Intratumoral Injections May Change Soft Tissue Sarcoma Microenvironment

An experimental compound known as G100 may be a potentially viable agent for local control of metastatic soft tissue sarcomas (STS), with or without radiation, according to a phase I study presented at the American Association for Cancer Research (AACR) Annual Meeting 2017, held April 1–5 in Washington, DC.

In a poster presentation, researchers from the University of Washington reported that G100, which is a toll-like receptor 4 agonist, appears to shift the tumor microenvironment into a more inflammatory state with significant infiltration of T cells.

The researchers report that G100 could be used in combination with a checkpoint inhibitor to treat these heterogeneous mesenchymal tumors, which are morbid and highly lethal. The preliminary findings suggest that intratumoral injections with G100 appear to make the tumor “hot” from an immune activation standpoint.

G100 is a lipopolysaccharide that is found in the cell walls of certain bacteria. Another drug based on the same component of lipopolysaccharide is used as part of approved vaccines to prevent hepatitis B and HPV. G100 is used experimentally in vaccines as well.

The team conducted a study with 15 metastatic STS patients. All of the patients had undergone a median of 3 prior lines of therapy and the mean tumor size was 5.6 cm. Each patient received the intratumoral injections weekly for 8 to 12 weeks. Among these 15 patients, 12 received concurrent radiation for 2 weeks and three patients received G100 alone for 6 weeks prior to radiation.

The researchers found there were no grade 3 or higher treatment-related toxicity and local tumor control was achieved in 14 of the patients (93%). In six patients (40%), stable disease occurred after treatment and one patient had complete regression of their injected tumor.

“This is still an experimental treatment,” senior study author Seth Pollack, MD, told the OncoTherapy Network. “We are currently discussing how to combine it with other established immnuotherapies to help them work better.”

Pollack, who is an assistant professor at the Fred Hutchinson Cancer Research Center in Seattle, said the study showed that the injections resulted in what appeared to be systemic expansion of tumor-specific T cells. The researchers found in seven patients evaluable for tumor-associated macrophages, 71% had a shift from an M2 to M1 phenotype. In all patients who received G100 alone, there was an increase in T-cell infiltration into their tumors.   

The study showed that the proportion of CD3-positive live cells went from < 1% to 62% in a tumor in one of the patients. The team observed positive signs in patients who received radiation concurrent with G100 injections as well as in the three patients whose radiation began later. The researchers concluded that G100 appears to alter the tumor microenvironment into a more inflammatory state, resulting in an increase in T-cell infiltration into the tumors.

“We’ve learned a lot, and we’re most excited about getting a new cohort open,” said Pollack.