A5053959088- CAR-T cell therapy research
- Virus-based gene therapy research
- Sarcoma Diagnosis and Treatment
- Neuroblastoma Research and Treatments
- Neurofibromatosis and Schwannoma Cases
- RNA Interference and Gene Delivery
- Vascular Tumors and Angiosarcomas
- Protein Degradation and Inhibitors
- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Cancer Research and Treatments
- Immune Cell Function and Interaction
Nationwide Children's Hospital
2024-2025
The Ohio State University
2024
Abstract Interleukin-12 (IL-12) is a potent NK cell–stimulating cytokine, but the presence of immunosuppressive myeloid cells such as myeloid-derived suppressor (MDSC) can inhibit IL 12-induced NK-cell cytotoxicity. Thus, we hypothesized that trabectedin, cell–depleting agent, would improve efficacy IL-12 in triple-negative breast cancer (TNBC). In vitro treatment healthy donor with trabectedin increased expression activation marker CD69 and mRNA T BET (Tbx21), cytotoxic ligands TRAIL...
<p>Combination IL-12 and trabectedin effectively reduces TNBC tumor burden. <b>A,</b> General treatment schema for murine studies. PBS was used as the control. (0.5 μg) given intraperitoneally 3×/week 0.15 mg/kg intravenously 1×/week. <b>B,</b> BALB/c mice were inoculated with 4T1 cells divided into one of four groups once tumors reached ∼50 mm<sup>3</sup> [PBS control (<i>n</i> = 11), 10), plus 12)]. Tumor growth measured 15 days....
<p>Supplementary Figure S6</p>
<p>Supplementary Figure S8</p>
<p>Supplementary Figure S1</p>
<p>IL-12 and trabectedin treatment increases human NK-cell activation <i>in vitro</i>. <b>A,</b> viability after 48-hour with DMSO (control), 10 ng/mL IL-12, 2.5 nmol/L trabectedin, or IL-12 plus (<i>n</i> = 5 donors). <b>B,</b> Surface CD69 expression on NK cells 24-hour treatment. Values are mean fluorescence intensity (MFI; <i>n</i> The mRNA of (<b>C</b>) <i>IFNG</i>, <i>GZMB</i>,...
<p>Digital spatial profiling reveals areas of enhanced and activated immune cell infiltration in combination-treated tumors. <b>A,</b> Schematic detailing the digital workflow. 4T1 tumors were harvested mice treated for 15 days with PBS control, IL-12, trabectedin, or IL-12 plus trabectedin sectioned into formalin-fixed paraffin-embedded (FFPE) tissue slides. <b>B,</b> Representative images tumor slides immunofluorescently stained an antibody mix nuclei (SYTO13,...
<p>Supplementary Figure S4</p>
<p>Supplementary Figure S5</p>
<p>Supplementary Figure S7</p>
<p>Combination IL-12 and trabectedin selectively reduces immunosuppressive myeloid cells while increasing intratumoral CD8<sup>+</sup> T cells. Mass cytometry analysis of splenic tumor-infiltrating immune from 4T1 tumor–bearing mice treated with PBS control (<i>n</i> = 7), 6), plus 4) for 15 days. <b>A,</b> Representative Uniform Manifold Approximation Projection (UMAP) plots cell populations at day in each treatment group clustered an unsupervised...
<p>NK-cell depletion reduces combination-induced efficacy and intratumoral CD8a. BALB/c mice were inoculated with 4T1 cells divided into one of two groups once tumors reached ∼50 mm<sup>3</sup>. Mice either depleted NK using anti–asialo-GM1 antibody or treated an IgG isotype control antibody. Anti–asialo-GM1 was administered by intraperitoneal injection at 100 μg/100 μL 3 days prior to the start IL-12 trabectedin treatment every 4 thereafter. The in nondepleted same time...
<p>Supplementary Figure S2</p>
<div>Abstract<p>IL-12 is a potent NK cell–stimulating cytokine, but the presence of immunosuppressive myeloid cells such as myeloid-derived suppressor (MDSC) can inhibit IL-12–induced NK-cell cytotoxicity. Thus, we hypothesized that trabectedin, cell–depleting agent, would improve efficacy IL-12 in triple-negative breast cancer (TNBC). <i>In vitro</i> treatment healthy donor with trabectedin increased expression activation marker CD69 and mRNA T-box transcription...
<p>Supplementary Figure S3</p>
<p>CD8a depletion abrogates IL-12/trabectedin-induced tumor control. BALB/c mice were inoculated with 4T1 cells. Once tumors reached ∼50 mm<sup>3</sup>, either depleted of CD8a<sup>+</sup> cells using α-CD8a antibody (<i>n</i> = 7) or treated an IgG isotype control 6). was performed through intraperitoneal injection αCD8 1 day prior to the start IL-12 and trabectedin treatment (at a dose 200 μg) every 4 days thereafter 100 μg). Nondepleted same at...
<p>Anti–PD-L1 therapy improves response to combination IL-12 and trabectedin treatment. Mice bearing ∼50 mm<sup>3</sup> 4T1 tumors were treated with 0.5 μg i.p. 3×/week 0.15 mg/kg i.v. 1×/week for 7 days either αPD-L1 (100 3×/week, <i>n</i> = 5) or isotype control IgG 6). <b>A,</b> Tumor growth curves throughout <b>B,</b> images after excision. One mouse from the triple group had a complete therefore no tumor imaging. For statistical...
We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though mechanism remained to be elucidated. Here we report disrupts intrinsic cellular anti-viral response which increases viral transcript spread throughout tumor cells. also extended our synergy findings syngeneic murine are poorly susceptible virus infection. In absence of robust replication,...
We previously reported that the DNA alkylator and transcriptional-blocking chemotherapeutic agent trabectedin enhances oncolytic herpes simplex viroimmunotherapy in human sarcoma xenograft models, though mechanism remained to be elucidated. Here we report disrupts intrinsic cellular antiviral response which increases viral transcript presence tumor cells. also extended our synergy findings syngeneic murine are poorly susceptible virus infection. In absence of robust replication, found...
Sarcomas comprise a wide range of diverse cancers the bone and soft tissues, with ∼100 different types as classified by World Health Organization.1,2 arise in any organ at time, throughout lifespan, and, depending on specific type, can be treated many known cancer therapies, including surgery, radiation, chemotherapy, targeted therapy, immunotherapy. Care teams thus require multidisciplinary pediatric adult expertise.
Abstract Osteosarcoma and Ewing sarcoma are the most common pediatric bone malignancies and, despite decades of research, efforts to treat patients with advanced disease remain dismal. To address this inadequacy, we leverage oncolytic herpes simplex virotherapy as a double-edged attack against tumors through 1) tumor cell-specific lysis 2) antitumor immune stimulation. However, previous trials in sarcomas displayed limited responses, likely due observed presence immunosuppressive monocytes...