Agents and methods to elicit anti-tumor immune response
Inventors
Gu, Hua • Hodes, Richard • Chiang, Jeffrey J. • Jang, Ihnkyung
Assignees
Columbia University in the City of New York • US Department of Health and Human Services
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Publication Number
US-10822588-B2
Publication Date
2020-11-03
Expiration Date
2027-09-13
Abstract
The invention provides an isolated, purified population of human cells comprising CD8+ T cells with reduced Cbl-b activity. The invention provides uses of such cells in methods for inducing or enhancing an anti-tumor immune response in a subject. These methods comprise: (a) providing a cell population, from a subject or from another source, which comprises CD8+ T cells, (b) reducing Cbl-b activity in the CD8+ T-cells, (c) administering the cells of step (b) to the subject. The invention provides methods for making CD8+ T cells that do not require stimulation through a co-receptor in order for the cell to become activated or proliferated in response to contact via its T cell receptor. Such methods are based upon reducing function of Cbl-b. The invention also provides methods for identifying agents which affect Cbl-b expression or activity.
Core Innovation
The invention provides an isolated, purified population of human cells comprising CD8+ T cells with reduced Cbl-b activity. It includes methods for inducing or enhancing an anti-tumor immune response by providing a cell population comprising CD8+ T cells, reducing Cbl-b activity in these cells, and administering them to a subject. The methods generate CD8+ T cells that do not require co-receptor stimulation to become activated or proliferate upon T cell receptor engagement, achieved by reducing or eliminating the function or expression of Cbl-b.
The problem being solved is that many tumors evade immune surveillance despite the presence of tumor antigen-specific cytotoxic T lymphocytes (CTLs). Tumors often lack costimulatory ligands required for full T cell activation, leading to T cell anergy or non-responsiveness. Existing immunotherapy approaches have limited success due to tumor-mediated suppression and absence of effective T cell co-stimulation. Thus, there is a need for methods to induce or enhance anti-tumor immune responses independent of costimulatory signals.
The invention addresses this by showing that reduction or ablation of Cbl-b in CD8+ T cells permits activation and proliferation independent of co-stimulation, such as via CD28, overcoming tumor immune evasion. This enables generation of "super killer" CTLs that can effectively respond to tumors, including those producing suppressive factors like TGF-beta or lacking costimulatory molecules. The invention also provides methods to identify agents that modulate Cbl-b expression or activity, and demonstrates the use of Cbl-b deficient CD8+ T cells in adoptive transfer therapy to eradicate established tumors.
Claims Coverage
The claims disclose multiple inventive features related to methods for making and using CD8+ T cells with reduced Cbl-b activity for anti-tumor immune responses and therapeutic applications.
Reduction of Cbl-b activity in CD8+ T cells by siRNA from peripheral blood
The method involves providing CD8+ T cells from peripheral blood and reducing Cbl-b activity in these cells by introducing an siRNA targeting Cbl-b, specifically the siRNA comprising the sequence of SEQ ID NO:1, resulting in CD8+ T cells that do not require co-stimulation to become activated and proliferate.
Methods for inducing anti-tumor immune response by administering CD8+ T cells with reduced Cbl-b activity
The method includes providing CD8+ T cells from peripheral blood, reducing Cbl-b activity by siRNA of SEQ ID NO:1, and administering these modified cells to a subject to induce anti-tumor immunity, particularly against solid tumors expressing MHC-I antigens recognized by CTLs, including metastatic tumors.
Adoptive tumor immunotherapy using CD8+ T cells with reduced Cbl-b activity
Adoptive transfer therapy comprises isolating CD8+ T cells from peripheral blood, reducing Cbl-b activity via siRNA (SEQ ID NO:1), optionally stimulating proliferation after reduction, and administering these cells to a subject with one or more solid tumors to treat or promote immune rejection.
Isolated populations of CD8+ T cells with reduced Cbl-b activity for cancer treatment
Provides isolated CD8+ T cell populations from peripheral blood of subjects having solid tumors, having reduced Cbl-b activity by introduction of siRNA targeting Cbl-b (SEQ ID NO:1). These populations can be included in pharmaceutical compositions used for treating cancer or immune rejection of tumors, including metastatic tumors.
The claims collectively cover methods for producing CD8+ T cells with reduced Cbl-b activity by siRNA from peripheral blood and their therapeutic use via adoptive transfer to induce anti-tumor immune responses and treat solid tumors, alongside compositions comprising such modified CD8+ T cells.
Stated Advantages
Cbl-b deficient or ablated CD8+ T cells can be activated and proliferate without requiring co-stimulation, enabling them to respond to tumors lacking costimulatory signals.
Adoptive transfer of Cbl-b deficient CD8+ T cells effectively eradicates established tumors, including those with strong or weak antigenicity and metastatic tumors.
Cbl-b deficient CD8+ T cells are resistant to tumor-derived immunosuppressive factors such as TGF-beta, enhancing their anti-tumor efficacy.
Reduction or ablation of Cbl-b eliminates the need for large amounts of exogenous cytokines or costimulatory vaccines in immunotherapy, simplifying treatment.
Modification of tumor-infiltrating lymphocytes to reduce Cbl-b activity enhances their responsiveness to tumor antigens and enables generation of a potent therapeutic "super killer" T cell population.
Documented Applications
Using isolated CD8+ T cells with reduced Cbl-b activity to induce or enhance anti-tumor immune responses in subjects with tumors.
Adoptive transfer immunotherapy of cancer by administering CD8+ T cells with reduced Cbl-b activity to treat solid tumors, including metastatic tumors.
Generating CD8+ T cells that do not require co-stimulation for activation or proliferation for cancer immunotherapy.
Screening for agents that modulate Cbl-b expression or activity to identify potential tumor immunotherapy agents.
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