Methods of conditioning patients for T cell therapy
Inventors
Bot, Adrian • WIEZOREK, Jeffrey S. • GO, William • JAIN, Rajul • KOCHENDERFER, James N. • Rosenberg, Steven A.
Assignees
Kite Pharma Inc • US Department of Health and Human Services
Publication Number
US-10322146-B2
Publication Date
2019-06-18
Expiration Date
2036-05-27
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Abstract
The invention provides methods of increasing the efficacy of a T cell therapy in a patient in need thereof. The invention includes a method of conditioning a patient prior to a T cell therapy, wherein the conditioning involves administering a combination of cyclophosphamide and fludarabine.
Core Innovation
The invention provides methods of conditioning a patient prior to administering a T cell therapy, including engineered CAR T cell therapies, by administering a combination of cyclophosphamide and fludarabine at specified doses. This conditioning regimen reduces endogenous lymphocytes, increases serum levels of homeostatic cytokines and/or pro-inflammatory factors, and enhances antigen presenting cell activation and availability, thereby creating an optimal microenvironment for the transplanted T cells to proliferate and function effectively in the patient.
The problem solved by this invention addresses the difficulty in predicting the effectiveness of T cell therapies and the toxicity associated with previous preconditioning regimens involving high doses of cyclophosphamide and fludarabine. Current high-dose conditioning regimens cause severe and sometimes fatal adverse events, limiting the tolerability and efficacy of T cell adoptive transfers. The invention demonstrates that lowered doses of cyclophosphamide and fludarabine can reduce endogenous lymphocyte numbers and enhance cytokine availability, leading to improved efficacy of T cell therapies while minimizing toxicity.
Claims Coverage
The patent contains multiple independent claims focusing on methods of treating patients using specific dosing regimens of cyclophosphamide and fludarabine combined with engineered CAR T cell therapy targeting CD19.
Specific dosing regimen combining cyclophosphamide, fludarabine, and CAR T cells targeting CD19
A method of treating patients with tumors by administering cyclophosphamide at about 500 to 600 mg/m2/day daily for three days combined with fludarabine at about 30 to 50 mg/m2/day, followed by a therapeutically effective amount of engineered CAR T cells expressing a chimeric antigen receptor comprising an scFv capable of binding CD19.
Therapeutically effective amounts and dosing parameters
In the methods, the therapeutically effective amount of engineered CAR T cells ranges between about 1×106 and 5×106 cells per kg, with specific claims including about 1×106 or 2×106 cells/kg. The dosing of fludarabine can be administered daily for two to five days, including three days.
Conditioning preceding T cell therapy with specific timing
The administration of cyclophosphamide and fludarabine as a conditioning regimen begins at least about five days prior to T cell therapy administration (day 0). The administration of the two agents can be on the same day or sequentially, with either agent initiated before the other by about one day.
Patient and disease specificity in treatment
Methods cover treating patients with non-Hodgkin's lymphoma, including diffuse large B cell lymphoma (DLBCL), primary mediastinal large B cell lymphoma (PMBCL), follicular lymphoma (FL), and leukemia, integrating the conditioning regimens with anti-CD19 CAR T cell therapy.
Modulation of homeostatic cytokines after conditioning
Post-conditioning, patients exhibit increased serum concentrations of homeostatic cytokines such as interleukin 7 (IL-7), interleukin 15 (IL-15), IL-10, IL-5, IP-10, MCP-1, PLGF, CRP, sICAM-1, sVCAM-1, or combinations thereof.
The claims collectively cover methods of patient conditioning using specific doses and timing of cyclophosphamide and fludarabine combined with administration of engineered CAR T cells targeting CD19, detailing dosing ranges, timing, cytokine responses, and treatment of hematological cancers such as NHL and leukemia.
Stated Advantages
Improvement of T cell therapy efficacy by creating a supportive immune environment through reduced endogenous lymphocytes and elevated homeostatic cytokines.
Reduction of adverse events and toxicities associated with high dose conditioning chemotherapy by lowering the doses of cyclophosphamide and fludarabine.
Optimization of cytokine availability for transferred T cells, enhancing their proliferation, activation, and trafficking.
Documented Applications
Treatment of cancers including B cell malignancies such as diffuse large B cell lymphoma, primary mediastinal large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, and other indolent non-Hodgkin lymphomas.
Preconditioning patients to increase the effectiveness of adoptive T cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy, autologous cell therapy, engineered autologous cell therapy (eACT™), and allogeneic T cell transplantation.
Use in clinical settings involving engineered CAR T cell therapies targeting CD19 in refractory or relapsed lymphoma patients.
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