Project 4:Targeting M2-like Macrophages and MDSC with Myelolytic-Virotherapy

项目 4:利用溶髓病毒疗法靶向 M2 样巨噬细胞和 MDSC

基本信息

项目摘要

Abstract - Project 4: Cure rates for pediatric patients with relapsed or metastatic solid tumors remain unacceptably low. Cancer immunotherapies hold great promise, but scores of disappointing studies highlight our relative ignorance in understanding the immunosuppressive microenvironment within solid tumors. Because of their central role in mediating immunosuppression, tumor associated macrophages (TAMs), typically “polarized” to a so-called M2- like immunosuppressive phenotype, and myeloid-derived suppressor cells (MDSC), are thought to be important therapeutic targets. We have found a clinically viable strategy that simultaneously reduces TAMs/MDSC (we dub “myelolytic”) and polarizes the microenvironment (via oncolytic virus infection), resulting in significant antitumor efficacy. We hypothesize that targeting TAM and MDSC by combining “myelolytic” therapies with pro- inflammatory therapies activates innate antitumor mechanisms that cause cancer regressions and reshapes the solid tumor microenvironment to be more permissive to cellular immunotherapies. In aim 1, we will determine the mechanism(s) by which combined myelolytic-virotherapy drives tumor regressions. We will use novel technologies such as fluorescent nanodiamonds to determine effects on innate immune cell phagocytosis of tumor cells. We will utilize the Genomics & Immune Monitoring Shared Resource Core B directed by Dr. Elaine Mardis to conduct flow cytometry with time-of-flight mass spectrometry and single cell transcriptomics to determine the effects on immune cell composition and polarization. We will also utilize gain- and loss-of-function approaches to determine if loss of MDSC are critical for enabling tumor regressions with myelolytic-virotherapy. We will also test combination therapies in xenograft and immunocompetent models of other cancer types to confirm its generalizability (osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma). In aim 2, we will determine the effects of myelolytic-virotherapy on T cell-mediated immunotherapies. We will examine the effect of myelolysis alone and combined with virotherapy on the efficacy of antitumor T cells in a T cell exhaustion setting and with CAR-T cells (with Project 1 Leader Dean Lee and co- investigator Ruoning Wang, PI-DDN U01 member). We will work with Core B to examine the effects on T cell clonality using TCR sequencing. In aim 3, we will determine whether combined myelolytic-virotherapy enhances the efficacy of NK-based cellular therapies. We will work with Project 1 Leader Dean Lee and Project 2 Leader Mitch Cairo to study the effects on adoptive NK and CAR-NK cell therapy. Overall, with this project we will further elucidate, test and develop strategies to modulate the tumor microenvironment to facilitate innate immune cells as cancer therapy. Our findings may be applicable across a broad panel of pediatric cancer types and thus fits well into the aims of the Pediatric Immunotherapy Discovery and Development Network.
摘要-项目四:

项目成果

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{{ truncateString('TIMOTHY P CRIPE', 18)}}的其他基金

Project 4:Targeting M2-like Macrophages and MDSC with Myelolytic-Virotherapy
项目 4:利用溶髓病毒疗法靶向 M2 样巨噬细胞和 MDSC
  • 批准号:
    10885260
  • 财政年份:
    2023
  • 资助金额:
    $ 36.69万
  • 项目类别:
Oncolytic virus bispecific gene delivery for high grade gliomas
用于高级别神经胶质瘤的溶瘤病毒双特异性基因递送
  • 批准号:
    10832350
  • 财政年份:
    2023
  • 资助金额:
    $ 36.69万
  • 项目类别:
Novel Immunomodulation and Facilitation of “Suppression Proof” CAR NK cell against Ewing sarcoma
新型免疫调节和促进“抑制证明”CAR NK 细胞对抗尤文肉瘤
  • 批准号:
    10834579
  • 财政年份:
    2023
  • 资助金额:
    $ 36.69万
  • 项目类别:
Training Program in Basic and Translational Pediatric Oncology Research
基础和转化儿科肿瘤学研究培训计划
  • 批准号:
    10408197
  • 财政年份:
    2022
  • 资助金额:
    $ 36.69万
  • 项目类别:
Admin-Core-001
管理核心-001
  • 批准号:
    10707766
  • 财政年份:
    2022
  • 资助金额:
    $ 36.69万
  • 项目类别:
Admin-Core-001
管理核心-001
  • 批准号:
    10707767
  • 财政年份:
    2022
  • 资助金额:
    $ 36.69万
  • 项目类别:
Overcoming Immunological Tumor Microenvironment Resistance in Ewing Sarcoma
克服尤文肉瘤的免疫肿瘤微环境耐药性
  • 批准号:
    10616121
  • 财政年份:
    2022
  • 资助金额:
    $ 36.69万
  • 项目类别:
Core A:Administrative Core
核心A:行政核心
  • 批准号:
    10680851
  • 财政年份:
    2022
  • 资助金额:
    $ 36.69万
  • 项目类别:
Training Program in Basic and Translational Pediatric Oncology Research
基础和转化儿科肿瘤学研究培训计划
  • 批准号:
    10590705
  • 财政年份:
    2022
  • 资助金额:
    $ 36.69万
  • 项目类别:
IL1RAP CAR NK cells enhance targeting of Ewing Sarcoma (ES) alone and with combinatorial targeted immunotherapy
IL1RAP CAR NK 细胞单独或联合靶向免疫疗法可增强对尤文肉瘤 (ES) 的靶向作用
  • 批准号:
    10401167
  • 财政年份:
    2021
  • 资助金额:
    $ 36.69万
  • 项目类别:
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