Methods of administering chimeric antigen receptor immunotherapy

Abstract

The disclosure provides cells comprising CD19-directed chimeric antigen receptor (CAR) genetically modified autologous T cell immunotherapy for the treatment of, e.g., relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Some aspects of the disclosure relate to methods of treatment and monitoring following infusion of T cell therapy provided herein.

1 . A method of treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma after two or more lines of systemic therapy in a patient comprising:
 administering to the patient in need thereof axicabtagene ciloleucel suspension by intravenous infusion at a dose between about 1×10 6  and about 2×10 6  CAR-positive viable T cells per kg body weight up to a maximum dose of about 1×10 8  CAR-positive viable T cells,   wherein axicabtagene ciloleucel is a CD19-directed genetically modified autologous T cell immunotherapy, comprising the patient's own T cells harvested and genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) comprising an anti-CD19 single chain variable fragment (scFv) linked to CD28 and CD3-zeta co-stimulatory domains.   
     
     
         2 . The method of  claim 1 , wherein the intravenous infusion time is between 15 and 120 minutes. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the infusion volume is between 50 and 100 mL. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the immunotherapy is infused from an infusion bag. 
     
     
         7 . The method of  claim 6 , wherein the infusion bag is agitated during the infusion. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the suspension further comprises albumin. 
     
     
         10 . The method of  claim 9 , wherein albumin is present in an amount of about 2-3% (v/v). 
     
     
         11 - 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the suspension further comprises DMSO. 
     
     
         14 . A method of treating relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in a patient comprising:
 (a) administering to the patient in need thereof CD19-directed genetically modified autologous T cell immunotherapy; and   (b) monitoring the patient following infusion for signs and symptoms of an adverse reaction.   
     
     
         15 . The method of  claim 14 , wherein the relapsed or refractory large B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma. 
     
     
         16 . The method of  claim 14 , wherein the adverse reaction is selected from the group consisting of cytokine release syndrome (CRS), a neurologic toxicity, a hypersensitivity reaction, a serious infection, a cytopenia and hypogammaglobulinemia. 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 14 , wherein the method further comprises administering an effective amount of tocilizumab to treat a symptom of an adverse reaction. 
     
     
         19 . The method of  claim 18 , further comprising administering a corticosteroid to treat a symptom of an adverse reaction. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 14 , comprising monitoring for signs and symptoms of cytokine release syndrome (CRS) at least daily for about 7 days following infusion. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 14 , wherein the method further comprises administering a non-sedating, anti-seizure medicine for seizure prophylaxis. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 14 , wherein the method further comprises administering at least one of erythropoietin, darbepoetin alfa, platelet transfusion, colony-stimulating factor (CSF), granulocyte colony-stimulating factor, filgrastim, pegfilgrastim, or granulocyte-macrophage colony-stimulating factor. 
     
     
         26 . The method of  claim 14 , further comprising measuring cytokine and chemokine levels. 
     
     
         27 . The method of  claim 26 , wherein the level of at least one of IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and sIL2Rα is measured. 
     
     
         28 . A container comprising a suspension of CD19-directed genetically modified autologous T cells, about 5% dimethylsulfoxide (DMSO) and about 2.5% human albumin (v/v). 
     
     
         29 . The method of  claim 14 , further comprising
 assessing if cytokine release syndrome (CRS) greater than Grade 2 is observed and administering tocilizumab at a dose of about 8 mg/kg IV over 1 hour, repeating tocilizumab every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen;   assessing if CRS symptoms observed do not improve after 24 hours of administering tocilizumab, administering methylprednisolone about 1 mg/kg IV twice daily or administering equivalent dexamethasone dose and continuing corticosteroids use until the event is Grade 1 or less, then tapering over 3 days;   assessing if CRS Grade 3 is observed and, administering tocilizumab at a dose of 8 mg/kg IV over 1 hour, repeating tocilizumab every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen and administering methylprednisolone 1 mg/kg IV twice daily or administering equivalent dexamethasone dose and continuing corticosteroids use until the event is Grade 1 or less, then tapering over 3 days; and   assessing if CRS Grade 4 is observed and, administering tocilizumab at a dose of about 8 mg/kg IV over 1 hour, repeating tocilizumab every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen and administering about 1,000 mg IV methylprednisolone per day for 3 days.   
     
     
         30 . (canceled)