Tumor downstaging with small molecule therapeutics to enhance Uveal Melanoma metastasis eradication by B7-H3 CAR T cells

利用小分子疗法降低肿瘤期,增强 B7-H3 CAR T 细胞对葡萄膜黑色素瘤转移的根除

基本信息

  • 批准号:
    10652851
  • 负责人:
  • 金额:
    $ 16.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-20 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Project summary Uveal Melanoma (UM) is a rare cancer with an incidence of 5 cases per million in the United States. Nearly half UM patients develop isolated liver metastases due to the high tendency of UM cells to spread to the liver. No cure has been found for patients with metastatic UM (mUM). Tebentafusp, is the only FDA-approved therapy for mUM. However, it has shown modest improvements in terms of overall response and progression-free survival and its applicability is limited to only 40% of mUM patients. The lack of effective treatment options for mUM has prompted us to design a novel combinatorial immunotherapeutic strategy based on the use of Chimeric Antigen Receptor (CAR) T cells specifically redirected against B7-H3. The latter has been selected as the target of our immunotherapeutic strategy, since it is highly expressed on UM cell lines and mUM tumor tissue samples, but has a limited expression on normal tissues. It is a general experience that CAR T cell-based immunotherapy is not effective in eradicating solid tumors both in preclinical and clinical investigations. This result is likely caused by multiple mechanisms, among which the major role is played by their use in hosts with high tumor load; the resulting unfavorable effector to target (E:T) ratio in the tumor microenvironment has a negative impact on the antitumor activity of CAR T cells, as indicated by the results generated by preclinical and clinical investigations. The information in the literature and our preliminary results have provided the rationale to design a strategy which applies first a tumor debulking approach to reduce tumor load and then CAR T cell- based immunotherapy to eradicate UM metastases. We will use the combination of trametinib, a mitogen-activated protein kinase kinase inhibitor (MEKi) and of panobinostat, a histone deacetylase inhibitor (HDACi), since this combination has been shown to induce marked regression of UM liver metastases in mice. Furthermore, this combination does not affect B7- H3 expression by UM cells and the antitumor activity of B7-H3 CAR T cells. Therefore, after having shown that B7-H3 CAR T cells can recognize and eliminate UM cells surviving the treatment with the MEKi and HDACi combination, we will investigate whether tumor debulking induced by the MEKi and HDACi combination can enhance the ability of B7-H3 CAR T cells to eradicate UM liver metastases in NSG mice. Since one major limitation of CAR T cell-based therapy is represented by its potential toxicity and/or cytokine release syndrome, we have incorporated in our CAR construct an inducible caspase 9 safety switch which allows rapid elimination of CAR T cells in case of unexpected toxicities. If the results generated by our experiments are positive, they will have a major impact on the treatment of mUM.
项目总结

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Cristina R. Ferrone其他文献

795 NEOADJUVANT THERAPY-INDUCED SARCOPENIA IS ASSOCIATED WITH DECREASED OVERALL SURVIVAL IN PANCREATIC DUCTAL ADENOCARCINOMA
  • DOI:
    10.1016/s0016-5085(20)34496-6
  • 发表时间:
    2020-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Naomi M. Sell;Carlos Fernandez-del Castillo;Cristina R. Ferrone;Keith Lillemoe;Thomas P. Hank;Colin D. Weekes;Martin Torriani;Colleen G. Buckless;Julie K. Silver;Florian J. Fintelmann;Motaz Qadan
  • 通讯作者:
    Motaz Qadan
PHH3 immunostaining: a novel prognostic biomarker in pancreatic neuroendocrine tumors
  • DOI:
    10.1016/j.jamcollsurg.2013.07.298
  • 发表时间:
    2013-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Matteo Ligorio;Jan Paul Briet;Eduardo Alfaro;Francesco Sabbatino;Jennifer Wargo;Deshpande Vikram;Carlos Fernandez-del Castillo;Stephanie Goff;Keith D. Lillemoe;Cristina R. Ferrone
  • 通讯作者:
    Cristina R. Ferrone
Fluid administration and surgical outcomes after pancreatoduodenectomy: External validation of variable fluid regimens at a tertiary referral center
  • DOI:
    10.1016/j.clnesp.2018.03.006
  • 发表时间:
    2018-06-01
  • 期刊:
  • 影响因子:
  • 作者:
    Marta Sandini;Carlos Fernandez-Del Castillo;Cristina R. Ferrone;Katarina J. Ruscic;Matthias Eikermann;Andrew L. Warshaw;Keith D. Lillemoe;Motaz Qadan
  • 通讯作者:
    Motaz Qadan
B7-H3-Specific Chimeric-Antigen Receptor T-Cell–Based Immunotherapy for Intrahepatic Cholangiocarcinoma
  • DOI:
    10.1016/j.jamcollsurg.2018.07.622
  • 发表时间:
    2018-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Tomohiro Kurokawa;Teppei Yamada;Lei Cai;Soldano Ferrone;Cristina R. Ferrone
  • 通讯作者:
    Cristina R. Ferrone
Tumor-Associated Macrophage Infiltration and Clinical Course of the Disease in Pancreatic Ductal Adenocarcinoma
  • DOI:
    10.1016/j.jamcollsurg.2018.07.653
  • 发表时间:
    2018-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Lei Cai;Theodoros Michelakos;Martin S. Taylor;Vikram Deshpande;Teppei Yamada;Soldano Ferrone;Cristina R. Ferrone
  • 通讯作者:
    Cristina R. Ferrone

Cristina R. Ferrone的其他文献

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{{ truncateString('Cristina R. Ferrone', 18)}}的其他基金

Potential role of brachyury in HLA class I antigen processing machinery component downregulation in chordoma cells
Brachyury 在脊索瘤细胞 HLA I 类抗原加工机制成分下调中的潜在作用
  • 批准号:
    10908087
  • 财政年份:
    2020
  • 资助金额:
    $ 16.7万
  • 项目类别:

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