Introduction
The tumor microenvironment (TME) is the surrounding network of immune cells, stromal components, fibroblasts, and proteins that surround and infiltrate the tumor. The TME is regulated by tumor cells to support tumor invasion and metastasis as well as immune evasion of therapy-induced immune responses. This study explores how targeted approaches to the TME have more effective outcomes due to increased retention and penetration. Oncolytic herpes simplex virus-1 (oHSV) is the primary approved oncolytic virus in the US, currently indicated for metastatic melanoma. oHSVs exert antitumor effects through two complementary mechanisms: direct oncolysis of infected cancer cells and stimulation of systemic antitumor immunity through tumor antigen release, also known as viro-immunotherapy. Usage of oHSV remains limited to small patient subsets, which implicates tumor microenvironment resistance. IGF1R is the Insulin-like Growth Factor 1 Receptor, a protein receptor that receives signals from IGF1 and IGF2, which are bodily growth factors. Once binding happens, it activates pathways that promote cell growth and survival. IGF2 is a protein that promotes tumor growth and immune evasion, leading to worse prognosis in patients with brain and breast cancer. Conventional drugs that are used to target IGF2 have most often failed due to ineffective penetration. Thus, this study aims to address whether oHSV causes IGF2 to be released, thereby preventing the efficacy of this drug. The researchers found that IGF2 release is confirmed in oHSV therapy. Instead, oHSV-D11mt is an engineered virus designed to release the IGF2 blocker from inside the tumor and counteract IGF2 resistance.
Methods
RNA sequencing was used to find genes switched on in tumor cells after oHSV infection. IGF2 levels were measured in cell cultures and in mouse brain tumors. Experiments were done to learn which part of the IGF2 genes is activated by oHSV and what molecular switch turns it off. oHSV-D11mt is a new virus engineered to release proteins that act as a decoy to trap and deactivate IGF3. This new virus was tested in multiple mouse models of brain tumors to measure survival, tumor growth, and immune challenges. T cells and neutrophils were selectively depleted in some experiments to confirm which immune cells were responsible for the effects. Clinical data from 14 Glioblastoma (GBM) patients in a real oHSV trial were also analyzed.
Results
After oHSV infection, IGF2 was one of the most positively upregulated proteins that were secreted by tumor cells, with no significant correlation with IGF1. In fact, 71.4% of GBM patients in the clinical trial showed increased IGF2 after oHSV treatment. Thus, blocking IGF2 with an antibody improved tumor killing in the lab and extended survival in mice; however, only when delivered directly into the tumor. oHSV-D11mt successfully released the IGF2 protein, which bound specifically to IGF2. Mice treated with oHSV-D11mt lived significantly longer than those treated with standard oHSV, across multiple tumor models. 26% of mice with breast cancer brain metastases were completely cured, even rejecting new tumors when re-challenged, which suggests associated lasting immune memory. oHSV-D11mt additionally reduced the number of immunosuppressive neutrophils in the tumor, increased anti-tumor T cells, and overall reprogrammed the tumor microenvironment. Researchers confirmed the efficacy of oHSV-D11mt with an anti-PD-L1 checkpoint drug in these trials.
Limitations
The decoy protein binds human IGF2 much more effectively than that of mouse IGF2, so it’s possible the experiments including mice underestimates how well therapy works in humans, and it would be beneficial to extend these hypotheses beyond a lab setting. Second, oHSV doesn’t replicate as efficiently in mouse cells as it does in humans, which may also underestimate results. Both factors emphasize the need for a more comprehensive understanding of oHSV-D11mt interaction with human immunity. Additionally, only 26% of treated mice achieved long-term cure, underscoring the improvement of the therapy if used more pervasively in human patients. There were also discrepancies in GBM and breast cancer brain tumors in response to the therapy, the reason for which is not fully understood. Each of these limitations provides direction for future research in order to promote this beneficial therapy.
Conclusion
oHSV therapy unintentionally triggers IGF2 release, promoting tumor growth, survival, and immune suppression, calling attention to the need for more effective treatment. oHSV-D11mt is an engineered virus designed to release an IGF2 locking decoy protein directly inside the tumor, addressing the problem of drug resistance through strategies or TME targeting. TME reprogramming shows capacity for lasting systemic immunity rather than transient therapeutic responses from non-targeted therapy. Not only has this approach improved prognosis, including survival, but it has also reduced immunosuppression, bolstered anti-tumor T cells, and lasting immune memory; it has shown potential in adjuvance with checkpoint therapy (PD-L1). This clinical study introduces a modified drug therapy that addresses therapy toxicity and promotes effective prognosis in patients with brain tumors and GBM through reprogramming and direct addressing of the TME.
