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-10421945-B2
Publication Date
2019-09-24
Expiration Date
2027-09-13
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 and uses of such cells to induce or enhance an anti-tumor immune response in a subject. The methods include providing a cell population comprising CD8+ T cells, reducing Cbl-b activity in these cells, and administering the modified cells to the subject. This approach enables CD8+ T cells to become activated and proliferate upon T cell receptor engagement without requiring co-receptor costimulation, such as CD28 costimulation.
The invention addresses the problem that many tumors evade immune rejection because tumor-specific cytotoxic T lymphocytes (CTLs) fail to become fully activated due to tumors lacking co-stimulatory ligands and exert active suppression through tumor-derived factors like transforming growth factor-beta (TGF-beta) and host immune regulatory mechanisms. Consequently, despite T cell recognition, most tumors are not rejected, partly because CTLs recognize tumor antigens but remain anergic or suppressed in the tumor environment.
By reducing or ablating Cbl-b function in CD8+ T cells, the invention overcomes the need for co-stimulatory signals during T cell activation, enabling these T cells to respond effectively to tumors that otherwise inhibit T cell activation via insufficient costimulation or inhibitory factors like TGF-beta. The invention also provides methods for identifying and using agents that modulate Cbl-b expression or function and methods of adoptive transfer of Cbl-b deficient CD8+ T cells for tumor immunotherapy, including enhancing tumor-specific immune responses and eradicating established tumors without requiring exogenous cytokines or vaccine components.
Claims Coverage
The patent discloses 3 independent main inventive features related to a pharmaceutical composition, an adoptive cellular immunotherapy method, and agents targeting Cbl-b.
Composition of CD8+ T cells with reduced Cbl-b activity
A pharmaceutical composition comprising a purified population of CD8+ T cells in which Cbl-b activity is reduced by introduction of a Cbl-b antagonist. The composition may be derived from peripheral blood, lymph organs, or tumor infiltrates, with possible ex vivo modification and stimulation to increase proliferation and tumor specificity.
Adoptive cellular immunotherapy method with Cbl-b activity reduction
A method of adoptive cell immunotherapy comprising providing a population of cells containing CD8+ cells, reducing Cbl-b activity in these cells, and administering the CD8+ T cells with reduced Cbl-b activity to a subject. This method can be applied for tumor immunotherapy using cells isolated from the subject and can include ex vivo modification.
Use of Cbl-b antagonists targeting gene expression
Use of polynucleotide compounds, including antisense polynucleotides, ribozymes, RNA interference molecules (such as siRNA, particularly SEQ ID NO:1), and triple helix polynucleotides, to reduce Cbl-b activity in CD8+ T cells effective to about 20% to 99% reduction compared to untreated cells.
The independent claims cover compositions comprising CD8+ T cells with reduced Cbl-b activity, methods of adoptive immunotherapy using such cells, and the use of polynucleotide agents targeting Cbl-b to reduce its activity in T cells for inducing anti-tumor immune responses.
Stated Advantages
Cbl-b−/− CD8+ T cells can be activated independent of CD28 costimulation and CD4+ T cell help, enabling effective anti-tumor responses.
Adoptive transfer of CD8+ T cells with reduced Cbl-b activity can eradicate established tumors without the need for exogenous cytokines or vaccines.
Cbl-b deficient CD8+ T cells are resistant to TGF-beta mediated immunosuppression, overcoming tumor immune evasion mechanisms.
Ablation of Cbl-b enhances tumor infiltrating lymphocyte function, increasing infiltration and activation within tumor tissues.
Systemic inhibition or ablation of Cbl-b reduces spontaneous tumor incidence, for example in ATM−/− mouse models, indicating potential for tumor prevention.
Modulation of the Cbl-b pathway enables generation of 'super killer' CTLs effective against tumors lacking costimulatory signals.
Documented Applications
Adoptive cellular immunotherapy for cancer treatment by administering CD8+ T cells with reduced Cbl-b activity to subjects with tumors.
Treatment of melanoma, lymphoma, and solid tumors expressing MHC-I with an antigen recognizable by cytotoxic T lymphocytes.
Use of Cbl-b-deficient CD8+ T cells derived from tumor infiltrates to induce tumor antigen-specific immune responses in subjects.
Generation of tumor-specific cytotoxic T lymphocytes by reducing Cbl-b activity in tumor-infiltrating lymphocytes or clonal T cell lines.
Screening for agents that modulate Cbl-b expression or activity for use in tumor immunotherapy.
Interested in licensing this patent?