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Modulation of the tumor microenvironment with probiotic therapies

Award Number: R01CA249160
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/03/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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Modulation of the tumor microenvironment with probiotic therapies - Recent advances in cancer immunotherapy have provided promising treatment options for patients with triple-negative breast cancer (TNBC). Despite overall success in treating these malignancies, immunotherapeutic approaches face a number of unique challenges: (1) dose limitation due to off-target side effects, (2) additive toxicity of combination therapies, (3) and relatively low immunogenicity of breast cancer. To overcome these limitations, this proposal seeks to engineer probiotic strains of bacteria that selectively colonize breast cancer and locally release immunotherapeutics. The ultimate goal is to elicit more robust and diversified antitumor T cell immunity and promote the clearance of colonized primary and metastatic breast cancer lesions and systemically growing breast cancer-derived foci. The accompanying project will first focus on deciphering mechanisms that define the intratumoral tropism of the probiotic strain E. coli Nissle 1917 (EcN) by using antibody-mediated depletion approaches and targeted genetic knockouts to pinpoint host immunological pathways that regulate tumor-specific growth. Using synthetic biology approaches, EcN will then be engineered to stably express and release checkpoint inhibitor nanobodies targeting CD47, PD-L1, and CTLA-4 locally inside of tumors. Pro-inflammatory cytokines will additionally be expressed to promote antigen presentation and enhance cytotoxic T cell responses. The primary innovations of this proposal are in the combined approach of both developing a better understanding of probiotic colonization of tumors, along with engineering probiotics as an immunotherapeutic delivery vector. Specifically, this approach has several advantages over current therapeutic strategies, including: (1) identification of novel EcN host strains and mechanistic understanding of their tumor colonization for further improvements in engineered therapies, (2) tumor-specific production of immunotherapeutics, (3) bacteria lysis that leads to effective release of novel immunotherapeutics and lipopolysaccharides (LPS) adjuvant, and (4) local delivery of novel immunotherapeutic combinations that are toxic to deliver systemically. This work seeks to overcome current limitations of immunotherapies, by providing a targeted vehicle to locally deliver immunotherapies that stimulate antitumor immunity while preventing systemic toxicity and mitigating immune-related adverse effects.


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 = $525,502 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	002	5	4/18/2024	NON-COMPETING CONTINUATION	$27,659
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	001	5	3/20/2024	NON-COMPETING CONTINUATION	$497,843
2024	2023	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	000	4	1/17/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $525,502

Issue Date FY: 2023 ( Subtotal = $638,464 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	001	4	3/27/2023	SUPPLEMENT FOR EXPANSION	$86,602
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	000	4	3/24/2023	NON-COMPETING CONTINUATION	$551,862
														Subtotal = $638,464

Issue Date FY: 2022 ( Subtotal = $647,141 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	001	3	4/15/2022	SUPPLEMENT FOR EXPANSION	$85,800
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	000	3	4/15/2022	NON-COMPETING CONTINUATION	$561,341
														Subtotal = $647,141

Issue Date FY: 2021 ( Subtotal = $625,574 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	000	2	3/31/2021	NON-COMPETING CONTINUATION	$582,197
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	001	2	9/13/2021	SUPPLEMENT FOR EXPANSION	$43,377
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	002	2	9/21/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $625,574

Issue Date FY: 2020 ( Subtotal = $591,316 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Cancer Treatment Research	000	1	4/3/2020	NEW	$591,316
														Subtotal = $591,316

Grand Total All Awards = $3,027,997

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Modulation of the tumor microenvironment with probiotic therapies

Award Number: R01CA249160

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/03/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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