Method of manufacturing dual-specific T-cells for use in cancer immunotherapy
Inventors
Assignees
BLOODCENTER RESEARCH FOUNDATION • Versiti Blood Research Institute Foundation Inc
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Publication Number
US-10941381-B2
Publication Date
2021-03-09
Expiration Date
Abstract
The present invention relates to autologous dual-specific lymphocytes, methods of making and uses for the treatment of tumors. In particular, the invention relates to methods producing autologous dual-specific lymphocytes comprising an endogenous receptor for at least one tumor associated antigen and an exogenous receptor for a strong antigen.
Core Innovation
The invention provides reenergized adoptive cell transfer (ReACT) using autologous dual-specific lymphocytes. Each lymphocyte expresses an endogenous receptor for a tumor associated antigen (TAA) and is genetically engineered to express an additional receptor for a strong antigen derived from a pathogen. The dual-specific lymphocytes target a plurality of TAAs and a strong antigen derived from a pathogen.
The approach links pathogen-derived strong antigen sensing with tumor targeting by engineering a second receptor (TCR or CAR) that recognizes the strong pathogen antigen. The reenergized dual-specific cells are described as enabling expansion, tumor migration, reversal of immunosuppressive tumor microenvironment effects, including reduced Tregs and MDSCs, and enhanced effector function.
The document further describes compositions and a manufacturing approach in which lymphocytes are isolated from a patient, tumor-specific lymphocytes are purified, and the purified lymphocytes are genetically engineered to express a second receptor specific to a strong antigen derived from a pathogen. A treatment approach is described in which the engineered autologous dual-specific lymphocytes are administered and a strong pathogen-derived antigen is injected, including intratumoral delivery.
Claims Coverage
The partial content identifies two independent claims: one directed to a purified population of autologous dual-specific lymphocytes and one directed to a method of producing such a population. Across the independent claims, the coverage centers on two principal inventive feature sets: dual-specific lymphocytes that combine endogenous TAA receptor specificity with a genetically engineered second receptor for a pathogen-derived strong antigen, and a production workflow that isolates, purifies tumor-specific lymphocytes, and genetically engineers the second receptor so the resulting population targets a plurality of TAAs and at least one pathogen-derived strong antigen.
Autologous dual-specific lymphocytes targeting multiple TAAs and a pathogen-derived strong antigen
A purified population of autologous dual-specific lymphocytes having specificity for two or more antigens, wherein a population of lymphocytes is isolated from a patient and each lymphocyte expresses an endogenous receptor for a tumor associated antigen (TAA) and is genetically engineered to express an additional receptor for a strong antigen derived from a pathogen, wherein the population of dual-specific lymphocytes target a plurality of TAAs and the strong antigen derived from a pathogen.
Production of dual-specific lymphocytes by isolating, purifying tumor-specific lymphocytes, and expressing a second pathogen-antigen receptor
A method of producing an autologous population of dual-specific lymphocytes that can target a plurality of tumor associated antigens and at least one strong antigen derived from a pathogen, comprising isolating lymphocytes from a patient, purifying the tumor-specific lymphocytes from the isolated lymphocytes, and genetically engineering the purified lymphocytes to express a second receptor specific to a strong antigen derived from a pathogen, wherein the resulting population comprises dual-specific lymphocytes.
Overall, the independent claim coverage requires purified autologous dual-specific lymphocytes that combine endogenous TAA receptor expression with engineered recognition of a pathogen-derived strong antigen, and a corresponding production method that isolates, purifies tumor-specific lymphocytes, and genetically engineers a second receptor to generate the dual-specific population.
Stated Advantages
Enables expansion of the dual-specific lymphocytes.
Enables tumor migration.
Reverses immunosuppressive tumor microenvironment effects, including reduced Tregs and MDSCs.
Enhances effector function.
Shows tumor regression/eradication and long-term protection in mouse tumor models.
Documented Applications
Tumor treatment by administering autologous dual-specific lymphocytes and injecting a strong pathogen-derived antigen to activate the lymphocytes and treat a patient’s tumor.
Preclinical tumor model applications described as mouse tumor models showing tumor regression/eradication and long-term protection, including B16-F10, B16-OVA, and E0771.
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