溶瘤呼肠孤病毒与 PD1-PDL1 抑制剂联合应用在结直肠癌模型中增强了 CEA 免疫疗法的效果

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.

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.

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. 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.