Patients with liver cancer can find their options limited, especially in later stages when damaged tissue and tumor growth in mass or numbers can make some approaches too dangerous to consider. But cancer researchers are hopeful for an approach that combines minimally-invasive injections with cutting-edge medication that boosts immune response.
Researchers are now investigating the application of a cancer immunotherapy, talimogene laherparepvec (T-VEC), for treating late-stage liver cancer. The immunotherapy is a modified herpes virus that selectively infects and kills cancer cells while stimulating the body’s immune response. T-VEC is already FDA-approved for melanoma treatment, in which it is injected directly into skin lesions. The new application is one of a number of investigations into targeted immunotherapies which require imaging technology, such as ultrasound, to deliver treatment precisely to tumors inside the body.
“It’s a different way of thinking about treatment,” says Steven Raman, an interventional radiologist at the UCLA Medical Center. “We’re trying to translate something that’s worked in melanoma [to liver cancer].” Raman will present preliminary results of a safety trial today, March 21, at a meeting of the Society of Interventional Radiologists.
The study is a Phase I clinical trial, so researchers are focused on the safety and dosage of the treatment, rather than its efficacy. If T-VEC is eventually approved for liver cancer, that day is likely years away. For now, the only way patients can receive T-VEC for liver cancer is through clinical trials like Raman’s. In an early-reporting group of 14 patients with late-stage hepatocellular carcinoma, the most common form of liver cancer, or metastasized liver tumors, Raman and his team tested a low dose of the drug. They then escalated the amount of T-VEC injected every three weeks until it matched the dose currently approved for melanoma. The researchers observed no serious side effects linked to the T-VEC therapy, beyond what was expected, such as tolerable flu-like symptoms Two patients also died during the course of the study due to their disease.
Although the sample is small, it demonstrates the safety of the delivery method, says Alda Tam, the director of clinical research in the department of interventional radiology at the MD Anderson Cancer Center. Observing effects of repeated injections was important, says Tam. “Every time you puncture a liver or lung lesion with a needle, there is a risk of complications.”
“The results are expected, and pave the way for future studies where they can combine it with a checkpoint inhibitor,” says Tim Greten, a liver cancer and immunology researcher and head of the gastrointestinal malignancy section at the National Cancer Institute. Immune checkpoint inhibitors are a now-common class of immunotherapy that block pathways by which cancer cells can trick immune system cells into sparing them.
There’s a baseline for expectations because precision injection of immunotherapies is new, but not brand-new. For the past five years or so, there has been similar work investigating alternatives to systemic therapy, in which medication might be introduced intravenously, rather than delivered directly to tumors.
Researchers at MD Anderson, for example, are asking some basic questions about the most effective ways to deliver new therapies. “Can you do direct, intratumoral injection?” says Tam, “and will that have a bigger influence than systemic injection alone, and set the immune system running in the right direction?”
As with any early-phase study, many of these questions remain unanswered for T-VEC applied to liver cancer. Investigating possible synergistic benefits with other types of treatment, like immune checkpoint inhibitors, is a likely next step, experts say. In this particular case, the best delivery method may also eventually be called into question. Greten works with a similar immunotherapy, called Pexa-Vec. Pexa-Vec has been investigated using both local injection and systemic, intravenous delivery of the medication. No advantage for local injection has yet been demonstrated.
Like Pexa-Vec, T-VEC is an oncolytic virus, a virus that targets and kills cancer cells. It is modified to make cancer cells produce granulocyte-macrophage colony-stimulating factor (GM-CSF), a molecular signal that promotes the production of immune system cells, which is sometimes itself injected as a cancer therapy. The study is being conducted in collaboration with Amgen, the manufacturers of T-VEC.
Raman emphasizes that the work is exploratory and that much remains to be seen, such as the best time to use the drug or therapeutic partners. “We don’t know where it will ultimately shake out,” he says, “We’re trying it in an area that has the most need right now.”