SEATTLE—The effort to hijack bacteria and their biology to help humans, rather than hurt them, has been underway for decades, as seen with the use of adeno-associated virus in gene therapy. But now, new work from the Fred Hutchinson Cancer Research Center is looking to harness an ancient immune response to a particular bacteria molecule by using an experimental drug to treat cancer.
The experimental drug, G100, is a version of a component of a lipopolysaccharide, a molecule found in the cell walls of some bacteria. Given that this molecule isn't found in other organisms, it serves as a warning of infection when it is present and exposure to it triggers an inflammatory response from the immune system. As noted in a Fred Hutchinson press release, “The signaling pathway that activates this response to lipopolysaccharide is so evolutionarily ancient that is nearly identical in animals ranging from honeybees to humans.”
This trial featured 15 participants with metastatic soft-tissue sarcomas who had a tumor just under the epidermis, where it could be easily targeted for injection. Sarcoma refers to a variety of cancers that target connective tissues and occur in bone, muscle, tendons, fat, blood vessels and other areas. According to Dr. Seth Pollack, the study’s senior researcher and a faculty member at Fred Hutchinson, the number of sarcoma subtypes ranges from 50 to 100. Nearly all trial subjects had undergone and failed other cancer treatments. The patients received weekly injections into their tumors for two to three months, in addition to focused radiation.
Fifteen patients were injected, and of those, 14 saw their tumors stop growing, shrink or even disappear, in a single case. After more than a year of follow-up, the tumors have yet to start growing again. Additionally, six patients saw their tumor growth halted throughout the body, at least temporarily.
The data were presented April 3 at this year's annual meeting of the American Association for Cancer Research in a posted titled “Intratumoral injection of the toll-like receptor 4 agonist G100 induces a T-cell response in the soft tissue sarcoma microenvironment.”
The main focus for this first trial was safety, and as noted in the posted, “No grade 3 or higher treatment-related toxicity was observed.” The poster also reported that “local tumor control was achieved in 93 percent (14/15). 6 (40 percent) had stable disease after treatment, and 1 (P06) had complete regression of injected tumor … In 7 patients evaluable for tumor-associated macrophages (tumors with >1000 CD45+CD11b+ cells), 71 percent had a shift from an M2 to M1 phenotype.” (In macrophages, M2 macrophages play a role in the stimulation of healing and regeneration, while M1 macrophages are the immune system's attack dogs, so to speak.)
Signs of heightened immune responses were seen in the injected tumors, potentially that the drug might have induced immune cells to respond to tumor cells specifically, but it hasn't been confirmed. The signs were seen in participants who received radiation together with their injections and in three participants who began radiation later, however, so potentially the drug could have some effect as a standalone treatment.
The authors concluded in their poster that “[Intratumoral] G100 provides a potentially viable agent for local control of metastatic [soft tissue sarcomas]. With or without radiation, G100 appears to shift the tumor microenvironment into a more inflammatory state with significant infiltration of T cells. The increase in clonality in [peripheral blood mononuclear cells] and [tumor-infiltrating lymphocytes], as well as increased overlap of tumor-associated versus peripheral [T cell receptor] sequences, suggest induction of a tumor-specific response. Combination of G100 with other immunomodulators may further enhance the adaptive anti-tumor response.”
“It remains yet to be seen whether this will lead to clinically significant systemic responses, as we had hypothesized in the beginning,” said study investigator Dr. Y. David Seo, who presented the AACR poster and is a research fellow at Fred Hutch and a general surgery resident at the University of Washington. “But the fact that intratumoral injections appear to make the tumor ‘hot’ from an immune-activation standpoint may lend itself to combination therapies using other modalities.”
The team is moving forward with the work based on that hope. They have plans of a follow-up trial to combine G100 injections with a yet-to-be-determined immunotherapy agent in hopes of boosting the anti-cancer immune response throughout the body, rather than just in the injected tumor.
This trial was supported by funds from Seattle Translational Tumor Research as well as Immune Design, the company that owns G100.