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Controllable In Vivo Genome Editing for Immune-Checkpoint Blockade in Solid Tumors

Award Number: R01EB026893
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/21/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Controllable In Vivo Genome Editing for Immune-Checkpoint Blockade in Solid Tumors - Project Summary The blockade of immune-checkpoint pathways has emerged as a promising therapeutic strategy for a variety of cancers. However, the diverse tumor responses to immunotherapy seen in preclinical and clinical studies prompt the development of combination immunotherapies that can be tailored to the complex immune milieu of individual patients. On the other hand, the severe adverse effects associated with the combination therapies with multiple antagonist antibodies address the necessity for alternative safe and effective therapeutic approaches. In light of this, we aim to develop a hybrid nanoparticle-viral vector system for CRISPR/Cas9- based in vivo therapeutic genome editing, which will be used for multiplexed disruption of immune suppressive pathways in the tumor microenvironment. CRISPR/Cas9 systems are very efficient in generating DNA double- strand breaks, thus disrupting genes through the non-homologous end-joining (NHEJ) pathway. However, inducing uncontrolled CRISPR/Cas9 activities in vivo may lead to systemic genotoxicity. We will develop a novel in vivo gene delivery system that integrates a baculoviral vector (BV) with magnetic nanoparticles (MNPs). Our studies have shown that by taking advantage of the interplay between the MNP-mediated BV margination and endocytosis and the innate immunity against insect viruses, this delivery system can provide spatial and temporal control of CRISPR/Cas9 activity. We will use the MNP-BV system to deliver optimized CRISPR/Cas9 for gene disruption of immune suppressive signals PD-L1 and TGF- in the tumor tissue. We will evaluate CRISPR/Cas9 induced anti-tumor immune responses using two well-established mouse models, an immunogenic model (MC38) where monotherapy with PD-1 blockade is sufficient, and non-immunogenic models pancreatic ductal adenocarcinoma (PDAC) which portrays most non-immunogenic human solid tumors that require combination strategies. In aim 1 studies, we will design and optimize CRISPR/Cas9 gRNAs for targeting PD-L1 and TGF-, package Cas9 and gRNAs into a BV vector, and construct the MNP- BV system. In aim 2 studies, we will evaluate MNP-BV-induced multiplexed gene disruption in cell culture, and determine the on-target and off-target indel rates. In aim 3 studies, we will test the controlled in vivo delivery of CRISPR/Cas9, determine the immunological and therapeutic effects of local gene disruption vs. systemic blockade with antagonist antibody in mouse tumor models. The success of the proposed studies will provide a multiplexed intratumoral immunoengineering platform and pave the way for the clinical translation of a highly efficient in vivo genome editing strategy for personalized cancer immunotherapy.


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: 2025 ( Subtotal = -$79,977 )
2025	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	5	1/3/2025	NON-COMPETING CONTINUATION	-$79,977
														Subtotal = -$79,977

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	5	7/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $494,605 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	5	6/3/2022	NON-COMPETING CONTINUATION	$494,605
														Subtotal = $494,605

Issue Date FY: 2021 ( Subtotal = $494,410 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	7/23/2021	NON-COMPETING CONTINUATION	$494,410
														Subtotal = $494,410

Issue Date FY: 2020 ( Subtotal = -$37,359 )
2020	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	004	3	9/19/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	002	2	4/9/2020	NON-COMPETING CONTINUATION	-$161,471
2020	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	3	4/3/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$307,164
2020	2019	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	4/1/2020	NON-COMPETING CONTINUATION	-$344,523
2020	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	003	3	4/9/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$161,471
														Subtotal = -$37,359

Issue Date FY: 2019 ( Subtotal = $513,929 )
2019	2019	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	5/31/2019	NON-COMPETING CONTINUATION	$513,929
														Subtotal = $513,929

Issue Date FY: 2018 ( Subtotal = $533,472 )
2018	2018	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	8/21/2018	NEW	$533,472
														Subtotal = $533,472

Grand Total All Awards = $1,919,080

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Controllable In Vivo Genome Editing for Immune-Checkpoint Blockade in Solid Tumors

Award Number: R01EB026893

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/21/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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