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-10716809-B2
Publication Date
2020-07-21
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
Adoptive cell therapy (ACT) using tumor reactive T cells has demonstrated positive clinical responses in some cancer patients; however, T cells isolated from peripheral blood may lack sufficient tumor-specific reactivity. This limitation presents an obstacle to the successful use of ACT and creates a need for improved methods to obtain tumor-reactive T cells from peripheral blood.
The invention provides a method of obtaining a cell population enriched for tumor-reactive T cells. This method includes obtaining a bulk population of peripheral blood mononuclear cells (PBMCs) from peripheral blood, specifically selecting CD8+ T cells that also express PD-1 and/or TIM-3 from this population, and separating these selected cells from unselected cells to obtain an enriched population. Selecting CD8+ T cells based on PD-1 and/or TIM-3 expression enriches for tumor-reactive T cells more effectively than selecting CD8+ cells lacking these markers.
The inventive methods allow enrichment of tumor-reactive T cells without the need for screening for autologous tumor recognition or non-specific stimulation of the bulk T cell population. Further, the enriched T cells may be expanded in vitro, cultured with certain agents to enhance their anti-tumor reactivity, stimulated with tumor antigens or autologous tumor cells, and optionally genetically modified to express immune-modulating factors. These cell populations can also be administered therapeutically or formulated into pharmaceutical compositions.
Claims Coverage
The patent includes two independent claims covering methods to obtain tumor-reactive T cell populations and pharmaceutical compositions comprising such cells. Three main inventive features are extracted from these claims.
Method of obtaining tumor-reactive T cells from peripheral blood
A method comprising: (a) obtaining a bulk population of peripheral blood mononuclear cells (PBMCs) from peripheral blood; (b) specifically selecting CD8+ T cells that express PD-1 and/or TIM-3 from the bulk population; and (c) separating the selected cells from unselected cells to obtain a population enriched for tumor-reactive T cells.
Method of obtaining a pharmaceutical composition with enriched tumor-reactive T cells
A method comprising: (a) obtaining a bulk population of PBMCs from peripheral blood; (b) specifically selecting CD8+ T cells expressing PD-1 and/or TIM-3; (c) separating the selected cells from unselected cells to enrich for tumor-reactive T cells; and (d) combining the enriched cells with a pharmaceutically acceptable carrier to produce a pharmaceutical composition.
Variations in selection of tumor-reactive T cells based on marker expression
Specifically selecting CD8+ T cells that express TIM-3 only, PD-1 only, or combinations thereof (including TIM-3+/PD-1+, TIM-3−/PD-1+, or TIM-3+/PD-1−) from the bulk PBMC population, without prior screening for autologous tumor recognition and without non-specific stimulation prior to selection.
The claims cover methods to enrich tumor-reactive T cells from PBMCs by selecting CD8+ cells expressing PD-1 and/or TIM-3, producing pharmaceutical compositions containing such cells, and variations in selection based on specific expression of these markers, enabling enriched tumor-reactive cell populations for therapeutic use.
Stated Advantages
The inventive methods shorten the time of in vitro culture while selecting for tumor-reactive T cells without the need for screening for autologous tumor recognition.
They enrich for greater numbers of tumor-reactive T cells compared to selecting CD8+ cells lacking PD-1 and/or TIM-3 expression.
The methods avoid non-specific stimulation of bulk T cells prior to selection, preserving tumor-specific reactivity.
The enriched populations can be expanded substantially in vitro, potentially enhancing therapeutic efficacy.
Culturing enriched cells with agents like TWS119, IL-21, or IL-12 may enhance anti-tumor reactivity by maintaining less differentiated cell states.
Documented Applications
Obtaining cell populations enriched for tumor-reactive T cells from peripheral blood for adoptive cell therapy.
Administration of enriched tumor-reactive T cell populations to mammals, including humans, for treatment or prevention of cancer.
Formulating pharmaceutical compositions comprising enriched tumor-reactive T cells with pharmaceutically acceptable carriers for therapeutic administration.
Treatment or prevention of a wide range of cancers, including but not limited to melanoma, sarcomas, lymphomas, carcinomas of various tissues, gliomas, multiple myeloma, and leukemia.
Use of the enriched T cell populations in methods involving lymphodepletion prior to cell administration to enhance treatment efficacy.
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