T-VEC IMMUNOTHERAPY FOR LIVER METASTASES?

The oncologic immunotherapy talimogene laherparepvec (T-VEC, Amgen Inc), already approved for the treatment of melanoma in the United States, is now being explored for its potential to eradicate advanced tumors in patients with primary and metastatic liver cancer.

T-VEC is a genetically modified herpes simplex virus-1 that contains a gene for granulocyte-macrophage colony-stimulating factor (GM-CSF). The product is injected directly into the tumor, and the GM-CSF stimulates the production of T cells so that they better recognize proteins released by the tumor, effectively attacking and eradicating them.

For the treatment of melanoma, it is injected directly into the skin lesion. In this new study, the product was administered via an intrahepatic injection directly into the liver tumor, and this injection was guided by ultrasound or computed tomography (CT).

The new study was discussed in a presscast ahead of the Society of Interventional Radiology (SIR) 2018 annual scientific meeting in Los Angeles, California

"Interventional radiologists have been key in managing early and intermediate stages of both primary and metastatic liver tumors, but there are limited treatment options for advanced liver tumors," Steven Raman, MD, professor of radiology, surgery and urology, David Geffen School of Medicine at UCLA, Los Angeles, California, told journalists.

"So we carried out a series of intrahepatic injections of T-VEC with escalating doses up to the maximum FDA [Food and Drug Administration]-approved tolerated dose. The main side effect was temporary flu-like symptoms, so the safety of T-VEC has been established in a small number of patients and this is the first step towards making this treatment more accessible," he added.

Advanced Liver Metastases

A total of 14 patients with advanced liver metastases from a variety of cancers received increasing doses of T-VEC injections, starting with an initial dose of 10⁶plaque-forming units (PFU)/mL. T-VEC was injected directly into the tumor using ultrasound or CT guidance, and the injection volume was determined by the size of the lesion.

"The primary objective of the study was to determine the maximum dose that was tolerated in this setting because it's never been done before in this setting," Raman noted.

"And we did a series of injections with biopsy every 3 weeks, with escalating doses of T-VEC up to the maximum FDA-approved tolerated dose, the idea being to see which dose was the most effective with the least number of side effects," he added.

The initial dose was followed by up to 4 mL of 10⁷ PFU/mL or 10⁸ PFU/mL given every 21 days or up to 8 mL.

A separate group received up to 8 mL of the maximum tolerated concentration every 21 days. Eight milliliters was established as the maximum tolerated concentration.

The median number of injections patients received was three, and one patient received all 12 injections.

Twelve of the 14 patients who received the injections were evaluable for dose-limiting toxicity.

Only one dose-limiting toxicity was observed, a grade 3 aspartate aminotransferase increase accompanied by a grade 2 increase in bilirubin after a single dose.

Investigators also observed grade 3 to 4 treatment-related adverse events in approximately 27% of patients, which included anemia and an increase in liver enzymes.

However, no serious adverse events were observed, although there were two deaths, both caused by disease.

Ramen stressed that the study is ongoing and the next step is to move to a phase 2 trial to assess the strategy for efficacy.

An additional investigation is planned in which T-VEC will be combined with a programmed cell death-1 inhibitor.

Commenting on the study, Suresh Vedantham, MD, president of the SIR and professor of radiology and surgery, Washington University School of Medicine in St. Louis, Missouri, noted that for many years, interventional radiologists have relied on a procedure known as chemoembolization to treat liver tumors. Chemoembolization blocks the blood supply to tumors via a minimally invasive approach.

"We also deliver chemotherapy in a targeted way to tumors to try and minimize side effects, and we have a number of other technologies that involve imaging-guided ablation of the tumor as well," Vedantham added.

The novel oncolytic immunotherapy concept under exploration here is to use a genetically modified virus to trigger the immune system itself to attack tumors, he noted.

"We do a good job at treating early- and intermediate-stage liver cancer where we can use thermal ablation technologies, and then, if patients progress, we have other treatments like radioembolization where we can use catheters to inject radioactive beads to treat tumors," he said.

"But if patients progress despite this — and a significant percentage of them do — then we currently don't have any treatments for late-stage disease and this is where this particular therapy will fit in," Vedantham indicated.

The study was sponsored by Amgen. Raman has disclosed no relevant financial relationships. Vedantham reports receiving a research grant from Cook Medical. 

Society of Interventional Radiology (SIR) 2018 Annual Scientific Meeting. Abstract 375. To be presented March 21, 2018.