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-11491187-B2
Publication Date
2022-11-08
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 to improve the efficacy of T cell therapy by conditioning a patient with a combination of cyclophosphamide and fludarabine prior to administration of the therapy. The method comprises administering cyclophosphamide between about 200 mg/m2/day and about 2000 mg/m2/day and fludarabine between about 20 mg/m2/day and about 900 mg/m2/day to condition the patient, which enhances the T cell therapy's effectiveness.
The problem solved by the invention arises from the difficulty in predicting the efficacy of T cell therapies in individual patients due to immune system factors. Existing preconditioning regimens rely on high doses of toxic and non-specific drugs, causing significant adverse events. This creates a need for an effective conditioning regimen that improves T cell therapy outcomes while reducing toxicity.
The invention addresses this problem by administering specific doses of cyclophosphamide and fludarabine that reduce endogenous lymphocytes, increase serum levels of homeostatic cytokines and pro-immune factors, and promote an optimal microenvironment for transplanted T cells. This improves the proliferation, activation, and effector functions of the adoptively transferred T cells while minimizing toxicity associated with higher doses of chemotherapy.
Claims Coverage
The claims include two independent claims focusing on methods combining specific dosing regimens of cyclophosphamide and fludarabine with CAR T cell administration to treat tumors expressing antigens, and incorporating cytokine biomarker-based patient selection.
Method of treating a tumor with CAR T cells following specific conditioning chemotherapy and cytokine monitoring
Administering a therapeutically effective amount of engineered CAR T cells (from about 1×10⁶ to about 5×10⁶ cells/kg) to a patient at day zero whose tumor has been pre-exposed to a single dose of cyclophosphamide between about 900 mg/m² and 1000 mg/m² and one or more doses of fludarabine between about 25 mg/m²/day and 50 mg/m²/day. Prior to CAR T cell administration, the patient is determined to exhibit higher serum levels of IL-15 and MCP-1 than baseline, indicating suitability for treatment.
Feature of CAR T cells used in treatment
The CAR T cells express a chimeric antigen receptor comprising an scFv antibody capable of binding a tumor antigen, with the tumor antigen optionally being CD19.
Administration timing and dosing details of conditioning chemotherapy
Cyclophosphamide and fludarabine doses can be administered daily for three days, with administration starting at least about five days before CAR T cell administration, including scenarios where cyclophosphamide and fludarabine doses are administered on the same day or one before the other.
The independent claims cover methods of treating tumors with engineered CAR T cells following conditioning with specified doses of cyclophosphamide and fludarabine, with monitoring of serum cytokines IL-15 and MCP-1 as biomarkers predictive of response, and describe features of the CAR constructs and timing of administration.
Stated Advantages
Improves efficacy of T cell therapy by creating an optimal environment for transplanted T cells to proliferate and function.
Reduces the number of endogenous lymphocytes that compete with therapeutic T cells.
Increases serum levels of homeostatic and pro-immune cytokines enhancing T cell activation and effector function.
Minimizes toxicity associated with high-dose conditioning regimens by using specific reduced dosing of cyclophosphamide and fludarabine.
Documented Applications
Treatment of cancers, especially lymphomas and leukemias, including diffuse large B cell lymphoma, primary mediastinal large B cell lymphoma, follicular lymphoma, and related B cell malignancies.
Preconditioning patients prior to receiving adoptive T cell therapies, including engineered autologous CAR T cell therapies targeting CD19.
Methods to predict patient responsiveness to T cell therapies by measuring serum cytokine levels following conditioning chemotherapy.
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