# Mechanistic factors limiting utility of adenovirus vectors for treatment of neopla

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $632,232

## Abstract

ABSTRACT
Adenovirus-based vectors are a very attractive platform for development of novel drug candidates for treatment
of numerous genetic diseases and cancer. Currently, the prevailing view of requisites for effective virus-based
cancer therapeutics includes i) a potent cytotoxic capacity to trigger virus-mediated killing of as many tumor cells
as possible in the shortest period of time, and ii) the capacity for stimulating adaptive anti-tumor immune
response. While early efforts to develop potent oncolytic therapeutics were primarily focused on harnessing or
even increasing virus-mediated tumor cell cytotoxicity, new data suggest that in vivo, therapeutic efficacy of
viruses with low cytotoxic capacity is comparable or even better than that of viruses which are highly effective at
killing cancer cells in vitro. The mechanistic factors underlying this mismatch between efficacy and potency in
vivo remain poorly understood. While evaluating the therapeutic efficacy of systemically administered
adenovirus-based vectors in a mouse model of disseminated lung cancer, we found that virus dose escalation
leads to a reduction in median survival of tumor-bearing mice. In mice that developed a ‘non-responder’
phenotype, myeloid cells become highly activated in response to adenovirus administration. Based on these
findings we propose the novel concept of a “reparative call”, whereby efficient tumor cell killing by the virus
triggers activation of tumor-associated myeloid cells, which in turn secrete pro-tumorigenic growth factors,
triggering accelerated tumor growth. This project is designed to comprehensively address mechanistic aspects
of this concept by analyzing how cytotoxic potency may affect the efficacy of systemic virotherapy with Ad-based
vectors. We will determine the mechanistic role of tumor-derived IL-33 in driving myeloid cell activation and will
develop novel Ad vectors expressing soluble IL-33R to block IL-33-dependent tumor-cell activation. We will
further analyze the therapeutic efficacy of soluble IL-33R-expressing Ad vectors in combination with clinically
relevant drugs that target myeloid cells and the PD-1 pathway. The successful completion of this project will
significantly advance our understanding of fundamental factors that are critical for effective clinical translation of
Ad-based vector systems for therapy of neoplastic disease.

## Key facts

- **NIH application ID:** 10356582
- **Project number:** 1R01CA267694-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Dmitry Shayakhmetov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $632,232
- **Award type:** 1
- **Project period:** 2022-05-05 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356582

## Citation

> US National Institutes of Health, RePORTER application 10356582, Mechanistic factors limiting utility of adenovirus vectors for treatment of neopla (1R01CA267694-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10356582. Licensed CC0.

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