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-9855298-B2
Publication Date
2018-01-02
Expiration Date
2036-05-27
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 increasing the efficacy of a T cell therapy in a patient by conditioning the patient prior to the therapy using a combination of cyclophosphamide and fludarabine. The conditioning comprises administering a dose of cyclophosphamide between about 200 mg/m2/day and about 2000 mg/m2/day and a dose of fludarabine between about 20 mg/m2/day and about 900 mg/m2/day. This method improves the efficacy of T cell therapies, including engineered CAR T cell therapies, by creating an optimal microenvironment for the transplanted T cells to proliferate once administered to the patient.
The problem being solved arises from the challenge in human cancers where cancer cells evade immune targeting by T cells, making adoptive T cell therapies modestly effective and difficult to predict in efficacy for individual patients. Current preconditioning methods employ high doses of immunosuppressive chemotherapy that are toxic and cause severe adverse events. Thus, there is a need to identify an effective preconditioning regimen that enhances adoptive T cell therapy efficacy while minimizing toxicity.
The invention identifies that administering specific doses of cyclophosphamide and fludarabine prior to a T cell therapy reduces endogenous lymphocytes that compete with adoptively transferred T cells, increases serum levels of homeostatic cytokines and pro-inflammatory factors such as IL-7 and IL-15, and enhances antigen-presenting cell activation. These effects collectively improve the anti-tumor efficacy of the T cell therapy, while lowering toxicities associated with higher doses of the chemotherapeutic agents.
Claims Coverage
The independent claims disclose methods of treating patients using specific dosing regimens of cyclophosphamide and fludarabine in combination with engineered CAR T cells. They cover conditioning regimens as well as treatment protocols involving therapeutic amounts of CAR T cells.
Conditioning method with defined dosing of cyclophosphamide and fludarabine prior to T cell therapy
Administer cyclophosphamide at about 500 mg/m2/day to about 600 mg/m2/day daily for three days and fludarabine at about 30 mg/m2/day, followed by administration of a therapeutically effective amount of engineered CAR T cells ranging from about 1×106 to about 5×106 cells/kg.
Treatment method for tumors including non-Hodgkin's lymphoma using engineered CAR T cells with preconditioning
Treat a patient having a tumor, especially non-Hodgkin's lymphoma (such as DLBCL, PMBCL, or FL), by administering cyclophosphamide at about 500 mg/m2/day to 600 mg/m2/day and fludarabine at about 30 mg/m2/day with the conditioning beginning at least about five days prior to T cell therapy, followed by administration of engineered CAR T cells expressing a chimeric antigen receptor comprising an scFv antibody capable of binding tumor antigen CD19.
Methods involving various dosing schedules and retreatment with conditioning chemotherapy and engineered CAR T cells
Includes cycles of retreatment with cyclophosphamide and fludarabine conditioning and subsequent administration of engineered CAR T cells; dosing of fludarabine may be for two to five days, preferably three days; cyclophosphamide and fludarabine may be administered on the same or different days with variations on order of administration; therapeutically effective amounts of engineered CAR T cells typically about 1×106 to 2×106 cells/kg.
Correlation with cytokine serum level changes after conditioning
Conditioned patients exhibit increased serum concentrations of homeostatic cytokines including IL-7, IL-15, IL-10, IL-5, IP-10, IL-8, MCP-1, PLGF, CRP, sICAM-1, and sVCAM-1 after administration of cyclophosphamide and fludarabine.
The claims cover methods of conditioning patients with specific dosing regimens of cyclophosphamide and fludarabine prior to engineered CAR T cell therapy administration, methods of treating various tumors including lymphomas and leukemias with these conditioning regimens and engineered CAR T cells, and the correlation of improved therapeutic outcomes with changes in patient cytokine profiles post-conditioning.
Stated Advantages
Preconditioning with specific doses of cyclophosphamide and fludarabine enhances the effectiveness of adoptively transferred T cells by reducing endogenous lymphocyte competition and increasing availability of homeostatic cytokines.
The conditioning regimen reduces toxicity compared to previous high-dose chemotherapy methods.
Conditioning modifies the immune environment to favor homeostatic expansion, activation, and trafficking of T cells, thereby improving therapeutic efficacy.
Conditioning prior to T cell therapy allows for increased serum levels of beneficial cytokines, which correlates with better patient response to therapy.
Documented Applications
Treatment of patients in need of T cell therapy, including engineered CAR T cell therapy for various cancers.
Treatment of lymphomas and leukemias, including diffuse large B cell lymphoma (DLBCL), primary mediastinal large B cell lymphoma (PMBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and other B cell malignancies.
Use in adoptive T cell therapies such as tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation.
Conditioning regimens for patients prior to administration of engineered CAR T cells targeting CD19.
Methods for improving response prediction and patient selection for T cell therapies by measuring cytokine level changes after conditioning.
Interested in licensing this patent?