Oncolytic viruses engineered to express a TGFβ inhibitor can “warm up” cold tumors and help checkpoint immunotherapy shrink or completely clear aggressive tumors. This possibility was demonstrated in a preclinical study led by researchers at the University of Pittsburgh School of Medicine.

The researchers, who were led by Greg Delgoffe, PhD, presented their findings in the Journal of Experimental Medicine, in an article titled, “An oncolytic virus–delivered TGFβ inhibitor overcomes the immunosuppressive tumor microenvironment.” The article pointed out that with few exceptions, oncolytic viruses have led to clinical trial failures. Moreover, the article argued that these clinical trial failures “point to a need for a deeper understanding of the unique mechanisms of resistance to oncolytics as resistance mechanisms may not apply broadly across immunotherapies.”

In their article, the researchers indicated that they used paired sensitive or resistant tumors (along with an immunologically inactive melanoma model) to dissect the “common” features of oncovirus treatment versus those that ultimately produce durable responses. “In doing so,” the researchers asserted, “we uncovered tumor-derived resistance mechanisms paving the way for a more potent therapy.”

The researchers first developed a head-and-neck squamous cell carcinoma (HNSCC) cell line that is very sensitive to an oncolytic virus called vaccinia. Tumors injected with the virus regress after a single dose. They also developed a second cancer cell line that was otherwise identical but resistant to vaccinia.

After injecting both types of cells into mice and comparing immunological differences in the tumors that grew, they found that resistance to vaccinia was driven by high levels of a signaling protein called TGFβ, which is known to promote cancer growth by suppressing the immune environment.

Next, the researchers engineered vaccinia to carry a gene encoding a TGFβ inhibitor. “TGFβ inhibitors are very potent,” Delgoffe remarked. “They’ve been tried in the clinic, but they’re usually toxic because they’re delivered systemically. What’s really cool about using oncolytic viruses is that they deliver this cargo directly to the tumor microenvironment, so it’s very targeted and a much safer way to treat.”

When the researchers injected the modified vaccinia into mice with vaccinia-resistant HNSCC, the tumors shrank or, in about 50% of mice, completely cleared, greatly increasing survival compared to animals that received the control virus, which didn’t carry the TGFβ inhibitor. Importantly, the treatment didn’t cause any autoimmune or toxicity-related side effects.

Finally, the researchers tested whether the modified viruses could work similarly in a highly aggressive form of melanoma that is resistant to anti-PD1 immune checkpoint inhibitors. Animals that received no treatment, anti-PD1, or control vaccinia all died within about 24 days, while about 20% of those that received the modified virus had complete clearance of the tumor.

The most dramatic results occurred when modified vaccinia was combined with anti-PD1. In 67% of mice, tumors completely cleared, and survival was greatly extended.

“Much of the focus within oncolytic viruses has been on increasing the immune stimulatory effects of the virus with such mechanisms as virally produced GM-CSF and IL-12 or a combination with checkpoint blockade,” the article’s authors concluded. “Shifting the focus of the field toward understanding the mechanisms of resistance against oncoviruses and rationally designing combination therapies to alleviate the tolerogenic mechanisms in the tumor microenvironment may be more beneficial to improve responses to oncoviruses.”

Delgoffe and his team hope that a version of their modified vaccinia virus, which they’ve licensed to Kalivir Immunotherapeutics, could soon be ready to test in human clinical trials as an adjuvant for immune checkpoint inhibitors in patients who haven’t responded to these immunotherapies.

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