Thursday, June 8, 2023 6/8/2023

Engineering bacteriophage Q? conjugates with tumor associated carbohydrate antigens as multi-component anti-cancer vaccines

Award Number: R01CA225105
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Targeting tumor-associated carbohydrate antigens (TACAs) for anticancer vaccines is exceptionally attractive because many TACAs are highly expressed on multiple types of cancer cells with no or negligible expression on normal cells. While passive immunity utilizing anti-TACA monoclonal antibodies has achieved clinical success, developing a TACA based immunogen to elicit effective anti-cancer immunity has been extremely difficult due to the notoriously low immunogenicity of TACAs. To address this challenge, exciting preliminary results have been obtained showing that TACA-based vaccines can significantly reduce cancer induced death by delivering a prototypical TACA, the Tn antigen, using virus like particle bacteriophage Qß. In this proposal, new ground in TACA based cancer vaccine design will continue to be broken by engineering Qß to generate powerful anti-cancer immune responses. Building on the exciting preliminary results, in Aim 1, an important tumor associated glycopeptide antigen human MUC-1 bearing Tn glycan will be targeted. Using Qß as the carrier, super-high titers of IgG antibodies were elicited against MUC1-Tn, which significantly reduced tumor growth in mice, even in transgenic mice tolerant to human MUC1. Besides Tn and tumor associated MUC1 glycopeptides, other TACAs including GD2 and SSEA-3 will be investigated as vaccine targets to reduce the risk of tumor escape from immune surveillance and to kill purported cancer stem cells, a possible cause for resistance to traditional treatments such as chemotherapy. In addition, guided by the crystal structure of Qß, Qß mutants will be developed to reduce undesirable anti-Qß antibodies and further boost desired anti- TACA responses. Cytotoxic T cells can also kill cancer cells. In Aim 2, Qß will be engineered to deliver cytotoxic T cell epitopes and built-in adjuvants in addition to generating anti-TACA IgG antibodies. The comprehensive antibody and cytotoxic T cell immune responses induced by Qß-TACA-cytotoxic T cell epitope conjugate should provide superior protection to immunized host against tumor development. To lay the groundwork for future translation, in Aim 3, the vaccine efficacy in treating canine cancer patients will be established. Canines can naturally develop cancer, which are clinically relevant large animal models for human diseases due to their high similarities to human cancer. This will be the first of its kind trial of such TACA based vaccine constructs in canine patients. Overall impacts: This project will establish a Qß vaccine platform vastly superior to currently available carriers to deliver both TACAs and cytotoxic T cell epitopes, which will elicit long-lasting anti-TACA IgG antibodies and cytotoxic T cells for cancer treatment. Deeper understanding of the connections between structural features of Qß-TACA conjugates and anti-tumor immunity will exert a sustained impact on cancer vaccine design and is essential for successful TACA-based anti-cancer vaccines.


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 = $541,578 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	001	6	3/14/2023	NON-COMPETING CONTINUATION	$44,209
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	000	6	12/7/2022	NON-COMPETING CONTINUATION	$497,369


Issue Date FY: 2022 ( Subtotal = $447,430 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	000	5	12/13/2021	NON-COMPETING CONTINUATION	$410,907
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	001	5	5/25/2022	NON-COMPETING CONTINUATION	$36,523


Issue Date FY: 2021 ( Subtotal = $100,000 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	000	4	2/23/2021	NON-COMPETING CONTINUATION	$100,000


Issue Date FY: 2020 ( Subtotal = $446,307 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	000	3	1/20/2020	NON-COMPETING CONTINUATION	$446,307


Issue Date FY: 2019 ( Subtotal = $795,843 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	000	2	1/11/2019	NON-COMPETING CONTINUATION	$420,237
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	001	2	8/16/2019	SUPPLEMENT FOR EXPANSION	$375,606


Issue Date FY: 2018 ( Subtotal = $420,593 )
2018	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Cancer Cause and Prevention Research	000	1	12/4/2017	NEW	$420,593


Grand Total All Awards = $2,751,751

Sum of Action Amount is $2,751,751;

Grand Total = $2,751,751

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Engineering bacteriophage Q? conjugates with tumor associated carbohydrate antigens as multi-component anti-cancer vaccines

Award Number: R01CA225105

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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