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Manipulation of Tumor Specific Immunity

Award Number: R01CA022677
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/1978
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Manipulation of Tumor Specific Immunity - The long-term objective is to use animal models to find mechanisms and approaches whereby adoptively transferred T cells transduced with mutant neoantigen-specific TCRs can eradicate solid cancers in patients without destroying normal tissues. Tumors in patients have been present at least for months or years and are usually at least 1cm in diameter at time of diagnosis. Therefore, large and long-established solid tumors expressing autochthonous (untransfected) mutant neoantigens are the focus of this proposal. A key element being explored is the destruction of the immunosuppressive stromal tumor microenvironment by transfer of MHC Class II restricted neoantigen-specific TCR-transduced CD4+ T cells (CD4+TCR). These T cells cause tumor destruction followed by long-term arrest of tumor growth. A second key element being explored is that CD4+TCR T cells form 4-cell-type clusters with MHC Class I restricted neoantigen-specific TCR-transduced CD8+ T cells (CD8+TCR) which are attracted to the cluster by recognizing the cross-presented neoantigen on stromal CD11b+ tumor-associated macrophages. Finally, intraclonal non-heritable heterogeneity is explored as novel mechanism of escape of cancers despite cancer cells seemingly lacking mutant neoantigen-negative variants. Aim 1 is to determine the requirements and mechanisms for CD4+TCR T cells to destroy, without CD8+ T cells, advanced solid tumors and subsequently arrest their growth. It will be tested whether targeting tumor stroma is essential for this CD4+TCR-mediated destruction/arrest and whether these effects are independent of direct cancer cell recognition. Furthermore, it will be examined whether therapeutic CD4+TCRs can be isolated from tumor-infiltrating lymphocytes (TILs) that are failing to reject the cancer. Finally, it will be tested whether appropriate lysosomal processing of mutant neoantigen is a decisive predictor for CD4+TCR- mediated tumor destruction. Aim 2 is to determine whether 4-cell-type clusters at the effector phase are essential for cancer eradication by CD4+TCRs and CD8+TCRs. It will be analyzed whether direct cancer cell recognition by the CD8+TCR is required for cancer eradication. Furthermore, it will be tested whether, for synergistic cancer cell destruction, the two neoantigens must be released from the same cancer cell because this would allow the CD8+TCR T cells to recognize the cross-presented neoantigen on the same CD11b+ stromal cell also being recognized by the CD4+TCR T cells. Antigen-specific 4-cell-type cluster formation will be quantified and modeled in vitro using longitudinal time-lapse imaging. Finally, will be determined whether cancers brought into equilibrium by CD4+TCRs can still be eradicated by subsequent treatment with CD8+TCR transduced T cells. Aim 3 is to determine mechanisms of escape and the molecular nature of CD8+TCR recognized antigens that can be used to eradicate cancers in synergy with CD4+TCRs. It will be examined whether cloned cancer cells seemingly lacking antigen-negative variants nevertheless escape by the presence of cancer cells with low mutant mRNA expression due to intraclonal heterogeneity.


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: 2027 ( Subtotal = $0 )
2027	2024	THE UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	43	10/20/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $316,778 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	43	6/13/2024	NON-COMPETING CONTINUATION	$316,778
														Subtotal = $316,778

Issue Date FY: 2023 ( Subtotal = $333,450 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	42	7/19/2023	NON-COMPETING CONTINUATION	$333,450
														Subtotal = $333,450

Issue Date FY: 2022 ( Subtotal = $326,781 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	41	6/21/2022	NON-COMPETING CONTINUATION	$326,781
														Subtotal = $326,781

Issue Date FY: 2021 ( Subtotal = $333,450 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	002	40	6/18/2021	NON-COMPETING CONTINUATION	$333,450
2021	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	39	1/7/2021	COMPETING CONTINUATION	$2,203
2021	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	38	1/7/2021	NON-COMPETING CONTINUATION	-$2,203
														Subtotal = $333,450

Issue Date FY: 2020 ( Subtotal = $348,950 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	39	6/26/2020	COMPETING CONTINUATION	$348,950
2020	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	38	6/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $348,950

Issue Date FY: 2019 ( Subtotal = $279,675 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	38	3/7/2019	NON-COMPETING CONTINUATION	$279,675
														Subtotal = $279,675

Issue Date FY: 2018 ( Subtotal = $288,325 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	37	2/26/2018	NON-COMPETING CONTINUATION	$259,492
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	37	5/24/2018	NON-COMPETING CONTINUATION	$28,833
														Subtotal = $288,325

Issue Date FY: 2017 ( Subtotal = $288,325 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	36	6/7/2017	NON-COMPETING CONTINUATION	$28,833
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	36	3/14/2017	NON-COMPETING CONTINUATION	$259,492
														Subtotal = $288,325

Issue Date FY: 2016 ( Subtotal = $288,325 )
2016	2016	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	35	3/29/2016	NON-COMPETING CONTINUATION	$288,325
														Subtotal = $288,325

Issue Date FY: 2015 ( Subtotal = $302,825 )
2015	2015	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	34	7/3/2015	COMPETING CONTINUATION	$302,825
														Subtotal = $302,825

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	33	4/2/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $243,389 )
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	33	7/2/2013	NON-COMPETING CONTINUATION	$126,873
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	33	2/28/2013	NON-COMPETING CONTINUATION	$116,516
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	002	33	4/2/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $243,389

Issue Date FY: 2012 ( Subtotal = $258,924 )
2012	2012	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	32	3/27/2012	NON-COMPETING CONTINUATION	$258,924
														Subtotal = $258,924

Issue Date FY: 2011 ( Subtotal = $258,853 )
2011	2011	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	31	2/25/2011	NON-COMPETING CONTINUATION	$240,173
2011	2011	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	001	31	5/16/2011	NON-COMPETING CONTINUATION	$18,680
														Subtotal = $258,853

Issue Date FY: 2010 ( Subtotal = $266,640 )
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	30	3/29/2010	NON-COMPETING CONTINUATION	$266,640
														Subtotal = $266,640

Issue Date FY: 2009 ( Subtotal = $294,566 )
2009	2009	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	29	4/27/2009	COMPETING CONTINUATION	$294,566
														Subtotal = $294,566

Issue Date FY: 2007 ( Subtotal = $253,046 )
2007	2007	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	28	5/1/2007	NON-COMPETING CONTINUATION	$253,046
														Subtotal = $253,046

Issue Date FY: 2006 ( Subtotal = $381,652 )
2006	2006	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	27	4/28/2006	NON-COMPETING CONTINUATION	$381,652
														Subtotal = $381,652

Issue Date FY: 2005 ( Subtotal = $401,733 )
2005	2005	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	26	4/29/2005	NON-COMPETING CONTINUATION	$401,733
														Subtotal = $401,733

Issue Date FY: 2004 ( Subtotal = $266,875 )
2004	2004	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Cancer Biology Research	000	25	7/30/2004	NON-COMPETING CONTINUATION	$266,875
														Subtotal = $266,875

Grand Total All Awards = $6,683,037

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Manipulation of Tumor Specific Immunity

Award Number: R01CA022677

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/1978

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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