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CTOT: Biomarker guided CNI substitution in kidney transplantation

Award Number: U01AI063594
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

In this competitive renewal of a Clinical Trials in Organ Transplantation consortium funded for >16 years, we will employ our established infrastructure and experience in clinical trials, biomarkers and mechanistic studies to perform a randomized controlled trial (RCT) aimed at individualizing therapy for kidney transplant (KTx) recipients. We propose prospective, multicenter, RCT to test the hypothesis that the HLA-DR/DQ molecular mismatch (eplet, mMM) between donor and recipient reliably stratifies post-transplant risk of graft injury in KTx recipients. To this end, we will determine the utility of HLA-DR/DQ mMM to safely guide tacrolimus (TAC) substitution with abatacept s.c (aim 1), validate HLA-DR/DQ mMM as a prognostic biomarker of primary alloimmunity (aim 2), and determine the utility of non-invasive biomarkers to detect biopsy-proven rejection (BPAR) and monitor the response to BPAR therapy in KTx subjects (aim 3)d. Accompanying mechanistic studies are designed to support and add interpretive value to the proposed clinical trial. Using serially collected and stored PBMC, plasma, serum, urine sediment and supernatant, and biopsy tissue, we will a) test the hypothesis that the degree of HLA DR/DQ mMM determines the size of the donor-reactive CD4+ T cell repertoire, b) test effects of abatacept substitution for TAC on the recipients' immune, c) use state-of-the-art technologies to identify molecular subtypes of graft rejection that could potentially guide novel treatment strategies to eliminate the injury, and d) discern mechanisms linking TAC to kidney dysfunction through molecular analysis of KTx tissue/cells using samples from the RCT in which we substitute TAC with abatacept. We also propose a multisite infectious disease trial concept with an overall objective to interrogate the durability of vaccine-preventable seroprotection across organs and immunosuppression regimens. Together, the work will attempt to validate the predictive utility of HLA-DR/DQ mMM in KTx recipients, determine the safety and efficacy of abatacept as a TAC substitute (hypothesized to be preferentially effective in subjects with low HLA mMM), and document whether and how this change in therapy affects off-target effects associated with CNI. As any transplant center can perform the HLA-DR/DQ mMM biomarker and we designed the proposed study to be informative regardless of outcomes, the work has the potential to have a paradigm- shifting and sustained transformative impact on the clinical care of KTx recipients. Additionally, as we designed accompanying mechanistic studies, using state-of-the-art tools/assays that will delineate the effects of abatacept on the recipients' donor-reactive immune response, the studies will provide mechanistic insights into how abatacept improves outcomes (or why it does not), further enhancing significance.


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	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	000	19	1/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$43,740 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	006	19	6/8/2022	NON-COMPETING CONTINUATION	$43,166
2022	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	003	18	3/25/2022	COMPETING CONTINUATION	$0
2022	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	002	18	2/17/2022	COMPETING CONTINUATION	$0
2022	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	004	17	5/11/2022	SUPPLEMENT FOR EXPANSION	-$88,529
2022	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	005	17	5/17/2022	SUPPLEMENT FOR EXPANSION	$1,623
2022	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	001	18	2/11/2022	COMPETING CONTINUATION	$1,222,414
2022	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	000	17	2/11/2022	NON-COMPETING CONTINUATION	-$1,222,414
														Subtotal = -$43,740

Issue Date FY: 2021 ( Subtotal = $598,677 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	002	18	8/30/2021	COMPETING CONTINUATION	$1
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	000	17	12/29/2020	SUPPLEMENT FOR EXPANSION	$598,676
2021	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	001	17	4/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $598,677

Issue Date FY: 2020 ( Subtotal = $4,509,740 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	001	17	8/14/2020	NON-COMPETING CONTINUATION	$2,509,740
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	003	17	9/11/2020	NON-COMPETING CONTINUATION	$0
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	002	17	9/2/2020	NON-COMPETING CONTINUATION	$2,000,000
2020	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	000	16	3/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $4,509,740

Issue Date FY: 2019 ( Subtotal = $4,445,862 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	001	16	8/30/2019	NON-COMPETING CONTINUATION	$2,000,000
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	000	16	8/20/2019	NON-COMPETING CONTINUATION	$2,445,862
														Subtotal = $4,445,862

Issue Date FY: 2018 ( Subtotal = $4,452,504 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	000	15	8/14/2018	NON-COMPETING CONTINUATION	$2,452,504
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	001	15	8/23/2018	NON-COMPETING CONTINUATION	$2,000,000
														Subtotal = $4,452,504

Issue Date FY: 2017 ( Subtotal = $4,460,275 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	001	14	8/24/2017	NON-COMPETING CONTINUATION	$2,000,000
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	000	14	8/10/2017	NON-COMPETING CONTINUATION	$2,460,275
														Subtotal = $4,460,275

Issue Date FY: 2016 ( Subtotal = $4,725,246 )
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	001	13	9/1/2016	NON-COMPETING CONTINUATION	$2,013,538
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	000	13	8/5/2016	NON-COMPETING CONTINUATION	$2,711,708
														Subtotal = $4,725,246

Issue Date FY: 2015 ( Subtotal = $4,528,331 )
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	000	12	7/29/2015	NON-COMPETING CONTINUATION	$2,514,794
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	001	12	9/1/2015	NON-COMPETING CONTINUATION	$2,013,537
														Subtotal = $4,528,331

Issue Date FY: 2014 ( Subtotal = $4,449,077 )
2014	2014	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	001	11	8/20/2014	COMPETING CONTINUATION	$1,870,486
2014	2014	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	000	11	6/25/2014	COMPETING CONTINUATION	$2,578,591
														Subtotal = $4,449,077

Issue Date FY: 2013 ( Subtotal = $2,320,181 )
2013	2013	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	000	10	8/7/2013	NON-COMPETING CONTINUATION	$2,320,181
														Subtotal = $2,320,181

Issue Date FY: 2012 ( Subtotal = $2,320,181 )
2012	2012	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	000	9	8/3/2012	NON-COMPETING CONTINUATION	$2,320,181
														Subtotal = $2,320,181

Issue Date FY: 2011 ( Subtotal = $2,367,532 )
2011	2011	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	000	8	8/15/2011	NON-COMPETING CONTINUATION	$2,367,532
														Subtotal = $2,367,532

Issue Date FY: 2010 ( Subtotal = $12,346,778 )
2010	2010	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	000	7	8/31/2010	NON-COMPETING CONTINUATION	$2,391,622
2010	2010	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Trans-NIH Recovery Act Research Support	001	7	9/13/2010	SUPPLEMENT FOR EXPANSION	$9,955,156
														Subtotal = $12,346,778

Issue Date FY: 2009 ( Subtotal = $3,405,652 )
2009	2009	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Trans-NIH Recovery Act Research Support	002	6	9/14/2009	SUPPLEMENT FOR EXPANSION	$920,550
2009	2009	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK	NY	10029	NEW YORK	USA	Allergy and Infectious Diseases Research	001	6	7/31/2009	COMPETING CONTINUATION	$2,485,102
2009	2008	MT SINAI SCHOOL OF MEDICINE	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Allergy and Infectious Diseases Research	000	5	6/26/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,405,652

Grand Total All Awards = $63,691,690

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CTOT: Biomarker guided CNI substitution in kidney transplantation

Award Number: U01AI063594

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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