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The impact of genetic diversity among Akkermansia strains on the effectivenes of immune checkpoint inhibitors in cancer immunotherapies

Award Number: R21CA249243
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT: Microbes in the gastrointestinal tract (GI) play a critical role in maintaining the metabolic and immunological health of their human hosts. The impact of the microbiota on local and systemic immunity is being increasingly recognized as an important modifier of the success of immunotherapies, including those directed against cancers. For instance, germ free animals colonized with microbiotas derived from cancer patients that responded (responders - R) to immune checkpoint inhibitors (ICI) displayed enhanced clearance of tumors upon ICI therapy as compared to animal colonized with microbiotas derived from patients that did not respond (non responders - NR). One of the organisms that is consistently associated with R patients is the obligate anaerobic bacterium Akkermansia muciniphila, which may contribute to dampening mucosal inflammation and regulating systemic immunity. Importantly for cancer immunotherapy, administration of A. muciniphila is sufficient to enhance the effectiveness of ICIs in mouse models of renal cell carcinomas (RCC) and non-small cell lung cancers. We propose to survey the diversity of clinical A. muciniphila isolates in two unique patient populations (one focused on cancer and one on metabolic disease), test their impact in mouse models of cancer immunotherapy, and apply new tools in Akkermansia molecular genetics to define the contribution of various A. muciniphila factor(s) on successful anti-tumor therapy. We expect that by the end of this study that we will have identified strains with the greatest potential for use as “adjuvants” of ICI and defined the genetic basis of some of the traits responsible for their enhanced activities. Given the current commercial interest on Akkermansia as a probiotic, we envision a relatively rapid path from strain identification and/or engineering to a biological that can be fast-tracked for clinical use.


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: 2022 ( Subtotal = $0 )
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Biology Research	001	2	6/1/2022	NON-COMPETING CONTINUATION	$0
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Biology Research	000	2	10/13/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $225,803 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Biology Research	000	2	2/22/2021	NON-COMPETING CONTINUATION	$225,803
														Subtotal = $225,803

Issue Date FY: 2020 ( Subtotal = $188,169 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Biology Research	000	1	2/27/2020	NEW	$188,169
														Subtotal = $188,169

Grand Total All Awards = $413,972

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The impact of genetic diversity among Akkermansia strains on the effectivenes of immune checkpoint inhibitors in cancer immunotherapies

Award Number: R21CA249243

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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