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Novel synthetic receptors with improved antigen specificity and specificity for cancer therapy

Award Number: R01CA114536
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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Abstract Adoptive cell therapy using T cells modified by gene transfer to express T cell receptors or synthetic chimeric antigen receptors (CARs) that specify T cell recognition of tumor associated antigens can be effective in patients with refractory malignancies. Clinical data has shown that tumor cells that express low levels of antigen or that have heterogeneous antigen expression can escape and cause relapse. To address the barrier of low antigen density on tumor cells, we have designed novel synthetic hybrid receptors based on principles of T cell receptor signaling that have superior properties and may be capable of eliminating tumor cells with low antigen levels. To address the barrier of heterogeneous antigen expression on tumor cells, we designed colocalization-dependent orthogonal protein switches that perform ‘AND’, ‘OR’, and ‘NOT’ Boolean logic at the cell surface. In principle, this approach can instruct T cells to eliminate heterogeneous tumor cell populations and spare normal antigen positive cells, extending the constellation of antigens that can be safely targeted. The studies in this application will advance these two classes of next generation synthetic receptors for multiple clinically relevant target antigens to achieve more effective and safe elimination of tumors with low and/or heterogeneous antigen expression. The specific aims are: Aim 1: To evaluate signaling and function of novel CAR/TCR hybrid receptors in primary T cells. Signaling, synapse formation, antigen sensitivity, and in vivo function and fate of T cells expressing CAR-TCR hybrid receptors introduced by lentiviral transduction or by knock-in to the T cell receptor alpha gene locus, will be compared to T cells expressing CD28/CD3z and 4-1BB/CD3z CARs targeting the same antigens. Aim 2: To evaluate chimeric costimulatory receptors for T cells engineered with CAR/TCRs. We will evaluate whether the addition of costimulation in CAR/TCR engineered T cells by co-expressing chimeric molecules that engage a tumor associated ligand will enhance antitumor function. Aim 3 To design OR and AND gated CARS specific for multiple myeloma (MM) antigens and evaluate their ability to prevent tumor escape. Multiple myeloma is responsive to T cell therapy targeting single antigens, but tumor cell heterogeneity allows escape. Co-localization dependent protein switches that can perform OR and AND logic gated recognition of heterogeneous tumor cells will be developed and evaluated for targeting multiple myeloma antigens.


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: 2024 ( Subtotal = $413,943 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	001	19	4/17/2024	NON-COMPETING CONTINUATION	$21,786
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	19	12/14/2023	NON-COMPETING CONTINUATION	$392,157
														Subtotal = $413,943

Issue Date FY: 2023 ( Subtotal = $435,730 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	18	12/30/2022	NON-COMPETING CONTINUATION	$392,157
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	003	18	3/17/2023	NON-COMPETING CONTINUATION	$34,859
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	004	18	9/15/2023	NON-COMPETING CONTINUATION	$8,714
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	001	18	1/12/2023	NON-COMPETING CONTINUATION	$0
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	002	17	1/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $435,730

Issue Date FY: 2022 ( Subtotal = $454,729 )
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	004	16	6/8/2022	COMPETING CONTINUATION	-$379,344
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	003	16	4/20/2022	COMPETING CONTINUATION	$0
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	001	16	1/4/2022	COMPETING CONTINUATION	$454,730
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	007	17	7/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$29,932
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	006	16	7/29/2022	COMPETING CONTINUATION	-$29,932
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	005	17	6/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$379,343
2022	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	002	15	4/20/2022	NON-COMPETING CONTINUATION	$0
2022	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	15	12/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $454,729

Issue Date FY: 2020 ( Subtotal = $458,731 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	15	6/17/2020	NON-COMPETING CONTINUATION	$458,731
														Subtotal = $458,731

Issue Date FY: 2019 ( Subtotal = $444,969 )
2019	2019	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	14	6/27/2019	NON-COMPETING CONTINUATION	$444,969
														Subtotal = $444,969

Issue Date FY: 2018 ( Subtotal = $458,731 )
2018	2018	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	000	13	6/8/2018	NON-COMPETING CONTINUATION	$458,731
														Subtotal = $458,731

Issue Date FY: 2017 ( Subtotal = $458,731 )
2017	2017	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	002	12	6/23/2017	NON-COMPETING CONTINUATION	$458,731
2017	2016	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	001	11	12/22/2016	COMPETING CONTINUATION	$21,821
2017	2014	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	10	12/22/2016	NON-COMPETING CONTINUATION	-$21,821
														Subtotal = $458,731

Issue Date FY: 2016 ( Subtotal = $458,735 )
2016	2016	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Treatment Research	001	11	7/20/2016	COMPETING CONTINUATION	$458,735
2016	2014	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	10	12/22/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $458,735

Issue Date FY: 2014 ( Subtotal = $448,945 )
2014	2014	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	10	5/19/2014	NON-COMPETING CONTINUATION	$32,399
2014	2014	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	10	11/19/2013	NON-COMPETING CONTINUATION	$416,546
														Subtotal = $448,945

Issue Date FY: 2013 ( Subtotal = $412,706 )
2013	2013	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	9	12/12/2012	NON-COMPETING CONTINUATION	$228,394
2013	2013	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	9	6/7/2013	NON-COMPETING CONTINUATION	$184,312
														Subtotal = $412,706

Issue Date FY: 2012 ( Subtotal = $442,047 )
2012	2012	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	8	5/3/2012	NON-COMPETING CONTINUATION	$36,248
2012	2012	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	8	12/29/2011	NON-COMPETING CONTINUATION	$405,799
														Subtotal = $442,047

Issue Date FY: 2011 ( Subtotal = $445,138 )
2011	2011	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	7	5/17/2011	NON-COMPETING CONTINUATION	$19,733
2011	2011	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	7	12/1/2010	NON-COMPETING CONTINUATION	$425,405
														Subtotal = $445,138

Issue Date FY: 2010 ( Subtotal = $224,371 )
2010	2010	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	6	7/6/2010	COMPETING CONTINUATION	$224,371
2010	2009	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	5	7/2/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $224,371

Issue Date FY: 2009 ( Subtotal = $396,427 )
2009	2009	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	5	3/20/2009	NON-COMPETING CONTINUATION	$39,642
2009	2009	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE NO J6-330	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	5	2/27/2009	NON-COMPETING CONTINUATION	$356,785
														Subtotal = $396,427

Issue Date FY: 2008 ( Subtotal = $386,144 ) (Continued on the next page)
Grand Total All Awards = $7,507,778

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Novel synthetic receptors with improved antigen specificity and specificity for cancer therapy

Award Number: R01CA114536

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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