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 B cell lymphoma or Acute Lymphoblastic Leukemia (ALL) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of CD19-directed genetically modified T cell immunotherapy, wherein the method further comprises:
 (i) Administering an effective amount of an inhibitor, or combination of inhibitors, of GM-CSF, CSF1, GM-CSFR, or CSF1R to treat a symptom of an adverse reaction;   (ii) Administering an effective amount of an immunosuppressant that depletes T lymphocytes, such as anti-thymocyte globulin (ATG), preferably wherein the adverse reaction is cerebral edema;   (iii) Administering an effective amount of a steroid (e.g., a corticosteroid) and/or tocilizumab to treat a symptom of an adverse reaction;   (iv) Administering a non-sedating, anti-seizure medicine for seizure prophylaxis;   (v) Administering at least one of erythropoietin, darbepoetin alfa, platelet transfusion, filgrastim, or pegfilgrastim;   (vi) Administering tocilizumab;   (vii) Administering anti-thymocyte globulin; and/or   (viii) Administering rituximab.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , 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. 
     
     
         4 . The method of  claim 1 , wherein the signs and symptoms of adverse reactions are selected from the group consisting of fever, hypotension, tachycardia, hypoxia, and chills, include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, organ toxicity, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), seizure, encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia anxiety, anaphylaxis, febrile neutropenia, thrombocytopenia, neutropenia, and anemia. 
     
     
         5 . The method of  claim 1 , wherein the adverse reaction is (1) neurologic toxicity, optionally, wherein the symptom of neurologic toxicity is encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, and/or anxiety, and/or (2) cytopenia. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein:
 (i) the GM-CSF inhibitor is selected from lenzilumab; namilumab (AMG203); GSK3196165/MOR103/otilimab (GSK/MorphoSys); KB002 and KB003 (KaloBios); MT203 (Micromet and Nycomed); MORAb-022/gimsilumab (Morphotek); or a biosimilar of any one of the same; E21R; and a small molecule;   (ii) the CSF1 inhibitor is selected from RG7155, PD-0360324, MCS110/lacnotuzumab), or a biosimilar version of any one of the same; and a small molecule; and/or   (iii) the GM-CSFR inhibitor and the CSF1R inhibitor is/are selected from Mavrilimumab (formerly CAM-3001; Medlmmune, Inc.); cabiralizumab (Five Prime Therapeutics); LY3022855 (IMC-CS4)(Eli Lilly), Emactuzumab, also known as RG7155 or R05509554; FPA008 (Five Prime/BMS); AMG820 (Amgen); ARRY-382 (Array Biopharma); MCS110 (Novartis); PLX3397 (Plexxikon); ELB041/AFS98/TG3003 (ElsaLys Bio, Transgene), SNDX-6352 (Syndax); a biosimilar version of any one of the same; and a small molecule.   
     
     
         8 . The method of  claim 7 , wherein at least one of the inhibitors, or combination of inhibitors of GM-CSF, CSF1, GM-CSFR, or CSF1R are administered on the same day as CD19-directed genetically modified T cell immunotherapy. 
     
     
         9 . The method of  claim 7 , wherein at least one of the inhibitors, or combination of inhibitors of GM-CSF, CSF1, GM-CSFR, or CSF1R is/are administered more than once after the administration of CD19-directed genetically modified T cell immunotherapy. 
     
     
         10 . The method of  claim 7 , wherein at least one of the inhibitors, or combination of inhibitors of GM-CSF, CSF1, GM-CSFR, or CSF1R is/are administered between 1 to 12 hours prior to the administration of CD19-directed genetically modified T cell immunotherapy, optionally, simultaneously. 
     
     
         11 . The method of  claim 7 , wherein at least one of the inhibitors, or combination of inhibitors of GM-CSF, CSF1, GM-CSFR, or CSF1R is/are administered more than once after the administration of CD19-directed genetically modified T cell immunotherapy. 
     
     
         12 . The method  claim 7 , wherein the inhibitor, or combination of inhibitors, is selected from lenzilumab and mavrilimumab. 
     
     
         13 . The method of  claim 1 , wherein the CD19-directed genetically modified T cell immunotherapy is administered as a single IV infusion at a target dose of 2×10 6  CAR-positive viable T cells/kg (maximum permitted dose: 2×10 8  cells) on Day 0, and mavrilimumab is administered once at 3 mg/kg of body weight subcutaneously, OP/IP, or IV on Day 0. 
     
     
         14 . The method of  claim 1 , wherein the adverse reaction is cytokine release syndrome (CRS). 
     
     
         15 . The method of  claim 1 , wherein the method comprises monitoring for signs and symptoms of cytokine release syndrome (CRS), optionally at least daily for about 7 days following infusion. 
     
     
         16 . The method of  claim 1 , wherein:
 (i) if cytokine release syndrome (CRS) greater than Grade 2 is observed, 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;   (ii) if CRS symptoms observed in (b) do not improve after 24 hours of (c), 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;   (iii) if CRS Grade 3 is observed in (b), 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   (iv) if CRS Grade 4 is observed in (b), 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.   
     
     
         17 . The method of  claim 1 , further comprising measuring cytokine and chemokine levels before and/or after one or more of the administrations, optionally, wherein the level of at least one of IL-2, IL-6, IL-8, IL-10, IL-12p40/p70, IL-15, IL-17a, TNF-α, IFN-γ, GM-CSF, and sIL2Rα is measured. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the method further comprises administering a non-sedating, anti-seizure medicine for seizure prophylaxis; administering at least one of erythropoietin, darbepoetin alfa, platelet transfusion, filgrastim, or pegfilgrastim; and/or administering tocilizumab 
     
     
         20 . The method of  claim 3 , wherein if cytokine release syndrome (CRS) and/or neurologic toxicity is observed, managing cytokine release syndrome (CRS) and/or neurologic toxicity according to Table 1, Table 2, Example 2, and/or Example 3. 
     
     
         21 . The method of  claim 1 , wherein the patient further receives rituximab for 5 additional doses at 28-day intervals after CD19-directed genetically modified T cell immunotherapy infusion. 
     
     
         22 . The method of  claim 21 , wherein the patient receives rituximab 375 mg/m 2  on Day −5, and conditioning chemotherapy with fludarabine 30 mg/m 2  and cyclophosphamide 500 mg/m2 on day −5, −4, and −3; followed by 2 days of rest on Day −2 and Day −1; followed by administration of anti-CD19 T cell immunotherapy. 
     
     
         23 . The method of  claim 1 , wherein the patient further receives lenalidomide 20 mg for 5 additional cycles at 28-day intervals (21 on treatment/28 days) after anti-CD19 T cell immunotherapy. 
     
     
         24 . The method of  claim 23 , wherein the patient receives lenalidomide 10 mg daily starting 7 days after leukapheresis and continuing through Day 3 after anti-CD19 T cell immunotherapy, followed by conditioning chemotherapy with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 on day −5, −4, and −3; followed by 2 days of rest on Day −2 and Day −1; followed by anti-CD19 T cell immunotherapy, administered at a target dose of 2×10 6  anti-CD19 CAR T cells/kg on Day 0. 
     
     
         25 . The method of  claim 1 , wherein the patient further receives mesna. 
     
     
         26 . The method of  claim 1 , wherein the CD19-directed genetically modified T cell immunotherapy comprises the administration of T cells genetically engineered to express an anti-CD19 chimeric antigen receptor (anti-CD19 CAR T cells). 
     
     
         27 . The method of  claim 26 , wherein the T cells are 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. 
     
     
         28 . The method of  claim 1 , wherein the CD19-directed genetically modified T cell immunotherapy comprises CD19-directed genetically modified T cell immunotherapy. 
     
     
         29 . The method of  claim 1 , wherein CD19-directed genetically modified T cell immunotherapy is administered as a single IV infusion at a target dose of 2×10 6  CAR-positive viable T cells/kg (maximum permitted dose: 2×10 8  cells) on Day 0, and/or mavrilimumab is administered once at 1 mg/kg of body weight, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 21 mg/kg, 22 mg/kg, 23 mg/kg, 24 mg/kg, 25 mg/kg, 26 mg/kg, 27 mg/kg, 28 mg/kg, 29 mg/kg, or 30 mg/kg, subcutaneously, OP/IP, or IV on Day 0. 
     
     
         30 . The method of  claim 1 , further comprising administering conditioning chemotherapy on Days −5 to −3, comprising fludarabine at 30 mg/m 2 /day and cyclophosphamide at 500 mg/m 2 /day. 
     
     
         31 . The method of  claim 1 , wherein the patient is refractory to a first-line of therapy, refractory to second or greater lines of therapy, refractory after autologous stem cell transplant. 
     
     
         32 . The method of  claim 1 , wherein the patient has previously received Anti-CD20 mAb and an anthracycline-containing chemotherapy regimen. 
     
     
         33 . The method of  claim 1 , 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, transformed follicular lymphoma, mantle cell lymphoma or diffuse large B cell lymphoma arising from follicular lymphoma. 
     
     
         34 . The method of  claim 1 , wherein the patient is more than 65 years old.