Mathematical Model-Guided Adoptive Immunotherapy in Bladder Cancer

数学模型引导的膀胱癌过继免疫治疗

基本信息

项目摘要

Summary Bladder cancer is the fourth most common cancer in men and a leading cause of cancer mortality among men and women with the rates of bladder cancer incidents and bladder cancer-related deaths that have not decreased over the last 40 years. Therefore, novel more precise treatment strategies are desired. Bladder cancer has long been recognized as a malignancy that is responsive to immune-based therapy. One of the novel immunotherapy approaches utilizes the adoptive cell therapy (ACT), where autologous tumor-infiltrating T lymphocytes (TIL) are expanded and activated ex vivo and then reinfused into the cancer patient. However, typical systemic administration of ACT-TIL requires prior lymphodepletion and thus TIL are injected infrequently and in large numbers. Bladder is a specific organ which allows for intravesical delivery by direct administration of drugs and T cells through a catheter making it amenable to multiple and more frequent infusions of TIL and other therapeutics, potentially with smaller doses. This gives an unprecedented opportunity to use mathematical modeling integrated with pre-clinical mouse models to design, optimize and validate ACT-TIL combination therapies that will maximize tumor response and minimize toxicity. Our methods include microscopic- and macroscopic-level in silico models supported by in vitro, in vivo and ex vivo experimental data, defined T cells and a murine models of bladder cancer that mimic clinically-relevant procedures. In Aim 1, we will develop in silico models to enhance T cell infiltration into the bladder tumors. In Aim 2, we will optimize T cell properties ex vivo for the most effective T cell-cancer cell interactions. In Aim 3, we will apply our integrated methodology to design most effective combination therapy protocols to increase the effectiveness of reinfused TILs. The deliverables of this study will improve our understanding of how the bladder tumor microenvironment impacts T cell infiltration and T cell-tumor cell interactions and will lead to strategies that improve bladder cancer treatment by mathematically optimizing treatment schedules.
总结 膀胱癌是男性第四常见的癌症,也是男性癌症死亡的主要原因 女性膀胱癌发病率和膀胱癌相关死亡率, 在过去的40年里下降了。因此,需要新的更精确的治疗策略。膀胱 癌症长期以来被认为是对基于免疫的治疗有反应的恶性肿瘤。之一 新的免疫治疗方法利用过继细胞疗法(ACT),其中自体肿瘤浸润性细胞被移植到肿瘤细胞。 T淋巴细胞(TIL)离体扩增和活化,然后再输注到癌症患者体内。然而,在这方面, ACT-TIL的典型全身给药需要预先淋巴细胞清除, 很少,而且数量很多。膀胱是允许通过直接给药进行膀胱内递送的特定器官。 通过导管给予药物和T细胞,使其适合于多种和更频繁的治疗。 TIL和其他治疗剂的输注,可能使用较小的剂量。这是前所未有的 有机会使用与临床前小鼠模型集成的数学建模来设计、优化和 验证ACT-TIL联合治疗,将最大限度地提高肿瘤反应并最小化毒性。我们的方法 包括由体外、体内和离体支持微观和宏观水平的计算机模型 实验数据,确定的T细胞和模拟临床相关的膀胱癌的鼠模型 程序.在目标1中,我们将开发计算机模拟模型以增强T细胞浸润到膀胱肿瘤中。在 目标2,我们将优化T细胞的特性,以获得最有效的T细胞-癌细胞相互作用。在目标3中, 我们将应用我们的综合方法来设计最有效的联合治疗方案, 回输TIL的有效性。这项研究的成果将有助于我们了解 膀胱肿瘤微环境影响T细胞浸润和T细胞-肿瘤细胞相互作用, 通过数学优化治疗方案来改善膀胱癌治疗的策略。

项目成果

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Shari Pilon-Thomas其他文献

Shari Pilon-Thomas的其他文献

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{{ truncateString('Shari Pilon-Thomas', 18)}}的其他基金

Mathematical Model-Guided Adoptive Immunotherapy in Bladder Cancer
数学模型引导的膀胱癌过继免疫治疗
  • 批准号:
    10180117
  • 财政年份:
    2021
  • 资助金额:
    $ 46.65万
  • 项目类别:
Mathematical Model-Guided Adoptive Immunotherapy in Bladder Cancer
数学模型引导的膀胱癌过继免疫治疗
  • 批准号:
    10599851
  • 财政年份:
    2021
  • 资助金额:
    $ 46.65万
  • 项目类别:
Anti-melanoma Activity of Combined Lymphopenia and Immunotherapy
淋巴细胞减少症和免疫疗法联合治疗的抗黑色素瘤活性
  • 批准号:
    8308635
  • 财政年份:
    2010
  • 资助金额:
    $ 46.65万
  • 项目类别:
Anti-melanoma Activity of Combined Lymphopenia and Immunotherapy
淋巴细胞减少症和免疫疗法联合治疗的抗黑色素瘤活性
  • 批准号:
    8142911
  • 财政年份:
    2010
  • 资助金额:
    $ 46.65万
  • 项目类别:
Anti-melanoma Activity of Combined Lymphopenia and Immunotherapy
淋巴细胞减少症和免疫疗法联合治疗的抗黑色素瘤活性
  • 批准号:
    8114435
  • 财政年份:
    2010
  • 资助金额:
    $ 46.65万
  • 项目类别:
Anti-melanoma Activity of Combined Lymphopenia and Immunotherapy
淋巴细胞减少症和免疫疗法联合治疗的抗黑色素瘤活性
  • 批准号:
    7470759
  • 财政年份:
    2008
  • 资助金额:
    $ 46.65万
  • 项目类别:
Anti-melanoma Activity of Combined Lymphopenia and Immunotherapy
淋巴细胞减少症和免疫疗法联合治疗的抗黑色素瘤活性
  • 批准号:
    7673558
  • 财政年份:
    2008
  • 资助金额:
    $ 46.65万
  • 项目类别:

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Mathematical Model-Guided Adoptive Immunotherapy in Bladder Cancer
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Mathematical Model-Guided Adoptive Immunotherapy in Bladder Cancer
数学模型引导的膀胱癌过继免疫治疗
  • 批准号:
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