| 项目编号: | 1644932
|
| 项目名称: | EAGER: Biomanufacturing: Selecting an appropriate conceptual model for the phenotypic evolution of cytotoxic T lymphocytes |
| 作者: | David Klinke
|
| 承担单位: | West Virginia University Research Corporation
|
| 批准年: | 2016
|
| 开始日期: | 2016-09-01
|
| 结束日期: | 2018-08-31
|
| 资助金额: | 300000
|
| 资助来源: | US-NSF
|
| 项目类别: | Standard Grant
|
| 国家: | US
|
| 语种: | 英语
|
| 特色学科分类: | Engineering - Chemical, Bioengineering, Environmental, and Transport Systems
|
| 英文关键词: | t cell
; immune cell
; project
; model
; tumor
; tumor immunology
; biomanufacturing process
; patient
; educational infrastructure
; regenerative medicine
; extracellular signal
; stem cell engineering
; tumor site
; programming
; biomanufacture
; appropriate conceptual model
; interface
; cellular therapy
; anti-tumor
; immunotherapy
; multiple discipline
; alternative model
; generational evolution
; adoptive cell therapy
; extracellular protein signal
; conventional method
; experimental method
; biological complexity
; single-cell phenotyping
; quantitative model
; cellular property
; phenotypic evolution
; collective cytotoxic response
; solid tumor mass
; cellular immunotherapy
; undergraduate student
; west virginia university
; individual cell phenotype
; optimal design
; single-cell resolution
; emergent functional response
; tumor mass
; cellular product
; new computational model
; complex signaling environment
; design objective
; tumor growth
; maximal effect
; anti-tumor response
; multidisciplinary team
; quantitative data analysis tool
; impact other field
; cellular differentiation
; silico model-based inference
; other field
; collective functional response
; team aim
; fundamental nature
; interdisciplinary training opportunity
; right combination
; cd8
; anti-tumor efficacy
; biological reality
; appropriate model
; mathematical model
; cancer
|
| 英文摘要: | 1644932 - Klinke
While cancer has touched the lives of almost every American, treating cancer is poised for a revolution by redirecting a patient's own immune cells to destroy cancer cells. Redirecting these immune cells can occur by administering drugs or by removing these immune cells from the body, reprogramming them through a biomanufacturing process, and adoptively transferring them back to the patient. In either case, a challenge for expanding the benefit of these therapies to patients is that it is unclear exactly what happens to these immune cells once they enter their field of battle: the tumor mass. This gap in understanding the fundamental nature of how immune cells collectively attack a solid tumor mass is a barrier for optimizing the biomanufacture of reprogrammed immune cells or selecting the right combination of drugs that elicit a maximal effect. Using a combination of experiments and quantitative data analysis tools, this project aims select the best among three competing models for how immune cells organize a response against tumors. The resulting knowledge is anticipated to impact the design of immunotherapies for cancer but also impact other fields, like stem cell engineering and regenerative medicine where similar ideas are used to reconstruct tissues. In addition, the project will train students at the interface between multiple disciplines; including biochemical engineering, tumor immunology, and pharmacology; and enhance the educational infrastructure at West Virginia University by infusing ideas from the bench to the classroom and clinic.
This project will develop new computational models for optimizing cellular properties during biomanufacture of cellular immunotherapies for solid cancers. By integrating concepts from bioengineering (mathematical models linking individual cell phenotypes to an emergent functional response), biotechnology (single-cell phenotyping), and tumor immunology (quantifying how primary CD8+ T cells change upon in vitro programming and localizing to a tumor site), the proposed approach aims to provide greater fidelity in understanding how in vitro programming can be used to optimize the anti-tumor efficacy of adoptively transferred CD8+ T cells than conventional methods. This approach also addresses a key challenge in the science and engineering of biomanufacturing cellular therapies: what is the appropriate conceptual model that describes how a cellular product responds to the complex signaling environment present within a tumor? Yet our understanding of how immune cells respond to in vitro programming and to the complex signaling environment within the tumor may not actually mirror biological reality. If the underlying biological process is not well understood, the design objectives for engineering a biomanufacturing process for cellular therapies are then unclear. The multidisciplinary team aims to select one among three competing models that best captures the emergent cell population response to extracellular signals for CD8+ T cells, an important cell type used for adoptive cell therapy. The team hypothesizes that quantifying the temporal and generational evolution of CD8+ T cell phenotypes at single-cell resolution upon localizing to a tumor coupled with in silico model-based inference will enable selecting the appropriate model for a T cell-mediated cytotoxic response among three alternative models that vary in biological complexity. To test this hypothesis, the team aims (1) to quantify the phenotypic evolution in time and generation of individual CD8+ T cells in response to in vitro programming and to in vivo deprogramming that occurs upon localizing to a tumor site; and (2) to select the model that best captures the collective functional response of T cells to these extracellular signals. This project is potentially transformative as, if successful, it will disrupt accepted models that are currently used to describe how extracellular protein signals, that is cytokines, influence immune cell responses. Having an appropriate conceptual model of how T cells organize an anti-tumor response is critical for designing effective cellular biomanufacturing processes. The key broader impacts of the proposed research are three-fold. 1) quantitative models describing how individual CD8+ T cells organize a collective cytotoxic response to control tumor growth will enable the optimal design of immunotherapies for cancer;. 2) the anticipated results will impact other fields, such as stem cell engineering and regenerative medicine, by developing integrated computational and experimental methods that can be used to solve problems related to the stability and phenotype of cellular differentiation and 3) the proposed research will provide interdisciplinary training opportunities for graduate and undergraduate students at the interface between multiple disciplines; including biochemical engineering, tumor immunology, and pharmacology; and enhance educational infrastructure at WVU by incorporating ideas derived from this project into classes that the PI teaches. |
| 资源类型: | 项目
|
| 标识符: | http://119.78.100.158/handle/2HF3EXSE/91189
|
| Appears in Collections: | 全球变化的国际研究计划
科学计划与规划
|
|
There are no files associated with this item.
|
| Recommended Citation: | |
David Klinke. EAGER: Biomanufacturing: Selecting an appropriate conceptual model for the phenotypic evolution of cytotoxic T lymphocytes. 2016-01-01.
|
|
|