An Immunological Ignition Switch
Regina Kelder

An Immunological Ignition Switch

How innate immune cells are turning on those killer T cells to attack cancer. Day Two of the Molecular Medicine Tri-C meeting.

Cancer immunotherapy is an effective strategy except when it isn’t. Though many patients with previously untreatable cancers are in remission after receiving checkpoint-blockade drugs, only about 20-30 percent of patients who receive them respond.

This is a problem for drug developers who want to make these therapies the standard of care.

The reasons for the low percentages aren’t entirely clear and the field currently lacks tools that can predict which patients will do well. Researchers are, however,  trying to boost the number of responders by testing, in combination, two different immune checkpoint inhibitors—drugs that loosen the brakes on T cells, allowing them to see and go after cancer—or combining an immunotherapy with another kind of targeted therapy. Studies suggest that these approaches do, in some cases, lead to a more durable response in patients who didn’t respond to monotherapy.

Pushing our innate system

The Minnesota biotech Biothera is using a slightly different tact to try and improve the results for those 70% or so of patients who do not benefit from immunotherapy. At the Molecular Medicine Tri-Conference in San Francisco this week, Jeremy Graff, Biothera’s senior vice president of pharmaceutical research, described a method that uses our innate immune system—the frontline defense in any pathogen attack and —to coax tepid T cells on our adaptive immune side to rise up, react more aggressively and turn so-called cold tumors into hot ones.

Some tumors, like melanoma or lung cancer, contain a lot of mutations that are more likely to be recognized by the immune system because it sees them as foreign. As a result, these hot tumors are often densely infiltrated with armies of killer T cells, and therefore ripe targets for immunotherapy.

Scientists have theorized that if they could find ways of turning up the heat on cold tumors, it might lead to more successes in immunotherapy. T cells form the backbone of the adaptive immune response. They retain a memory of their exact designated victims for years, and unleashing them is the main goal of most cancer immunotherapy.

Biotherma’s strategy involves a soluble yeast β-glucan (a natural immunomodulator) that targets pathogen associated molecular pattern molecules recognized by cells of the innate immune system. The drug, called Imprime PGG, acts as an immunological “ignition switch,” enlisting the innate immune system to enhance the therapeutic efficacy of tumor targeting, anti-angiogenic, and immune checkpoint inhibitor antibodies.

Imprime PGG impacts different parts of the innate system, but primarily it drives the maturation of dendritic cells, which are needed to activate killer T cells. Studies in mice implanted with a colon cancer cell line found that Imprime PGG, when combined with the checkpoint inhibitor repressed the growth of colon tumors in 80% of mice, compared to a 33% response in mice treated only with a checkpoint inhibitor. More importantly, the mice on combination therapy remained tumor free after being challenged again with the colon cancer cells, suggesting that the Imprime-based therapy enhanced immunologic memory.

Will the same results occur in humans? A study using Imprime PGG and a checkpoint inhibitor to treat triple negative breast cancer, a particularly lethal form of breast cancer resistant to most treatments, began this week. Similar studies in patients with head and neck cancer are expected to start by the end of the year, said Graff.

So stay tuned!