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
Publication Number
US-9951311-B2
Publication Date
2018-04-24
Expiration Date
2027-09-13
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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 isolated, purified populations of human CD8+ T cells with reduced Cbl-b activity and methods of using such cells to induce or enhance anti-tumor immune responses in a subject. It offers methods for making CD8+ T cells that become activated or proliferate upon T cell receptor (TCR) contact without requiring co-receptor stimulation, specifically by reducing or ablating Cbl-b function or expression. Approaches to reduce Cbl-b activity include RNA interference, dominant negative forms, or gene knockout.
The invention addresses the problem that many tumors express tumor antigens recognized by cytotoxic T lymphocytes (CTLs) but still are not rejected due to mechanisms that impair CTL responsiveness, including lack of costimulatory molecules like B7 on tumor cells, active suppression by tumor-derived factors such as TGF-beta, and host immunoregulatory mechanisms. This lack of co-stimulatory signals leads to T cell anergy and failure of anti-tumor immune surveillance. Current immunotherapy approaches are limited by the inability to activate tumor-specific CTLs in the absence of costimulatory ligand expression by tumor cells.
By reducing Cbl-b activity in CD8+ T cells, the invention overcomes the requirement for CD28 co-stimulation and enables CD8+ T cells to mount effective anti-tumor responses even against tumors that lack costimulatory signals. It provides methods for adoptive transfer of Cbl-b deficient CD8+ T cells, which are sufficient to eradicate established tumors, including both highly immunogenic tumors expressing tumor-specific antigens and weakly immunogenic or self-antigen expressing tumors. The invention also includes screening methods for agents that modulate Cbl-b expression or activity.
Claims Coverage
The patent includes a set of independent claims covering isolated populations of CD8+ T cells with reduced Cbl-b activity and methods of using such cells in compositions for therapeutic applications.
Isolated CD8+ T cells with reduced Cbl-b activity
An isolated, substantially purified population of CD8+ T cells with reduced Cbl-b activity compared to non-modified CD8+ T cells. The reduction in Cbl-b activity is achieved by one or more of: (i) contacting the cells with a chemical agent inhibiting Cbl-b expression or activity, (ii) introducing an siRNA targeting Cbl-b (specifically SEQ ID NO: 1), or (iii) knocking out the Cbl-b gene.
Source and characteristics of CD8+ T cells
The CD8+ T cells can be obtained from peripheral blood, lymph organs, or tumor infiltrates. They can be isolated from a subject, and when from tumor infiltrates may be polyclonal. The populations may be stimulated to proliferate, optionally with tumor cells from the subject and further stimulation with anti-CD3 antibody, IL-2, or both to increase tumor-specific CD8+ T cells with reduced Cbl-b activity.
Use in pharmaceutical compositions and treatment
The isolated CD8+ T cells with reduced Cbl-b activity are included in pharmaceutical compositions intended for treating cancer or tumor immune rejection in subjects. Applicable tumor types for treatment include melanoma, lymphoma, and any solid tumors expressing MHC-I with antigens recognized by cytotoxic T lymphocytes.
The claims cover isolated and purified CD8+ T cell populations with attenuated Cbl-b activity obtained by several methods including chemical inhibition, siRNA, or gene knockout, their sources, stimulation protocols to enrich tumor specificity, and their therapeutic use in treating various cancers by inducing or enhancing anti-tumor immune responses.
Stated Advantages
Cbl-b deficient CD8+ T cells can be activated and proliferate independent of CD28 co-stimulation, overcoming a major obstacle in tumor immune surveillance.
Such CD8+ T cells exhibit resistance to suppressive tumor-derived factors like TGF-beta, enabling effective function in immunosuppressive tumor environments.
Adoptive transfer of Cbl-b deficient CD8+ T cells can eradicate established tumors without the need for exogenous cytokines or costimulatory ligands.
These CD8+ T cells can target a broad range of tumors, including weakly immunogenic and highly immunogenic tumors, potentially reducing the need for vaccines or high-dose cytokines.
Modulation of Cbl-b function allows generation of “super killer” CTLs with enhanced tumor reactivity, improving clinical tumor immunotherapy approaches.
Documented Applications
Methods for inducing or enhancing anti-tumor immune responses in subjects suffering from tumors by adoptive transfer of CD8+ T cells with reduced Cbl-b activity.
Generation and administration of tumor antigen-specific CD8+ T cell populations, including those derived from tumor infiltrates or clonal T cell lines expressing tumor-specific T cell receptors.
Screening for agents that affect Cbl-b expression or activity to identify therapeutics that enhance T cell anti-tumor responses.
Use of CD8+ T cells with reduced Cbl-b activity for treating melanoma, lymphoma, and solid tumors expressing MHC-I with antigens recognized by cytotoxic T lymphocytes.
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