Methods and compositions for cells expressing a chimeric intracellular signaling molecule
Inventors
June, Carl H. • Milone, Michael • Zhao, Yangbing • Lum, Lawrence G. • Thakur, Archana
Assignees
Wayne State University • University of Pennsylvania Penn
Publication Number
US-11890301-B2
Publication Date
2024-02-06
Expiration Date
2036-08-26
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Abstract
The present invention relates to compositions and methods for enhancing T cell metabolism and activity for more effective adoptive T cell therapy. By expressing an chimeric antigen receptor and bispecific antibodies in T cells, the T cells are metabolically enhanced with improved cytotoxicity and resistance to immunosuppression imposed by tumor microenvironments. Certain aspects include modified T cells and pharmaceutical compositions comprising the modified cells for adoptive cell therapy and treating a disease or condition associated with enhanced immunity.
Core Innovation
The present invention provides methods and compositions for metabolically enhancing tumor specific T cells to improve the effectiveness of adoptive T cell therapy. This is achieved by expressing a chimeric antigen receptor (CAR), which includes an antigen binding domain, a transmembrane domain, and an intracellular domain from a co-stimulatory molecule within T cells. The CAR T cells are additionally armed with bispecific antibodies that can bind both a target antigen on a tumor cell and CD3 on the T cell, leading to stimulation of the co-stimulatory molecule and activation of intracellular signaling.
The resulting metabolically enhanced T cells exhibit improved cytotoxicity and resistance to the immunosuppressive effects of the tumor microenvironment. These modified T cells can be prepared by introducing nucleic acids that encode the CAR and the bispecific antibody, for example through electroporation of mRNA. Pharmaceutical compositions containing these metabolically enhanced T cells are contemplated for adoptive cell therapy and for treating diseases or conditions that benefit from enhanced immunity.
The problem addressed by this invention is the resistance of cancer cells within hypoxic tumor microenvironments to conventional therapies. Hypoxia in tumors creates conditions that allow cancer cells to evade chemotherapy and immune attack, resulting in treatment failure. By metabolically enhancing T cells to improve their function in these immunosuppressive and hypoxic environments, the invention seeks to overcome this significant challenge in cancer therapy.
Claims Coverage
There is one independent claim in this patent detailing multiple inventive features that center around metabolically enhancing CAR T cells through co-expression of specific CAR constructs and bispecific antibodies, as well as methods of administration and cellular irradiation.
Metabolic enhancement of tumor-specific T cells by co-expression of CAR and bispecific antibody
A method is provided for metabolically enhancing a tumor specific T cell by: - Introducing a first nucleic acid encoding a chimeric antigen receptor (CAR) into a T cell in vitro, where the CAR comprises an antigen binding domain that binds to CD19, a transmembrane domain, and intracellular signaling domains of 4-1BB and CD3zeta. - Arming the CAR T cell in vitro with a bispecific antibody, wherein this comprises introducing a second nucleic acid encoding the bispecific antibody into the CAR T cell. The bispecific antibody must bind CD3 on the CAR T cell and be capable of binding to an antigen on a tumor cell in vivo. - Administering the armed CAR T cell to a CD19+ subject such that the intracellular signaling domain is activated, thereby achieving metabolic enhancement of the tumor specific T cell.
The independent claim primarily covers methods of generating metabolically enhanced tumor-specific T cells by introducing specific CAR constructs and arming with bispecific antibodies, followed by administration to a subject, with additional inventive steps such as irradiation and detailed construct composition derived from dependent claims.
Stated Advantages
Metabolically enhanced T cells exhibit improved cytotoxicity and resistance to immunosuppression imposed by tumor microenvironments.
Modified T cells display greater survival and metabolic activity under hypoxic conditions compared to non-modified T cells.
The invention enables the use of T cells that remain effective in tumor sites that are resistant to conventional chemotherapies and immunotherapies.
Bispecific antibody arming further induces Th1 cytokine production, enhances cytolytic activity, and shifts the tumor microenvironment favorably.
Pharmaceutical compositions comprising these enhanced T cells can effectively stimulate immune responses against tumor cells.
Documented Applications
Treatment of cancer, including both solid tumors and hematological cancers, by adoptive cell therapy with metabolically enhanced T cells.
Stimulation of T cell-mediated immune response to target tumor cells or tumor tissue in a subject.
Treatment of autoimmune diseases and inflammatory disorders using metabolically enhanced T cells.
Use in the manufacture of a medicament for the treatment of a tumor or cancer in a subject.
Treatment of conditions associated with enhanced immunity, including transplant rejection, GVHD, and immune responses in autoimmune conditions.
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