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Exploration of different immunotherapy modalities in osteosarcoma

Award Number: R15CA283777
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Exploration of different immunotherapy modalities in osteosarcoma - Project Summary/Abstract Osteosarcoma (OS) is the most common primary bone malignancy affecting long bones in children and the third most frequent in adults in the United States. The survival rates over the last 20 years are unchanged. OS is also the most common malignant bone tumor (80%) in dogs. Treatment options for OS are limited. Immunotherapy is a promising new approach that has yet to be fully explored in OS. Chimeric antigen receptor (CAR) T cells are designed to express recombinant receptors to target specific tumor cell surface antigens and promote T cell- mediated cancer cell death. However, one of the biggest challenges in CAR T cell therapy is the immunosuppressive tumor micro-environment (TME). Another immunotherapy strategy is the use of immune checkpoint inhibitors, such as monoclonal antibodies (mAb) against PD-1. Anti-PD-1 mAbs have shown significant efficiency in treating multiple tumors but cause adverse effects due to systemic delivery of the mAb. To avoid systemic delivery, oncolytic viruses can be designed to produce immune checkpoint inhibitors directly in TME to boost the immune system and enable T cells to kill tumor cells. Conditionally replicative adenoviruses (CRAds) replicate only in tumor cells, lyse them, and stimulate anti-tumor immunity in TME and at distant sites of disease, causing a bystander effect. However, the limited number of effector T cells against cancer antigens limits the efficacy of this approach. Therefore, we propose a combination therapy to synergize these strategies to combat tumor cells. We will combine CAR T cell therapy, oncolytic virus, and PD-1/PD-L1 inhibitor to target osteosarcoma tumor cells. We have developed an armed oncolytic adenovirus to produce anti-PD-1 Ab in the TME. We will create two more armed oncolytic viruses that will produce secreted single domain antibodies (sdAb) to PD1 and PDL1. We will evaluate CRAd and CAR T cell (against B7-H3) induced tumor cells lysis. The conditionally replicated oncolytic viruses will produce anti-PD1 and anti-PDL1 sdAb in TME, reducing the adverse effects of systemic administration, and enhancing anti-tumor immunity. CAR T cells against B7-H3 will initiate tumor cell killing in an activated TME. Ultimately, beyond the scope of this proposal, this approach will be tested in spontaneous OS in canine patients, before translation to pediatric OS 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: 2027 ( Subtotal = $0 )
2027	2023	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Cancer Treatment Research	000	1	10/20/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $440,640 )
2023	2023	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Cancer Treatment Research	000	1	7/6/2023	NEW	$440,640
														Subtotal = $440,640

Grand Total All Awards = $440,640

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Exploration of different immunotherapy modalities in osteosarcoma

Award Number: R15CA283777

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/05/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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