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Increasing the potency of Listeria monocytogenes-based vaccines by eliminating vaccine-related gamma delta T cell responses.

Award Number: R21AI126151
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Vector-neutralizing immunity represents a major impediment to the induction of cellular immune responses using microbial-based vaccines. An ongoing trial of a novel recombinant Listeria monocytogenes (Lm) –based cancer vaccine at our institution has yielded poor tumor antigen-specific immune responses. This result is consistent with other clinical trials with Lm-based vaccines. Importantly, we observed the marked expansion of γδ T cells in every subject. This finding is in direct contrast to murine models, where Lm-based vaccines generate a strong anti-tumor αβ T cell response to both endogenous Lm antigens and the tumor antigen. A particular invariant γδ T cell population is responsible for this effect and the target has been identified – human Vγ9Vδ2 T cells respond to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), an intermediate of the MEP (or non-mevalonate) isoprenoid synthesis pathway. We hypothesize that HMBPP-deficient Lm does not activate the dominant human γδ T cell response and is a superior vaccine platform to generate αβ T cell responses for human immunotherapy when compared to vectors currently in clinical development. We propose that these γδ T cells facilitate the rapid clearance of Lm during 2º immunization, minimizing inflammation and the quantity and quality of antigen presentation to αβ T cells. The specific aims of this study are: 1: Test the hypothesis that rapid γδ T cell clearance of Listeria monocytogenes infected antigen presenting cells prevents generation of a αβ T cell response; and 2: Test the hypothesis that HMBPP-deficient Listeria monocytogenes is superior and safe vaccine for αβ T cell responses and does not generate γδ T cell responses. Our study design incorporates murine and humanized mouse models to determine whether a dominant γδ T cell response suppresses the capacity of Lm to generate αβ T cell responses and to evaluate comparative activation of αβ and γδ T cell responses in HMBPP-deficient versus standard Lm vaccines. This work is a necessary precursor to full trials of the vaccine in patients.


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: 2020 ( Subtotal = $0 )
2020	2017	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	2	11/16/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $206,250 )
2017	2017	PROVIDENCE HEALTH SYSTEM-OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	2	5/22/2017	NON-COMPETING CONTINUATION	$206,250
														Subtotal = $206,250

Issue Date FY: 2016 ( Subtotal = $247,500 )
2016	2016	PROVIDENCE PORTLAND MEDICAL CENTER	4805 NE GLISAN STREET	PORTLAND	OR	97213	MULTNOMAH	USA	Allergy and Infectious Diseases Research	000	1	6/14/2016	NEW	$247,500
														Subtotal = $247,500

Grand Total All Awards = $453,750

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Increasing the potency of Listeria monocytogenes-based vaccines by eliminating vaccine-related gamma delta T cell responses.

Award Number: R21AI126151

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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