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CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival

Award Number: R01CA121044
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/12/2007
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival - Multiple myeloma (MM) is a neoplasm of bone marrow (BM) resident long-lived plasma cells (LLPC) that comprises 20% of all hematologic malignancies - second only to non-Hodgkin’s lymphoma. Despite new chemotherapeutic agents, MM remains incurable. Although initially sensitive to chemotherapy, the primary cause of treatment failure is the development of progressively more chemo-refractory disease whose resistance is due to upregulation of pro-survival mechanisms. Thus defining the specific mechanisms of myeloma cell survival/drug resistance is essential for the development of curative treatment approaches in MM. It is now clear that myeloma cells are critically dependent on interactions with BM microenvironment (ME) for their survival, just like their normal LLPC counterparts, and these interactions play a major role in MM resistance to chemotherapy. Despite their central importance in myeloma survival however, the specific molecular and cellular components involved in these interactions remain poorly characterized. In our original proposal, we hypothesized that CD28 was playing significant pro-survival role in myeloma. Although it has been primarily characterized as the prototype T cell costimulatory receptor involved in T cell activation and survival, CD28 is also expressed on normal PC and MM. Work accomplished during the last funding cycle has demonstrated that CD28 activation through two downstream signaling pathways plays an essential role in the survival of both normal LLPC and MM cells, and that therapeutically blocking CD28 activation leads to MM cell death/resensitization to chemotherapy in preclinical in vivo models. Based on these findings and initial evidence for clinical efficacy, we have just opened a phase II clinical trial of blocking CD28 activation in refractory/relapsed MM (NCT02334865) More recently, we have found that CD28 activation substantially enhances the metabolic fitness of MM cells, which plays a major role in its pro-survival effect. In addition to directly supporting MM survival, we have found that MM CD28 also modulates the MM ME. CD28 engagement of its ligands CD80 and CD86 on stromal dendritic cells (DC) initiates CD80/CD86 “backsignaling” that induces DC production of the pro-MM survival cytokine IL-6 and the immunosuppressive tryptophan (Trp)-catabolizing enzyme indoleamine 2, 3 dioxygenase (IDO). We have also shown that CD86 expressed on MM cells has independent pro-survival function. More recently we have determined that kynurenine (Kyn, produced by IDO degradation of Trp) is an endogenous ligand for the aryl-hydrocarbon receptor (AhR), and AhR activation has a significant but previously unrecognized pro-survival role in MM. The Specific Aims of this proposal are: 1). Characterize the effect of blocking CD28 activation on myeloma chemoresistance in a Phase 2 clinical trial in MM patients, 2). Define how CD28 activation enhances the metabolic fitness of myeloma cells, and 3). Determine the role of MM CD28-mediated modulation of DC in the BM ME in supporting MM survival.


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 = $335,089 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	17	9/7/2023	NON-COMPETING CONTINUATION	$328,387
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	17	9/18/2023	NON-COMPETING CONTINUATION	$6,702
														Subtotal = $335,089

Issue Date FY: 2022 ( Subtotal = $318,046 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	004	16	8/29/2022	NON-COMPETING CONTINUATION	$318,046
2022	2021	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	002	14	5/3/2022	NON-COMPETING CONTINUATION	-$61,878
2022	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	003	15	5/3/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$61,878
2022	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	15	3/18/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$195,504
2022	2021	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	14	3/18/2022	NON-COMPETING CONTINUATION	-$195,504
														Subtotal = $318,046

Issue Date FY: 2021 ( Subtotal = $367,813 )
2021	2021	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	14	2/12/2021	NON-COMPETING CONTINUATION	$367,813
														Subtotal = $367,813

Issue Date FY: 2020 ( Subtotal = $367,920 )
2020	2020	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	13	1/14/2020	NON-COMPETING CONTINUATION	$367,920
														Subtotal = $367,920

Issue Date FY: 2019 ( Subtotal = $385,757 )
2019	2019	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	12	2/15/2019	COMPETING CONTINUATION	$385,757
2019	2019	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	002	12	2/21/2019	COMPETING CONTINUATION	$2,521
2019	2018	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	001	11	2/21/2019	NON-COMPETING CONTINUATION	-$2,521
														Subtotal = $385,757

Issue Date FY: 2018 ( Subtotal = $171,814 )
2018	2018	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	11	4/13/2018	NON-COMPETING CONTINUATION	$171,814
														Subtotal = $171,814

Issue Date FY: 2017 ( Subtotal = $137,736 )
2017	2017	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	10	6/1/2017	NON-COMPETING CONTINUATION	$137,736
														Subtotal = $137,736

Issue Date FY: 2016 ( Subtotal = $309,550 )
2016	2016	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	9	4/11/2016	EXTENSION WITH OR WITHOUT FUNDS	$309,550
														Subtotal = $309,550

Issue Date FY: 2015 ( Subtotal = $309,550 )
2015	2015	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	8	4/24/2015	NON-COMPETING CONTINUATION	$309,550
														Subtotal = $309,550

Issue Date FY: 2014 ( Subtotal = $300,569 )
2014	2014	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	001	7	6/12/2014	NON-COMPETING CONTINUATION	$300,263
2014	2013	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	6	2/25/2014	COMPETING CONTINUATION	$306
														Subtotal = $300,569

Issue Date FY: 2013 ( Subtotal = $327,000 )
2013	2013	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	002	6	2/25/2014	COMPETING CONTINUATION	$306
2013	2013	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	001	6	7/1/2013	COMPETING CONTINUATION	$326,694
2013	2011	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	5	6/26/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $327,000

Issue Date FY: 2011 ( Subtotal = $294,191 )
2011	2011	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	5	7/21/2011	NON-COMPETING CONTINUATION	$294,191
														Subtotal = $294,191

Issue Date FY: 2010 ( Subtotal = $300,016 )
2010	2010	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	4	8/20/2010	NON-COMPETING CONTINUATION	$300,016
														Subtotal = $300,016

Issue Date FY: 2009 ( Subtotal = $296,838 )
2009	2009	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	3	6/29/2009	NON-COMPETING CONTINUATION	$296,838
														Subtotal = $296,838

Issue Date FY: 2008 ( Subtotal = $293,753 )
2008	2008	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	2	7/21/2008	NON-COMPETING CONTINUATION	$293,753
														Subtotal = $293,753

Issue Date FY: 2007 ( Subtotal = $290,757 )
2007	2007	HEALTH RESEARCH, INC - ROSWELL PARK DIVISION	666 ELM STREET	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	1	9/12/2007	NEW	$290,757
														Subtotal = $290,757

Grand Total All Awards = $4,806,399

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CD28-mediated Regulation of Multiple Myeloma Cell Proliferation and Survival

Award Number: R01CA121044

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/12/2007

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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