Methods of producing enriched populations of tumor reactive T cells from peripheral blood
Inventors
Gros, Alena • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-9844569-B2
Publication Date
2017-12-19
Expiration Date
2033-04-30
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Abstract
Methods of obtaining a cell population enriched for tumor-reactive T cells, the method comprising: (a) obtaining a bulk population of peripheral blood mononuclear cells (PBMCs) from a sample of peripheral blood; (b) specifically selecting CD8+T cells that also express PD-1 and/or TIM-3 from the bulk population; and (c) separating the cells selected in (b) from unselected cells to obtain a cell population enriched for tumor-reactive T cells are disclosed. Related methods of administering a cell population enriched for tumor-reactive T cells to a mammal, methods of obtaining a pharmaceutical composition comprising a cell population enriched for tumor-reactive T cells, and isolated or purified cell populations are also disclosed.
Core Innovation
The invention provides methods for obtaining a cell population enriched for tumor-reactive T cells by specifically selecting CD8+ T cells that express PD-1 and/or TIM-3 from a bulk population of peripheral blood mononuclear cells (PBMCs) obtained from peripheral blood. This selected population is then separated from unselected cells, resulting in an enriched cell population for tumor-reactive T cells. Such methods enable the identification and isolation of tumor-reactive T cells without requiring screening for autologous tumor recognition and without nonspecific stimulation of the bulk T cell population.
The problem addressed by the invention is that T cells isolated from peripheral blood may not exhibit sufficient tumor-specific reactivity, which limits the efficacy of adoptive cell therapy (ACT) for treating cancer and other diseases. There is a need for improved methods to obtain populations of tumor-reactive T cells from peripheral blood that are enriched and effective for clinical application.
Claims Coverage
The patent includes multiple independent claims directed to methods of administering cell populations enriched for tumor-reactive T cells, with inventive features related to cell selection criteria and preparation steps.
Method of administering tumor-reactive T cells enriched by selecting CD8+ cells expressing PD-1 and/or TIM-3
Claims a method comprising (a) obtaining PBMCs from peripheral blood, (b) specifically selecting CD8+ T cells that express PD-1 and/or TIM-3, (c) separating these selected cells from unselected cells to obtain an enriched tumor-reactive T cell population, and (d) administering this enriched cell population to a mammal.
Method of administering tumor-reactive T cells enriched by selecting specific PD-1 and TIM-3 expression combinations
Claims a method comprising (a) obtaining PBMCs, (b) specifically selecting CD8+ T cells that are either TIM-3+/PD-1+, TIM-3-/PD-1+, or TIM-3+/PD-1- from the bulk population, (c) separating these selected cells from unselected cells to enrich tumor-reactive T cells, and (d) administering the enriched population to a mammal.
Obtaining tumor-reactive T cells without screening for autologous tumor recognition
Claims methods where the enriched cell population is obtained without requiring screening for autologous tumor recognition, enhancing the efficiency of obtaining tumor-reactive cells.
Avoiding nonspecific stimulation of bulk T cells prior to selection
Claims that the bulk T cell population is not nonspecifically stimulated before specifically selecting CD8+ PD-1 and/or TIM-3 positive cells, preserving cell characteristics.
Expanding the numbers of T cells in the enriched population
Claims further expanding the enriched tumor-reactive T cells obtained after selection to increase cell numbers for therapeutic use.
Culturing enriched cells with specific factors to enhance anti-tumor reactivity
Claims culturing enriched T cells with one or more of TWS119, IL-21, IL-12, IL-15, IL-7, TGF-beta, and AKT inhibitor to enhance their antitumor efficacy.
Stimulating enriched T cells with tumor antigen or autologous tumor cells
Claims stimulating the enriched cell population with a tumor antigen and/or autologous tumor T cells to potentially enhance antitumor activity.
Genetic modification of enriched T cells
Claims transducing or transfecting enriched T cells with nucleotide sequences encoding molecules such as IL-12, IL-7, IL-15, IL-2, IL-21, mir155, or anti-PD-1 siRNA to modulate their function.
Methods of treating cancer with the enriched tumor-reactive T cell population
Claims methods of treating cancer in a mammal by administering the cell populations obtained by these methods in an amount effective to treat the cancer.
The independent claims collectively focus on methods for selecting CD8+ T cells expressing PD-1 and/or TIM-3 to obtain tumor-reactive populations from PBMCs, optionally expanding and modifying these cells, and administering them to mammals for cancer treatment, with emphasis on selection without nonspecific stimulation and without screening for autologous tumor recognition.
Stated Advantages
Enrichment of tumor-reactive T cells from peripheral blood by selecting CD8+ cells expressing PD-1 and/or TIM-3 provides greater numbers of tumor-reactive cells compared to cells lacking these markers.
The methods allow isolation of tumor-reactive T cells without screening for autologous tumor recognition, simplifying the process and shortening the time required for in vitro culture.
The methods produce tumor-reactive T cells without nonspecific stimulation of the bulk T cell population, preserving functionality and characteristics.
The enriched cell populations obtained facilitate effective treatment or prevention of cancer by adoptive cell therapy.
Documented Applications
The methods are applied in adoptive cell therapy for treating or preventing various cancers, including melanoma and a wide array of other solid and hematological malignancies listed in the description.
Producing pharmaceutical compositions comprising tumor-reactive T cells for administration to mammals, especially humans, to treat cancer.
Use in in vitro expansion and stimulation of tumor-reactive T cells for therapeutic applications.
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