As understanding of immune activity at the tumor site increases, immunotherapy has received widespread attention as an effective cancer treatment strategy, leading to a major shift in cancer research and clinical trials. The main purpose of tumor immunotherapy is to stimulate host anti-tumor immunity, establish an immune-sensitive microenvironment, and ultimately achieve tumor shrinkage while improving the overall survival rate of patients.
Chimeric antigen receptor (CAR)-T cell therapy, a form of adoptively transferred T cell therapy, has exceeded expectations in the treatment of B-cell malignancies. However, unlike hematological malignancies, solid tumors pose significant challenges. Adoptively transferred T cells must travel long distances to penetrate dense and elastic matrices and establish interactions with chemokine receptors. Once reaching the tumor microenvironment (TME), most T cells encounter obstacles and immunosuppressive factors that impede their ability to expand, infiltrate, and induce tumor-specific cytotoxicity. The limited effectiveness of T cell-based monotherapies in the treatment of solid tumors suggests the need for additional adjuvant therapies to overcome these resistance mechanisms and expand the use of adoptively transferred T cell therapies to solid tumors.
The accelerated availability of mRNA coronavirus disease 2019 (COVID-19) vaccines provides valuable health protection, but it only scratches the surface of the vast potential of mRNA vaccines. Additionally, mRNA vaccines have a compelling application beyond preventing infectious diseases: cancer vaccines. The potential of mRNA vaccines is being further realized through optimization of their structure, stability and delivery methods, as well as advances in personalized design and preparation processes. Dozens of clinical trials are currently testing the safety and effectiveness of mRNA vaccines against a variety of cancers, including pancreatic cancer, colorectal cancer and melanoma. Clinical and preclinical trials have demonstrated promising results for personalized mRNA-based cancer vaccines, indicating a potential paradigm shift in cancer treatment.
Recently, researchers from Xiamen University in China published an article titled "Combination therapy with oncolytic virus and T cells or mRNA vaccine amplifies antitumor effects" in the journal Signal Transduct Target Ther. This study shows that combined treatment with oncolytic viruses and adoptively transferred T cells can enhance their anti-tumor effect, and also reveals the mechanism by which oncolytic viruses (Ovs) enhance the anti-tumor effect of adoptively transferred T cells. This may provide valuable insights into its potential clinical applications.
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In recent years, significant progress has been made in antitumor therapies based on the adoptive transfer of T cells or oncolytic viruses. However, due to its limited efficiency in infiltrating solid tumors, it is difficult to achieve the expected anti-tumor effect when used alone. In this study, the researchers designed an oncolytic virus (rVSV-LCMVG) that is less susceptible to inducing virus-neutralizing antibodies and combined it with adoptively transferred T cells. By converting the immunosuppressive tumor microenvironment into an immune-sensitive tumor microenvironment, combination therapy showed superior anti-tumor effects than single therapy in B16 tumor-bearing mice. This occurs regardless of whether the OV is injected intratumorally or intravenously. Combination therapy significantly increased intratumoral cytokine and chemokine levels and recruited CD8+ T cells to the TME to trigger anti-tumor immune responses.
Figure 1. Schematic of oncolytic virus rVSV-LCMVG showing the G gene of VSV genome replaced by the G gene of LCMV.
Adoptively transferred T cell preconditioning and subsequent oncolytic virus therapy sensitize refractory tumors by promoting T cell recruitment, downregulating PD-1 expression, and restoring effector T cell function. To provide combination therapies with greater translational value, mRNA vaccines are introduced to induce tumor-specific T cells rather than adoptively transferring T cells. The combined use of OVs and mRNA vaccines can also significantly reduce tumor burden and prolong survival. This study proposes a rational combination therapy of OVs with adoptive T cell transfer or mRNA vaccines encoding tumor-associated antigens from the aspects of synergy and mechanism.
Figure 2. mRNA tumor vaccine combined with oncolytic virus improved the therapeutic effect.
In summary, this study shows that the combined treatment of oncolytic viruses and adoptively transferred T cells can enhance their anti-tumor effect, and also reveals the mechanism by which OVs enhance the anti-tumor effect of adoptively transferred T cells. This may provide valuable insights into its potential clinical applications. It is worth noting that this study proposes that the combination of mRNA vaccines and OVs is expected to become an effective treatment strategy for solid tumors.
Reference
Fu R, et al. Combination therapy with oncolytic virus and T cells or mRNA vaccine amplifies antitumor effects. Signal Transduction and Targeted Therapy, 2024, 9(1): 118.