Diagnostic methods 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-11779601-B2
Publication Date
2023-10-10
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 methods of identifying a patient who would respond well to a T cell therapy or conditioning a patient prior to a T cell therapy so that the patient responds well to a T cell therapy. The conditioning involves administering one or more preconditioning agents prior to a T cell therapy and identifying biomarker cytokines prior to administering a T cell therapy.
Core Innovation
The invention relates to methods of increasing the efficacy of T cell therapies in patients by identifying those suitable for such therapies and conditioning patients to respond better to T cell treatment. This conditioning comprises administering one or more preconditioning agents capable of increasing serum levels of specific cytokines before T cell therapy. The key biomarker cytokines include interleukin-15 (IL-15), interleukin-7 (IL-7), and at least one additional cytokine selected from monocyte chemotactic protein 1 (MCP-1), C-reactive protein (CRP), placental growth factor (PLGF), and interferon gamma-induced protein 10 (IP-10).
The invention addresses the problem of unpredictability in the effectiveness of T cell therapies, as existing approaches have only modest effects on tumor size and patient survival and it is difficult to foresee which patients will benefit. The disclosed methods involve administering preconditioning agents (e.g., cyclophosphamide and purine analogs such as fludarabine or pentostatin) that reduce endogenous lymphocytes and increase the serum levels of biomarker cytokines, creating an immune environment conducive to the expansion and activation of transplanted T cells.
Claims Coverage
The patent includes three independent claims focused on methods for treating lymphoma or identifying suitable patients for CAR T cell therapy, detailing preconditioning regimens and cytokine monitoring.
Method for treating lymphoma with preconditioning and CAR T cell therapy
This method involves administering preconditioning agents capable of decreasing serum perforin levels and increasing serum levels of IL-15, IL-7, and at least one additional cytokine selected from MCP-1, CRP, PLGF, IP-10. The preconditioning agents comprise cyclophosphamide and fludarabine. A therapeutically effective amount of anti-CD19 CAR T cell therapy is administered on day zero when the patient exhibits decreased perforin and increased cytokine levels relative to baseline, measured by ELISA or equivalent protein quantification methods.
Method for identifying patients suitable for anti-CD19 CAR T cell therapy
This method includes administering preconditioning agents (cyclophosphamide and fludarabine) that modulate serum cytokine levels (decreasing perforin and increasing IL-15, IL-7, and at least one additional cytokine from MCP-1, CRP, PLGF, IP-10). Cytokine serum levels are measured before preconditioning and on day zero (after preconditioning but before CAR T cell therapy). Patients exhibiting the specified serum level changes are selected for therapy.
Method for pre-conditioning patients by modulating serum cytokines prior to CAR T cell therapy
This method entails administering preconditioning agents capable of decreasing serum perforin and increasing IL-15, IL-7, and at least one additional cytokine (MCP-1, CRP, PLGF, IP-10), wherein patients are treated with anti-CD19 CAR T cell therapy upon exhibiting these serum level changes compared to baseline. Measurements of cytokine protein levels are performed by ELISA or equivalent methods. The preconditioning agents include cyclophosphamide and fludarabine.
The claims focus on methods involving preconditioning patients with cyclophosphamide and fludarabine to modulate specific cytokine serum levels—decreasing perforin and increasing IL-15, IL-7, and additional biomarker cytokines—prior to administering anti-CD19 CAR T cell therapy, along with methods to identify suitable patients via serum cytokine measurement.
Stated Advantages
Preconditioning with agents that increase serum IL-15, IL-7, and specific cytokines creates an optimal microenvironment for T cell therapy, enhancing its efficacy.
The methods provide a way to identify patients likely to respond well to T cell therapy, enabling personalized treatment approaches.
Reduction of endogenous lymphocytes by preconditioning agents minimizes competition and immune suppression, improving adoptively transferred T cell expansion and activation.
Monitoring serum cytokine levels allows adjustment of conditioning regimens and timing, improving therapeutic outcomes.
Documented Applications
Treatment of various human cancers using T cell therapies, including tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation.
Treatment of lymphomas and leukemias including diffuse large B cell lymphoma (DLBCL), primary mediastinal large B cell lymphoma (PMBCL), follicular lymphoma (FL), transformed follicular lymphoma (TFL), chronic lymphocytic leukemia, and other B cell malignancies.
Methods for preconditioning cancer patients prior to anti-CD19 CAR T cell therapy to improve response rates and duration of response in refractory and relapsed lymphoma patients.
Clinical trial applications involving dosing patients with cyclophosphamide and fludarabine prior to administration of engineered anti-CD19 CAR T cells, with monitoring of serum cytokine levels and treatment outcomes.
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