Under the Microscope: Helping immune cells harmonize their attack on cancer

In the past few years, new advances in immunotherapy have reenergized this approach to treat cancer. The approach, which was recognized with a Nobel Prize in 2018, turns the body’s own immune system into an army of tiny soldiers equipped to find—and kill—cancer cells.

With funding from the V Foundation for Cancer Research, Judith Varner, Ph.D., a professor at the Moores Cancer Center at the University of California (UC) San Diego, is developing a promising new type of immune therapy that uses a molecule known as IPI549 to boost cancer cell killers. Together with her Moores Cancer Center colleague Ezra Cohen, M.D., and Infinity Pharmaceuticals, her group is already testing the new drug in early phase clinical trials, with promising results. If clinical trials continue to go well, the new drug could improve treatment for a wide variety of cancers.

“The flexibility of the V Foundation funding helped our research team get our feet wet in the clinical arena and to forge new collaborations with colleagues here at UC San Diego,” said Varner. “Now, we collaborate on clinical trials on a regular basis.”

A new approach to immunotherapy

T cells play a key role in the body’s immune system by seeking out and destroying viruses, bacteria and other enemies. Most of today’s immunotherapies work by training T cells to find and kill cancer cells. However, when T cells enter tumors, another type of immune cell, known as macrophages, can cause problems. These are the cells that Varner and her team have set their sights on in their quest for better immunotherapies.

“A huge amount of the work in cancer immunology is focused on T cells—improving their ability to enter tumors or helping them stay active,” said Varner. “Instead, we’ve been studying how macrophages—the most abundant immune cells in tumors—prevent those T cells from killing tumor cells.”

Macrophages can take on either a wound-healing or pathogen-killing form. Tumors usually contain the wound-healing type. As a result, macrophages inside tumors typically inactivate T cells they encounter, as they would in a normal wound-healing process.

By deciphering the processes macrophages use to block T cells, Varner and her team are hunting for ways to convince the two types of immune cells to work in harmony—instead of against each other. They discovered changing macrophages into the pathogen-killing type causes them to recruit and activate T cells that will then kill and eradicate tumor cells. They also identified an enzyme called PI 3-kinase gamma that controls a vital switch in the macrophage transformation process.

Promising clinical trials

The researchers worked with Infinity Pharmaceuticals to develop a drug called IPI549 that targets PI 3-kinase gamma. With V Foundation funding, the researchers and Infinity Pharmaceuticals are performing early-phase clinical testing to determine whether the drug really changes the macrophages and activates and recruits T cells in patients.

As part of this work, the researchers used new technology known as NanoString Digital Spatial Profiling, which gives researchers incredibly detailed information about 80 different biomarkers in a single tumor sample. “This provides a great deal of data about the tumor microenvironment,” said Varner. “This data is still being analyzed, but early results are showing that the drug has the anticipated effects on tumor inflammation.”

After further testing, the researchers said doctors could one day use IPI549 in combination with drugs that keep T cells activated, such as checkpoint inhibitor immunotherapy drugs that are in use today, thus boosting the effectiveness of those therapies. They are also working on other approaches to target macrophages without the need for any other treatment.

“We’ve found that macrophages are abundant in almost every kind of cancer, even lymphomas and leukemia,” said Varner. “All of our data shows that this drug could be useful for almost every kind of cancer. Thus far, we’ve tested it in animals and shown its effectiveness in glioblastoma, ovarian carcinoma, breast carcinoma, colon carcinoma, melanoma, lung cancer and head and neck cancer.”