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Non-Invasive Monitoring of CRISPR/Cas-Edited Chimeric Antigen Receptor T (CAR-T) Cells with Reporter Gene-Based Magnetic Resonance Imaging and Positron Emission Tomography

Award Number: UH2EB028907
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease (CRISPR/Cas) genome editing has enabled scientists to design and build next-generation cell-based therapies. T cell-based immunotherapies are particularly suitable CRISPR/Cas tools as after editing they can be expanded to sufficient numbers for use in humans. Recent efforts have shown that precise CRISPR/Cas knock-in at the T cell receptor a constant (TRAC) locus with a chimeric antigen receptor (CAR) targeted towards the B cell antigen CD19 is more effective over randomly integrating viral-based engineered CAR-T cells in mouse models of human B cell leukemia. Therefore, while CRISPR/Cas cellular therapies may improve patient outcomes, like traditional CAR- T cell therapy, it is not known if every patient will respond equivalently or if some patients will be prone to off- target, life-threatening side effects. What is needed are translationally-relevant technologies that can monitor the fate of CRISPR/Cas-edited CAR-T cells in vivo to provide the information needed to understand patient treatment response/non-response, relapse and/or toxicity. The long-term objective of this application is to develop molecular imaging reporter gene technologies for non-invasive visualization of TRAC-targeted CAR-T cells in patients. Specifically, we propose to develop novel translationally-relevant magnetic resonance imaging (MRI) and positron emission tomography (PET) reporter gene assays to noninvasively track the fate of TRAC-edited CAR-T cells over time and to validate these technologies in preclinical mouse models. The specific aims of this new application are: to compare minicircle and non-integrating lentiviral CRISPR/Cas donor vectors for their ability to efficiently edit T cells at the TRAC loci with a CD19-targeted CAR (Aim 1.1); to develop donor vectors co-encoding our CAR, a bioluminescence reporter gene, and either the human MRI reporter organic anion transporter polypeptide 1B3 (OATP1B3) or the PET reporter sodium iodide symporter (NIS), and to validate TRAC-editing and functional reporter expression in vitro (Aim 1.2); to evaluate the sensitivity of OATP1B3-based MRI and NIS-based PET for visualizing CAR-T cells in vivo, as well as perform longitudinal PET and MRI of CAR-T cells in mouse models of B cell malignancies (Aim 2.1); and finally, to develop a dual-reporter translationally-relevant CRISPR/Cas system and evaluate the ability to noninvasively monitor CAR-T cells in mice with both PET and MRI (Aim 2.2). The significance of this work will be to provide powerful cell tracking technologies to allow the fate of CRISPR/Cas-edited CAR-T cells, or other CRISPR/Cas-edited cellular therapies, to be monitored noninvasively in preclinical models and patients. This information will allow more precise monitoring of these transformative therapies in individual patients to better assess safety as well as to relate cell biodistribution to patient outcomes.


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: 2023 ( Subtotal = $0 )
2023	2020	UNIVERSITY OF WESTERN ONTARIO	1393 WESTERN ROAD	LONDON	ON			CAN	Trans-NIH Research Support	000	2	11/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$8,103 )
2022	2020	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON			CAN	Trans-NIH Research Support	000	2	3/25/2022	NON-COMPETING CONTINUATION	-$8,103
														Subtotal = -$8,103

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON			CAN	Trans-NIH Research Support	001	2	3/1/2021	NON-COMPETING CONTINUATION	$0
2021	2020	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON			CAN	Trans-NIH Research Support	000	2	11/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $162,000 )
2020	2020	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON	N6A 5B8		CAN	Trans-NIH Research Support	000	2	8/25/2020	NON-COMPETING CONTINUATION	$162,000
														Subtotal = $162,000

Issue Date FY: 2019 ( Subtotal = $160,720 )
2019	2019	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON	N6A 5B8		CAN	Trans-NIH Research Support	000	1	9/5/2019	NEW	$160,720
2019	2019	UNIVERSITY OF WESTERN ONTARIO, THE	1151 RICHMOND ST SUITE 2	LONDON	ON	N6A 5B8		CAN	Trans-NIH Research Support	001	1	9/6/2019	NEW	$0
														Subtotal = $160,720

Grand Total All Awards = $314,617

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Non-Invasive Monitoring of CRISPR/Cas-Edited Chimeric Antigen Receptor T (CAR-T) Cells with Reporter Gene-Based Magnetic Resonance Imaging and Positron Emission Tomography

Award Number: UH2EB028907

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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