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Oncolytic Viroimmunotherapy Improved by Enhanced Cytokine Transgene Expression

Oncolytic Viroimmunotherapy Improved by Enhanced Cytokine Transgene Expression 1024 575 Lauren Dembeck

Researchers were able to suppress in vivo tumor growth with an oncolytic virus by enhancing the production of the cytokine interleukin-12 in the tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive sarcomas that exhibit resistance to non-surgical treatment and have high rates of metastasis and relapse. The prognosis for MPNSTs is poor, with a mortality rate of 26%. Thus, novel therapies are needed.

Oncolytic virotherapy is a novel therapy being considered for the treatment of MPNSTs. In this treatment, modified viruses capable of selectively replicating in malignant tumors are locally administered and induce direct cytotoxic or immune-related anti-tumor activity. These oncolytic viruses often express transgenes that can enhance their therapeutic effects.

At Nationwide Children’s Hospital, Yeaseul Kim, a research associate in the laboratory of Kevin Cassady, MD, spearheaded a project as a post-baccalaureate/pre-doctoral trainee to investigate oncolytic herpes simplex virus (oHSV) as an immunotherapeutic approach for the treatment of MPNSTs. Kim and collaborators compared viral replication, functional activity, and immune response between viruses that were unarmed or armed with an interleukin 12 (IL-12) transgene in virus-permissive and -resistant murine MPNSTs, both in vitro and in vivo.

“IL-12 is a cytokine that can regulate aspects of both the innate and adaptive immune responses, and previous studies have established its anti-tumor effects, making it an attractive transgene to include in oncolytic viral therapeutics,” says Kim. “Among the two IL-12-armed viruses that we tested in this study, the only difference between them is that one was able to produce more IL-12 protein than the other.”

The study compared two IL-12-expressing oHSVs containing the same IL-12 transgene: an early-generation IL-12-expressing virus and an enhanced IL-12-expressing virus. However, the enhanced IL-12-expressing virus also expresses a gene, called IRS1 from the human cytomegalovirus, which enhances its ability to produce viral proteins in tumor cells, meaning it can ultimately generate more IL-12 protein.

In the murine model of MPNST, the virus-permissive tumors supported viral gene expression of both IL-12 viruses and their replication more so than the virus-resistant tumors. However, the researchers’ findings on oHSV replication and gene expression in vitro were not predictive of oHSV direct oncolytic activity in vivo. The tumors that allowed viral replication in the cell culture restricted the viral replication of both oHSVs to the same degree as the virus-resistant tumors and suppressed only the activity of the early-generation IL-12-expressing virus but not the enhanced IL-12-expressing virus, in vivo.

The team discovered that although the two IL-12-expressing oHSVs had equivalent transcriptional activity, their IL-12 protein production differed in vivo. They found this difference in IL-12 protein levels was associated with therapeutic effect and immune activation.

Immune activation begins when specialized immune cells, called antigen-presenting cells (APCs), encounter targets such as tumor cells. APCs capture and process these cells, displaying tumor markers to another type of immune cells, the T cells. Once T cells recognize these markers, they differentiate into activated cells to attack the tumor and release signals to amplify immune activity.

“During the process of immune activation, APCs are themselves an important source of IL-12 cytokine. However, tumors often create an immunosuppressive environment that limits IL-12 production by APCs,” explains Ravi Dhital, PhD, an immunologist and part of the research team. “In such a setting, our IL-12-producing oHSV steps in as a major IL-12 cytokine source.”

Dr. Dhital adds, “IL-12 induces the release of another cytokine, gamma interferon (IFN-γ), which is highly effective against tumor cells and promotes a sustained immune response. In this study, we have shown that treating tumors with the enhanced IL-12-expressing virus increases immune cell presence in the tumor area, activates APCs, and triggers T cells to release IFN-γ, all key events in suppressing tumor growth.”

When treating virus-resistant tumors with the enhanced IL-12-expressing virus compared with the early-generation IL-12-expressing virus, the researchers saw improved proinflammatory immune activity, with increased dendritic cells, monocyte-macrophage activity, and a polyfunctional Th1-cell response in the tumor infiltrates.

“Our study demonstrates that transgene protein production differences between oHSVs in vivo can impact oncolytic virotherapy therapeutic activity,” explains Kim.

Going forward, the team will continue to investigate ways to improve oncolytic virotherapy efficacy. For example, their future studies will include combining oHSV oncolytic virotherapy with adjuvant therapies.

“Ms. Kim and Dr. Dhital’s results prove something that we had theorized but had not shown previously: there are differences between how different oncolytic viruses negotiate infected tumor cells in animals. We have shown similar activity in cells in culture dishes but never in animals, “says Dr. Cassady, a principal investigator for the Center for Childhood Cancer Research in the Abigail Wexner Research Institute at Nationwide Children’s. “This is exciting because it proves what we had theorized from virus-infected cells in culture dishes also occurs in vivo, and it suggests that the protein translation-optimized virus from which the enhanced IL-12-expressing virus was constructed provides a better platform for expressing other anti-tumor genes during treatment, providing both virus-related tumor lysis and transient gene therapy activity.”

 

Reference:

Kim Y, Saini U, Kim D, Hernandez-Aguirre I, Hedberg J, Martin A, Mo X, Cripe TP, Markert J, Cassady KA, Dhital R. Enhanced IL-12 transgene expression improves oncolytic viroimmunotherapy. Front Immunol. 2024 Jun 4;15:1375413. doi: 10.3389/fimmu.2024.1375413.

Image credit: Adobe Stock

About the author

Lauren Dembeck, PhD, is a freelance science and medical writer based in New York City. She completed her BS in biology and BA in foreign languages at West Virginia University. Dr. Dembeck studied the genetic basis of natural variation in complex traits for her doctorate in genetics at North Carolina State University. She then conducted postdoctoral research on the formation and regulation of neuronal circuits at the Okinawa Institute of Science and Technology in Japan.

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