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Defining impact of in situ activation of CD40 and type 1 interferon signaling on theTME and systemic T cell immunity in murine models and cancer patients

Award Number: R01CA283730
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Recent advances in cancer immunotherapies have revolutionized lung cancer treatment paradigms. However, many patients derive little or no benefit from FDA approved immune checkpoint inhibitors (ICI). A host of clinical studies have shown that pre-existing tumor-reactive T cells are critically important to achieve benefit from ICI. Therefore, augmenting the number and functionality of tumor-reactive T cells could pave the way for more effective cancer treatments. Oncolytic viruses (OVs) have been developed for their ability to specifically replicate in cancer cells leading to cancer cell lysis but not cytotoxicity towards normal cells. Recent studies indicate that stimulation of host anti-tumor immunity is also a key mechanism of action of OVs. Using a novel conditionally replicative adenovirus type 5 that expresses two powerful innate immunity stimulators, the studies proposed here can lead to the development of highly effective OV-based therapeutic strategies to kill tumor cells and simultaneously enhance an anti-tumor T cell response. Engagement of CD40 expressed on dendritic cells (DCs) by CD40 ligand (CD40L) leads to acquisition of crucial cross-priming function to activate CD8 T cells. MEM40 is a chimeric CD40L engineered for stable cell surface expression. In addition to pro-inflammatory and anti-viral functions, type 1 IFNs also function as crucial activators of DCs. Our preclinical studies in mouse melanoma and lung tumor models indicate that intralesional administration of MEM40 + IFNß expressing oncolytic adenovirus (MEM-288) we developed induces a robust systemic T cell response that in synergy with ICI is capable of significantly curtailing abscopal tumor growth. A key effect of CD40L and IFNß expression in the tumor microenvironment (TME) was the enhancement of DC activation and migration to draining lymph nodes to induce T cell priming. These findings prompted us to develop a novel conditionally replicative oncolytic adenovirus (MEM-288) that expresses a membrane-stable CD40L (MEM40) and IFNß. A phase 1 first-in-human dose escalation clinical trial of single agent MEM-288 is nearing completion while a combination trial of MEM-288 with ICI in NSCLC patients is expected to begin in Fall 2023. A primary goal of studies proposed here is to define MEM-288 clinical activity in NSCLC patients from both trials and assess immune stimulatory effects of MEM-288 in the tumor microenvironment (TME) and ability to generate a systemic anti-tumor T cell response. Two Specific Aims are proposed: Aim 1: Defining impact of in situ activation of CD40 and type 1 IFN signaling on DC and T cell responses in tumor models. Aim 2: Impact of oncolytic virus (MEM-288) induced CD40 and type 1 IFN signaling on TME remodeling and systemic T cell responses in NSCLC 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: 2024 ( Subtotal = $460,204 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	1	4/15/2024	NEW	$460,204
														Subtotal = $460,204

Grand Total All Awards = $460,204

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Defining impact of in situ activation of CD40 and type 1 interferon signaling on theTME and systemic T cell immunity in murine models and cancer patients

Award Number: R01CA283730

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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