Adoptive immunotherapy with enhanced T lymphocyte survival
Inventors
Morgan, Richard A. • Rosenberg, Steven A. • Hsu, Cary
Assignees
US Department of Health and Human Services
Publication Number
US-7998736-B2
Publication Date
2011-08-16
Expiration Date
2025-10-07
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Abstract
The invention provides for compositions, e.g., pharmaceutical compositions, comprising a T lymphocyte, or a population thereof, expressing at least one recombinant polynucleotide encoding a cytokine that enhances T lymphocyte survival during the contraction phase of an immune response. The invention further provides an isolated T lymphocyte, or population thereof, expressing at least one recombinant polynucleotide encoding the cytokine, wherein the polynucleotide comprises a non-native coding sequence encoding the cytokine. Also provided is the use of such compositions and T lymphocytes, or populations thereof, for the treatment or prevention of a medical condition e.g., cancer. A method of preparing the a T lymphocyte with enhanced T cell survival is further provided herein.
Core Innovation
The invention provides isolated T lymphocytes, or populations thereof, that express at least one recombinant polynucleotide encoding a cytokine which enhances T lymphocyte survival during the contraction phase of an immune response. This includes pharmaceutical compositions comprising such cells and methods of preparing them by transforming T lymphocytes, either in vivo or ex vivo, with recombinant polynucleotides encoding cytokines like IL-7 and IL-15, including functional portions, variants, or fusions of these cytokines. The transformed T lymphocytes exhibit enhanced survival, resistance to apoptosis, proliferative capacity, and maintained antigen recognition without the need for exogenous cytokines.
The problem addressed by the invention is the limited efficacy of adoptive immunotherapy due to the short-lived survival of transferred T lymphocytes, particularly during the contraction phase of the immune response. Conventional methods, such as administration of IL-2, do not sufficiently enhance survival during this phase and have significant toxicities, limiting their utility. Excessive contraction of T lymphocytes results in weak and short-lived immune responses. Therefore, there is a need to improve the survival of transferred T lymphocytes to enhance immune therapy effectiveness, while avoiding toxicity associated with high-dose IL-2.
The invention solves this problem by providing genetically modified T lymphocytes that express cytokines, particularly IL-7 and IL-15, from recombinant polynucleotides which enhance T lymphocyte survival during contraction and maintenance phases. This approach prolongs T lymphocyte viability and function in vitro and in vivo without the use of toxic exogenous cytokines, thus enhancing the potential efficacy of adoptive immunotherapy, including treatment of diseases such as cancer and infectious disease. The method of preparing these cells involves transduction with recombinant vectors that may include codon optimization and additional elements like suicide genes.
Claims Coverage
The patent describes twenty-one claims, among which claim 1 is an independent claim directly related to the core invention, and other claims depend on it or elaborate on specific features. The claims collectively cover isolated T lymphocytes expressing recombinant polynucleotides with enhanced cytokine coding sequences, compositions comprising these cells, and populations thereof.
T lymphocytes with non-native cytokine coding sequences enhancing survival
Isolated T lymphocytes express at least one recombinant polynucleotide encoding a cytokine that enhances T lymphocyte survival during the contraction phase of an immune response, wherein the recombinant polynucleotide includes a non-native, codon-optimized coding sequence comprising SEQ ID NO: 4.
T lymphocyte enhanced survival and proliferation without exogenous cytokines
The T lymphocytes survive in vitro without exogenous cytokines for at least 40 days, preferably at least 180 days, proliferate in vitro without exogenous cytokines, resist IL-2 withdrawal-induced apoptosis, and recognize antigen in vitro under the same conditions.
Inclusion of a suicide gene in the recombinant polynucleotide
The recombinant polynucleotide in the T lymphocytes further comprises a suicide gene, such as the Herpes Simplex Virus thymidine kinase (HSV TK) gene, enabling conditional cell death upon exposure to a specific agent.
Use of specific T lymphocyte subtypes and antigen receptors
The T lymphocyte can be a tumor infiltrating lymphocyte (TIL) or a human T lymphocyte and can comprise either endogenous T cell receptors (TCRs) or recombinant chimeric receptors specific for antigens of medical conditions such as cancer, specifically including melanoma.
Pharmaceutical compositions and populations of transformed T lymphocytes
Pharmaceutical compositions comprising the isolated T lymphocytes or populations thereof expressing the codon-optimized recombinant polynucleotide (SEQ ID NO: 4) are covered, including compositions for use in therapy.
The claims focus on genetically modified T lymphocytes expressing codon-optimized cytokine genes that enhance survival during immune response contraction, including detailed cellular and molecular features, helper elements such as suicide genes, specific receptor usage, and pharmaceutical compositions comprising these transformed cells.
Stated Advantages
The invention provides T lymphocytes with enhanced survival during the contraction phase of immune response, resulting in potentially more effective and sustained immune responses.
It offers a method to avoid the toxicity associated with conventional high-dose IL-2 therapy used in adoptive immunotherapy.
Transformed T lymphocytes can survive and proliferate in vitro without dependence on exogenous cytokines, facilitating sustained cellular therapies.
Enhanced memory T lymphocyte formation and function are enabled, improving long-term immunity.
Documented Applications
Treatment or prevention of medical conditions including cancers, such as melanoma.
Treatment or prevention of infectious diseases.
Treatment or prevention of autoimmune diseases.
Treatment or prevention of immunodeficiencies.
Use in vitro to modify cell cultures.
Application in adoptive immunotherapy involving transfer of autologous transformed T lymphocytes to mammals, especially humans.
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