# 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

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2024 · $460,204

## Abstract

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 + IFNβ 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 IFNβ 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 IFNβ. 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.

## Key facts

- **NIH application ID:** 10882012
- **Project number:** 1R01CA283730-01A1
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Amer Aziz Beg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,204
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882012

## Citation

> US National Institutes of Health, RePORTER application 10882012, 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 (1R01CA283730-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10882012. Licensed CC0.

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