasone.

(58) In some of any such embodiments, the genetically engineered cells include T cells, and the T cells contain CD4+ and/or CD8+ T cells. In some cases, the T cells are primary T cells obtained from a subject. In some embodiments, the cells of the cell therapy are autologous to the subject. In some of any such embodiments, the cells are allogeneic to the subject. In some embodiments, the threshold value for SPD is about 5 fold, 6 fold, 7 fold, 8 fold, or 9 fold. In some embodiments, the threshold value is a threshold value for fold change of a volumetric measure of disease burden that is SPD, wherein the fold change is at least about or is about or is 5 fold, 6 fold, 7 fold, 8 fold, or 9 fold.