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Principal Investigator: Shahab Asgharzadeh
Organization: CHILDREN'S RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $752,969
Funding agency: National Cancer Institute
PROBLEM. Pediatric tumors represent a very heavy social and economic burden with profound emotional
involvement not only for the directly affected children but also for their family and friends. Within pediatric tumors,
neuroblastoma (NB) is of particular relevance, since it is the most common solid cancer in children outside of
the skull and it still kills about 40% of patients diagnosed with the most aggressive forms. Therefore, there is a
clear need to improve the treatment for this deadly disease. Development of more potent immunotherapies could
improve outcome for these patients. PREMISE. Natural killer (NK) cells, especially when “activated” (aNK cells)
mediate direct cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC). All cell types release
extracellular vesicles called exosomes that contain biologically active components (proteins, DNA, mRNA, and
non-coding RNAs including miRs) that can be delivered to recipient cells and influence their functions. Exosomes
released by aNK cells, could increase the efficacy of chemoimmunotherapy in NB. Little is known about human
aNK cell-derived exosomes, their therapeutic potential and role as biomarkers of response to
chemoimmunotherapy in NB. Our group was the first to show that microRNAs (miRs) in aNK-derived exosomes
are able to kill NB cells. OUR DATA. We can propagate and activate blood NK cells from normal donors and
patients with NB using K562-mbIL21 artificial antigen presenting cells (aAPC) plus IL-2. We discovered that
these aNK cells release large quantities of exosomes and that purified aNK exosomes are cytotoxic for NB cell
lines. We also have preliminary evidence that aNK-derived exosomes contain miRs that contribute to the
cytotoxic effect of aNK-exosomes. We also observed that children affected by NB responsive to
chemoimmunotherapy, present markers of aNK activation in their blood. We hypothesize that aNK-derived
exosomes kill NB cells through the exosomal transfer of MYCN-, AURKA-, TGFBR1- and TGFBR2-targeting
miRs, and that these miRs can be exploited to develop an anti-tumor effect and implement the efficacy of
chemoimmunotherapy for NB patients. We also hypothesize that specific circulating and exosomal miRs can be
exploited as biomarkers of response to chemoimmunotherapy in children affected by NB. These hypotheses will
be tested in the following Specific Aims: 1) To study cytotoxicity mechanisms and therapeutic efficacy of aNK-
derived exosomes alone and combined with chemoimmunotherapy in NB; 2) To assess association of NK-
exosomal miRs, circulating RNAs, and gene expression profiles with response in patients treated on
chemoimmunotherapy regimens. SUMMARY. We focus upon a completely new immunotherapeutic strategy
using human miR-enriched aNK exosomes. The results of this study will provide important information for
producing highly cytotoxic aNK exosomes which could potentiate efficacy of existing chemoimmunotherapy. This
study will also identify new exosomal RNA cargo able to stratify neuroblastoma patients for response to
chemoimmunotherapy.
Terms: <0-11 years old><ACVRLK4><AIK gene><ARK1><AURKA><AURORA2><Ab-dependent cellular cytotoxicity><Activated Natural Killer Cell><Affect><Aik protein><Antibodies><Antigen-Presenting Cells><Aurora-Related Kinase 1><Aurora/IPL1-Like Kinase><BTAK><Biological Markers><Biology><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Bone-Derived Transforming Growth Factor><CD56><Cancer Patient><Cancers><Cell Body><Cell Line><Cell-Mediated Cytolysis><Cell-Mediated Lympholysis><CellLine><Cells><Cellular Cytotoxicity><Child><Child Youth><Childhood Cancers><Childhood Neoplasm><Childhood Tumor><Children (0-21)><Children's Oncology Group><Clinical><Co-Stimulator><Combined Modality Therapy><Costimulator><Cytotoxic cell><DNA><Data><Deoxyribonucleic Acid><Development><Diagnosis><Disease><Disorder><Economic Burden><Emotional><Engineering><Epidermal Thymocyte Activating Factor><Expression Signature><Family><Friends><Functional RNA><GM-CSF><Gene Action Regulation><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Genes><Genetic Transcription><Goals><Grant><Granulocyte-Macrophage Colony-Stimulating Factor><Hand><Histamine-Producing Cell-Stimulating Factor><Human><IL-15><IL-2><IL15><IL15 Protein><IL2 Protein><Immune mediated therapy><Immuno-Chemotherapy><Immunochemotherapy><Immunologically Directed Therapy><Immunotherapeutic agent><Immunotherapy><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-15><Interleukin-15 Precursor><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><K lymphocyte><K-562><K562><K562 blasts><Life><Lymphocyte Cytotoxicity><Lymphocyte Mitogenic Factor><Lymphocytotoxicity><Lytotoxicity><MGC9721><MYCN><MYCN gene><Malignant Cell><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Neoplasms><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant Tumor><Malignant childhood cancer><Mediating><Messenger RNA><Micro RNA><MicroRNAs><Milk Growth Factor><Mitogenic Factor><Modeling><Modern Man><Molgramostin><Multimodal Therapy><Multimodal Treatment><NCAM><NCAM1><NCAM1 gene><NK Cells><NK cell immunotherapy><NK cell-based immunotherapy><NK cytotoxicity><NMYC><NMYC Gene><Natural Killer Cell Immunotherapy><Natural Killer Cell toxicity><Natural Killer Cells><Natural Killer cytotoxicity><Neuroblastoma><Newly Diagnosed><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pediatric Neoplasm><Pediatric Oncology Group><Pediatric Tumor><Phase><Plasma><Plasma Serum><Platelet Transforming Growth Factor><Play><Prognostic Marker><Proteins><Protocol><Protocols documentation><RNA><RNA Expression><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Refractory><Regimen><Relapse><Resistance><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><Role><STK15><STK6><STK6 gene><STK6, Mouse, Homolog of><Sampling><Serine/Threonine Protein Kinase 15><Skull><Solid><Strains Cell Lines><Survival Rate><T cell growth factor><T-Cell Growth Factor><T-Cell Stimulating Factor><TC-GM-CSF><TGF B><TGF-Beta Type II Receptor><TGF-beta><TGF-β><TGFBR1><TGFBR1 gene><TGFBR2><TGFBR2 gene><TGFbeta><TGFβ><Testing><Therapeutic><Thymocyte Stimulating Factor><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Treatment Efficacy><Tumor-Cell Human GM Colony-Stimulating Factor><Untranslated RNA><Up-Regulation><Upregulation><Vesicle><Whole Blood><accessory cell><analyze gene expression><anti-tumor effect><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular cytotoxicity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><antitumor effect><aurora kinas><aurora kinase A><aurora-kinase A><bio-markers><biologic marker><biomarker><cancer cell><cancer in a child><cancer in children><cancer microenvironment><cancer type><cell mediated cytotoxicity><cell type><chemo-immuno therapy><chemoimmunotherapy><chemotherapy><child with cancer><childhood malignancy><cohort><combination therapy><combined modality treatment><combined treatment><cranium><cultured cell line><cytotoxic><cytotoxicity><developmental><disialogangliosides><exosome><experiment><experimental research><experimental study><experiments><extracellular vesicles><functional loss><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><granulocyte macrophage colony stimulating factor><hands><high risk><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunologic therapeutics><immunotherapeutics><immunotherapy agent><improved><improved outcome><intervention efficacy><kids><mRNA><malignancy><miRNA><miRNAs><monosialogangliosides><multi-modal therapy><multi-modal treatment><nano particle><nano-sized particle><nanoparticle><nanosized particle><natural killer cell based immunotherapy><neoplasm/cancer><neuroblastoma cell><noncoding><novel><pathway><patient oriented outcomes><patient response><patient specific response><patient stratification><pediatric cancer><pediatric malignancy><prognostic biomarker><receptor><resistant><response><response biomarker><response markers><responsive patient><sialogangliosides><social><social role><stratified patient><synergism><therapeutic efficacy><therapeutic outcome><therapeutically effective><therapy efficacy><therapy outcome><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><transforming growth factor-beta type II receptor><transforming growth factor-β type II receptor><tumor><tumor microenvironment><tumors in children><weapons><youngster>