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Clinical Implications of Natural Killer-derived exosomal miRNAs in Neuroblastoma

Award Number: R01CA279269
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Clinical Implications of Natural Killer-derived exosomal miRNAs in Neuroblastoma - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $732,471 )
2026	2026	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	3	4/7/2026	NON-COMPETING CONTINUATION	$732,471
														Subtotal = $732,471

Issue Date FY: 2025 ( Subtotal = $732,471 )
2025	2025	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$73,246
2025	2025	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	2	3/18/2025	NON-COMPETING CONTINUATION	$659,225
														Subtotal = $732,471

Issue Date FY: 2024 ( Subtotal = $752,969 )
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Cancer Treatment Research	000	1	3/26/2024	NEW	$752,969
														Subtotal = $752,969

Grand Total All Awards = $2,217,911

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Clinical Implications of Natural Killer-derived exosomal miRNAs in Neuroblastoma

Award Number: R01CA279269

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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