T-Rapa cells as novel effector cell type for chimeric antigen receptor therapy
Inventors
Medin, Jeffrey A. • Oldham, Robyn A. • Fowler, Daniel H. • Felizardo, Tania
Assignees
Medical College of Wisconsin • UVA Licensing and Ventures Group • University of Virginia UVA
Publication Number
US-12076344-B2
Publication Date
2024-09-03
Expiration Date
2039-11-27
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Abstract
The present disclosure provides chimeric antigen receptor (CAR)-T-Rapa cells and methods of making and using them. Specifically, methods of producing T-Rapa cells that can express chimeric antigen receptors is provided.
Core Innovation
The invention provides methods of producing T-Rapa cells that can express chimeric antigen receptors (CARs), thereby generating CAR-T-Rapa cells. This involves conditioning ex vivo CD3+ T cells with rapamycin to induce resistance, followed by transduction with a vector encoding a CAR, and optional in vitro expansion and cryopreservation. T-Rapa cells, previously used in other cellular therapies, have not been employed as effector cells for CAR therapy prior to this disclosure.
The disclosed methods use T cells obtained from peripheral blood of either patients or suitable donors. These T cells are isolated, treated with rapamycin in a defined medium (optionally supplemented with IL-2 and IFN-α), then transduced with a CAR-expressing vector such as a lentiviral vector. The resulting CAR-T-Rapa cells can be targeted to tumor antigens such as CD19, allowing for therapeutic specificity.
This invention addresses the limitations of current CAR therapies, namely the need for intensive, sometimes toxic, lymphodepleting preconditioning regimens and inconsistent efficacy against solid tumors. By using T-Rapa cells as a platform for CAR engineering, the invention enables the production of effector cells believed to require less intensive preconditioning, potentially reducing treatment-associated toxicity while maintaining anti-tumor efficacy.
Claims Coverage
The patent claims cover four main inventive features regarding the making, composition, use, and properties of CAR-T-Rapa cells.
Method of making T-Rapa cells expressing a chimeric antigen receptor (CAR)
The claimed method includes conditioning ex vivo CD3+ T-cells with rapamycin to generate rapamycin-resistant T-Rapa cells, and transducing these T-Rapa cells in vitro with a vector that expresses a CAR, thus producing CAR-T-Rapa cells.
CAR-T-Rapa cell composition
The inventive feature is a CAR-T-Rapa cell comprising an exogenous vector encoding and capable of expressing a chimeric antigen receptor (CAR), where the T-Rapa cell is made by culturing ex vivo CD3+ T-cells in chemically defined medium with rapamycin for long enough to generate T-Rapa cells.
Method of treating a subject diagnosed with a disease treatable with CAR therapy
This feature covers administering an effective amount of the CAR-T-Rapa cell to a subject diagnosed with a disease that is treatable with CAR therapy, including administering the cells by intravenous transfusion for diseases such as cancer, hematologic cancers, or solid tumors.
Stored and expandable populations of CAR-T-Rapa cells
The claims also include a population of CAR-T-Rapa cells where at least 95% express one or more biomarkers indicative of CAR expression, the capability of in vitro maintenance and expansion, and the storage of such populations at or below about −80° C. in a suitable storage solution.
The claims collectively cover the processes for creating CAR-T-Rapa cells, their composition, their use in treating diseases with CAR therapy, and their storage and expansion as cell populations.
Stated Advantages
CAR-T-Rapa cells are believed to require less intensive preconditioning to engraft, reducing toxicities for patients.
The method enables the production of CAR-T-Rapa cells that have reduced production of pro-inflammatory cytokines such as IFN-γ, potentially lowering the risk and severity of cytokine release syndrome (CRS).
T-Rapa cells can be manufactured from peripheral blood cells of affected patients or normal donors and efficiently transduced to express CARs targeting disease-specific antigens.
CAR-T-Rapa cells can be maintained and expanded in vitro, and stored for future administration, enabling flexibility in treatment scheduling.
T-Rapa cells have potent effector functions and demonstrate long-term persistence in recipients.
Documented Applications
Treatment of cancer, including hematologic cancers (such as leukemia and lymphoma) and solid tumors using CAR-T-Rapa cells.
Administration of CAR-T-Rapa cells to a mammalian subject, including humans, to alleviate symptoms, reduce growth, or prevent metastasis of cancers.
Clinical protocols involving intravenous transfusion of CAR-T-Rapa cells for anti-cancer therapy.
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