Methods of preparing T cells for T cell therapy
Inventors
Perez, Arianne • Sabatino, Marianna • Rosenberg, Steven A. • Restifo, Nicholas P.
Assignees
Kite Pharma Inc • US Department of Health and Human Services
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Publication Number
US-11723923-B2
Publication Date
2023-08-15
Expiration Date
2036-10-20
Abstract
Provided herein are methods for delaying or inhibiting T cell maturation or differentiation in vitro for a T cell therapy, comprising contacting one or more T cells from a subject in need of a T cell therapy with an AKT inhibitor and at least one of exogenous Interleukin-7 (IL-7) and exogenous Interleukin-15 (IL-15), wherein the resulting T cells exhibit delayed maturation or differentiation. In some embodiments, the method further comprises administering the one or more T cells to a subject in need of a T cell therapy.
Core Innovation
The invention provides methods for delaying or inhibiting T cell maturation or differentiation in vitro for T cell therapy by contacting one or more T cells from a subject in need of such therapy with an AKT inhibitor and at least one of exogenous Interleukin-7 (IL-7) and exogenous Interleukin-15 (IL-15). This results in T cells that exhibit delayed maturation or differentiation, enriching the population for immature or less differentiated T cells such as naïve and central memory T cells (Tcm).
The problem addressed is the limited in vivo persistence of T cells used in conventional T cell therapies, which often comprise a mixed population of largely mature, terminally differentiated cells whose effects diminish over time as tumors rebound. There is difficulty in predicting the effectiveness of T cell therapies for each patient, and transplantation of mixed T cell populations leads to limited therapeutic efficacy due to insufficient cell persistence.
The described methods improve efficacy of T cell therapies by enriching T cell populations with immature or stem-cell-like CD8+ T cells and by modulating T cell maturation or differentiation during in vitro culture through the combined use of AKT inhibitors and exogenous IL-7 and/or IL-15. The resulting T cells demonstrate increased in vivo persistence, increased expansion in vitro and in vivo, and superior anti-tumor activity. The methods can further include genetic modifications such as engineering of T cells to express chimeric antigen receptors (CARs) or T cell receptors (TCRs).
Claims Coverage
The claims cover innovative methods for culturing T cells to delay or inhibit their maturation or differentiation by using IL-7 and IL-15 without IL-2, and optionally including an AKT inhibitor with specified characteristics and concentrations, for T cell therapy.
Method of culturing T cells with IL-7 and IL-15 in absence of IL-2
Contacting one or more T cells with exogenous IL-7 and IL-15 in culture medium without exogenous IL-2 for 1 to 10 days, resulting in increased percentages of naïve and central memory CD4+ T cells relative to culturing with IL-2 alone.
Optional inclusion of AKT inhibitor in T cell culture
Further contacting the T cells with an AKT inhibitor selected from a defined group of molecules to enhance the delay or inhibition of T cell maturation or differentiation.
Specific AKT inhibitor and its concentration ranges
Use of 3-[1-[[4-(7-phenyl-3H-imidazo[4,5-g]quinoxalin-6-yl)phenyl]methyl]piperidin-4-yl]-1H-benzimidazol-2-one as AKT inhibitor, optionally at 1 nM to 1 mM, commonly about 8 μM; IL-7 and IL-15 concentrations ranging from 0.001 to 500 ng/ml each.
Inclusion of both CD4+ and CD8+ T cells for culturing
The method encompasses culturing populations comprising both CD4+ and CD8+ T cells under the specified conditions.
Retroviral transduction of T cells for receptor expression
Transducing T cells with retrovirus encoding cell surface receptors, including chimeric antigen receptors (CARs) or T cell receptors (TCRs), capable of binding specific tumor or target antigens.
T cell receptors or CARs targeting a wide panel of tumor-associated antigens
The engineered receptors bind antigens selected from an extensive list including CD19, CD20, EGFR, HER-2/neu, MAGE, and others, allowing the method's application to diverse cancer targets.
The claims provide comprehensive coverage of methods utilizing IL-7 and IL-15 without IL-2 to delay or inhibit maturation of T cells cultured for therapy, optionally with AKT inhibitors, including genetic modifications with CARs or TCRs targeting a broad array of tumor antigens, enhancing T cell therapy efficacy by enriching less differentiated T cell populations.
Stated Advantages
Increased in vivo persistence of transplanted T cells enhancing sustained anti-tumor effects.
Enrichment of immature, less differentiated T cells such as naïve and central memory T cells improves T cell therapy efficacy.
Resulting T cells exhibit increased expansion in vitro and in vivo.
Enhanced T cell function including increased proliferation, cytokine production (e.g., IFNg and TNFa), and cytolytic activity.
Documented Applications
Preparation of T cells for use in adoptive T cell therapies including tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous and allogeneic T cell therapies, engineered autologous cell therapy (eACT™), and engineered CAR or TCR T cell therapies.
Treatment of tumors and cancers by administering T cells cultured with AKT inhibitors and IL-7 and/or IL-15 to subjects in need of T cell therapy.
Use in therapy against a wide range of cancers, including hematological malignancies such as non-Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma, and primary mediastinal large B cell lymphoma, as well as solid tumors.
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