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Targeting the immunosuppressive tumor microenvironment to enhance efficacy of radiotherapy and immuno-radiotherapy for oral cancer

Award Number: U01DE028233
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeting the immunosuppressive tumor microenvironment to enhance efficacy of radiotherapy and immuno-radiotherapy for oral cancer - PROJECT SUMMARY AND ABSTRACT: Radiation therapy (RT) is a mainstay of cancer treatment. However many tumors are resistant to RT, making it possible for microscopic tumor cells to remain or travel to other parts of the body and cause cancer recurrence at a later date. Immunotherapies can train the patient’s immune system to seek out and identify hidden tumor cells. The combination of RT with immunotherapy is a very exciting approach, but RT can have both immune- stimulating and immune suppressive effects, and further study is needed to understand how best to combine RT with immunotherapy. Many scientists now believe that understanding the tumor microenvironment – the types of cells which make up a tumor, and their interactions – is required to maximize the immune-stimulating effects of RT. We have discovered a strategy to alter the balance of cells in the tumor microenvironment of oral cancer and other solid tumor types, by simultaneously targeting immunosuppressive myeloid derived suppressor cells (MDSC) and regulatory T cells (Treg), so that immune-stimulating effects of RT predominate. Studies in mouse tumors show that this strategy is particularly effective when combined with an immunotherapy approach called “checkpoint inhibition” that targets molecules that limit effectiveness of anti- tumor T cells. This leads to our scientific hypothesis that tumor-infiltrating MDSC and Treg render the tumor microenvironment resistant to immune activation by RT and/or checkpoint inhibition, and limit the induction of tumor-specific CD8+ T cells and other immune effector immune cells. The goals of this proposal are to 1) determine whether modulating the tumor immune microenvironment enhances responsiveness of oral cancer to RT and/or checkpoint inhibition, leading to long-lasting and powerful anti-tumor effects; 2) determine the immunological mechanisms which make these combination therapies effective; and 3) develop a novel drug formulation which will make this approach more effective and suitable for testing in clinical trials. We will accomplish these goals by carrying out the following specific aims: In Aim 1 we will functionally dissect the immune mechanisms by which MDSC contribute to radioresistance in mouse oral cancer models. In Aim 2 we will assess the ability of dual targeting of MDSC and Treg to sensitize oral cancer to treatment with RT + anti-PD-1 and induce durable protective memory responses. In Aim 3 we will develop a novel drug delivery system that can enhance delivery of inhibitors of MDSC function directly to the tumor and tumor-infiltrating MDSC.


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: 2025 ( Subtotal = $0 )
2025	2022	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	6	5/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	6	3/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $746,242 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	5	3/23/2022	SUPPLEMENT FOR EXPANSION	$21,034
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	005	6	8/4/2022	SUPPLEMENT FOR EXPANSION	$64,165
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	004	6	8/3/2022	NON-COMPETING CONTINUATION	$661,043
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	006	6	8/5/2022	NON-COMPETING CONTINUATION	$0
2022	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	003	5	7/12/2022	NON-COMPETING CONTINUATION	$0
2022	2020	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	4	4/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$244,810
2022	2019	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	2	4/20/2022	NON-COMPETING CONTINUATION	-$244,810
														Subtotal = $746,242

Issue Date FY: 2021 ( Subtotal = $745,334 )
2021	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	5	7/23/2021	NON-COMPETING CONTINUATION	$745,334
2021	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	4	11/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$761,749
2021	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	11/12/2020	NON-COMPETING CONTINUATION	-$761,749
														Subtotal = $745,334

Issue Date FY: 2020 ( Subtotal = $761,749 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	7/15/2020	NON-COMPETING CONTINUATION	$761,749
														Subtotal = $761,749

Issue Date FY: 2019 ( Subtotal = $840,679 )
2019	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	001	2	8/16/2019	SUPPLEMENT FOR EXPANSION	$63,718
2019	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	2	7/23/2019	NON-COMPETING CONTINUATION	$776,961
														Subtotal = $840,679

Issue Date FY: 2018 ( Subtotal = $804,594 )
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/18/2018	NEW	$804,594
														Subtotal = $804,594

Grand Total All Awards = $3,898,598

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Targeting the immunosuppressive tumor microenvironment to enhance efficacy of radiotherapy and immuno-radiotherapy for oral cancer

Award Number: U01DE028233

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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