Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr;17(6):425-435.
doi: 10.1080/1750743X.2025.2501926. Epub 2025 May 12.

Oncolytic reovirus enhances the effect of CEA immunotherapy when combined with PD1-PDL1 inhibitor in a colorectal cancer model

Atefeh Yari  1 , Seyed Younes Hosseini  2 , Sanaz Asiyabi  1 , Nazila Hajiahmadi  1 , Mohammad Farahmand  3 , Taravat Bamdad  1
Affiliations

Oncolytic reovirus enhances the effect of CEA immunotherapy when combined with PD1-PDL1 inhibitor in a colorectal cancer model

Atefeh Yari et al. Immunotherapy. 2025 Apr.

Abstract

Aim: The effectiveness of immunotherapy with tumor associated antigen vaccines can be enhanced by combining oncolytic viruses with immune checkpoint inhibitors. This study evaluates the efficacy of oncolytic reovirus in combination with an adenovector expressing carcinoembryonic antigen (Ad-CEA) and a programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor in a mouse model.

Methods: Mice bearing CEA-expressing CT26 tumor cells were immunized with Ad-CEA along with a PD-1/PD-L1 inhibitor. Subsequently, three doses of reovirus were injected into the tumors. Tumor size, histopathological examination, CD8 and FOXP3 expression, the cytotoxicity of spleen T cell lymphocytes, and the secretion of Interferon-γ (IFN-γ) and Tumor necrosis factor- α (TNF-α) were examined.

Results: The triple therapy used in this study resulted in the lowest tumor growth and the highest level of cytotoxic immunity. The Foxp3 levels in the tumor microenvironment and TNF-α secretion decreased compared to other control groups. Additionally, this group exhibited the lowest number of mitotic figures and the highest amount of tumor-infiltrating lymphocytes.

Conclusion: The combination of tumor vaccines with oncolytic viruses significantly improves treatment efficacy. Furthermore, inhibiting the PD-1/PD-L1 interaction during vaccination and also with virotherapy enhances immunovirotherapy by reducing immunosuppressive effects and stimulating the immune system, leading to improved therapeutic outcomes.

Keywords: Adenovector; Foxp3; interferon gamma; tumour necrosis factor alpha; virotherapy.

Plain language summary

Colorectal cancer (CRC) is a common cancer with poor outcomes for advanced cases, highlighting the need for better treatments. One promising approach is cancer immunotherapy, that can activate the immune system against Tumor-associated antigens (TAA). TAAs overexpress on tumor cells, but are also expressed at lower levels on some healthy cells.. Many cancer patients struggle with a weak immune response due to tolerance to TAAs, which are often overexpressed in tumors but fail to trigger a strong immune reaction. One specific TAA, carcinoembryonic antigen (CEA), is notably overexpressed in CRC and has been targeted by various cancer vaccines, including those using recombinant adenoviruses that have been genetically modified in a way to acquire a new characteristic or to express a new protein. This viral platform is favored for its safety, stability, and ability to induce strong immune responses. CEA is significant in cancer progression and immune response, making it a key target for therapies aimed at activating cytotoxic T lymphocytes (CTLs), a type of lymphocytes that can kill certain cells, including foreign, tumor and infected cells. Tumors are categorized as “hot” or “cold” based on immune cell presence. Hot tumors have high levels of immune cell infiltration and neoantigens, (unique proteins that appear on cancer cells), which help provoke strong immune responses. Strategies to convert cold tumors into hot ones could enhance treatment effectiveness. Despite advances in immunotherapy, CRC still shows limited response. Researchers are investigating combination therapies that pair immunotherapy with other treatments like chemotherapy, radiotherapy, and targeted therapies to improve outcomes. One such combination involves oncolytic viruses like reovirus, which selectively infects and kills cancer cells. This approach could enhance the overall effectiveness of CRC treatments. In addition, blocking the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) interaction, which negatively regulates immune response by inhibiting the activity of effector T cells can improve the efficiency of CD8 effector cells as the cells that actively respond to a target cell displaying a specific antigen.

PubMed Disclaimer

Conflict of interest statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Similar articles

See all similar articles

References

    1. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA: a cancer journal for clinicians. CA Cancer J Clin. 2016;66(4):271–289. doi: 10.3322/caac.21349 - DOI - PubMed

    2. • This article examines treatment and survival statistics in cancer patients and provides useful information about current trends in cancer treatment and the needs of patients in the survival phase.

    1. Ni Q, Zhang F, Liu Y, et al. A bi-adjuvant nanovaccine that potentiates immunogenicity of neoantigen for combination immunotherapy of colorectal cancer. Sci Adv. 2020;6(12):eaaw6071. doi: 10.1126/sciadv.aaw6071 - DOI - PMC - PubMed

    2. • This study focuses on a dual nano-vaccine that can enhance the immunogenicity of neoantigens and aid in the combination of immunotherapy treatments for colorectal cancer.

    1. Aldhamen Y, Seregin S, Kousa Y, et al. Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2. Cancer Gene Ther. 2013;20(10):564–575. doi: 10.1038/cgt.2013.53 - DOI - PMC - PubMed
    1. Lichtenstern CR, Ngu RK, Shalapour S, et al. Immunotherapy, inflammation and colorectal cancer. Cells. 2020;9(3):618. doi: 10.3390/cells9030618 - DOI - PMC - PubMed

    2. • An article that explores the relationship between immunotherapy, inflammation, and colorectal cancer, analyzing the importance of immune responses in disease progression.

    1. Meng WS, Butterfield LH, Ribas A, et al. α-fetoprotein-specific tumor immunity induced by plasmid prime-adenovirus boost genetic vaccination. Cancer Res. 2001;61(24):8782–8786. - PubMed

Publication types

MeSH terms

LinkOut - more resources