Tumor microenvironment poses unique challenges for effective ovarian cancer T-cell therapy

Fred Hutchinson Cancer Research Center immunotherapy researchers Drs. Kristin Anderson and Philip Greenberg and their colleagues are working on ways to tweak their team's early successes with T-cell therapy for leukemia to apply to solid tumors.

In a presentation on April 4 at the annual meeting of the American Association of Cancer Research in Washington, D.C., Anderson will describe preclinical research on T-cell therapy for ovarian tumors and the particular tumor microenvironment factors that any clinical version of this therapy will need to take into account.

For some patients, certain forms of immunotherapy are showing promise in treating previously difficult-to-treat cancers. In the case of T-cell therapies, though, most of the early experimental successes have been seen in blood cancers. Solid tumors, like breast, lung, ovarian and pancreatic cancers, pose a tougher nut to crack for this new wave of cancer therapies.

There are a number of additional hurdles T-cell therapy has to overcome to reach these cancers, which kill more people in the U.S. than blood cancers, according to the American Cancer Society. There's the simple issue of access — patients with leukemia or lymphoma can receive an infusion of engineered T cells directly into their bloodstream, but it can be more difficult to tweak the cells to traffic to a tumor tucked away in the body. A major roadblock to adopting T-cell therapy to solid tumors is what's known as the tumor microenvironment, the local milieu of non-cancerous cells and molecules in and around the tumor.

Anderson and her colleagues have identified proteins overproduced by ovarian cancer cells, known as WT1 and mesothelin, and have found that T cells engineered to specifically recognize these proteins can kill both human and mouse ovarian cancer cells in the lab. They've also found that the T cells significantly extend survival in a mouse model of the cancer, but there's a ways to go before this therapy is ready for clinical trials in humans, Anderson said.

"Tumor microenvironment issues come hand-in-hand with working on solid tumors," she said.

In her presentation, Anderson will describe three types of roadblocks to an effective ovarian cancer T-cell therapy — and how the research team is working to overcome each. They are:

•Immunosuppressive cells and proteins in the microenvironment that can signal the engineered T cells to shut down or ignore tumors. Existing checkpoint inhibitor drugs could circumvent this problem, Anderson said, and the Fred Hutch team is also exploring engineering the therapeutic T cells to block those immunosuppressive signals.
•A "death signal" produced by both ovarian tumor cells and nearby blood vessels on their surfaces. This molecular signal causes T cells coming to the tumor from the bloodstream to commit suicide before they can fight the cancer. Dr. Shannon Oda in the Greenberg lab is working on a new type of fusion protein the engineered T cells will carry that will rewire their internal circuitry, causing the death signal to instead boost their anti-tumor activity.
•The tumors' low-sugar environment. Fast-growing ovarian cancer cells churn through the glucose in their environment — the same energy source engineered T cells need to do their work. Researchers in the Greenberg lab are working to re-engineer the therapeutic T cells to process other sources of energy.

Although her current work focuses on ovarian cancer, a particularly difficult-to-treat solid tumor, Anderson hopes the work will shed light on new therapeutic avenues for other solid tumors as well.

"If we can solve some of the issues that really plague us with these hard ones, then we can more readily apply them to some of the cancers that have fewer of these hurdles," she said.​