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.
Fred Hutchinson Cancer Research Center immunotherapy researchers Drs. Kristin Anderson and Phil 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 Tuesday at the annual meeting of the American Association of Cancer Research in Washington, D.C., Anderson described her preclinical results working toward T-cell therapy for ovarian tumors — and the hurdles any clinical version of this therapy will need to overcome. To date, the therapies Anderson and her colleagues are developing have only been tested in mice and in mouse and human cells in the lab.
Developing T-cell therapy for solid tumors is more challenging than for leukemias and lymphomas, Anderson said, but many patients with these cancers are in desperate need of new treatment options. The top five cancer killers in the U.S. are all solid tumors, according to the American Cancer Society. Although ovarian cancer is less common in the U.S. than other solid cancers, it’s highly deadly — it tends to be diagnosed at late stages, in part because it often doesn’t cause obvious symptoms, and it has a high relapse rate, Anderson said.
“All of these are huge problems,” she said. An estimated 22,000 women in the U.S. are diagnosed per year with the disease, according to the ACS, and approximately 14,000 die of the cancer.
The challenges of T-cell therapy for cancers like ovarian cancer include 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. Another 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.
“Tumor microenvironment issues come hand-in-hand with working on solid tumors,” said Anderson, who is one of 10 recipients of this year’s AACR Women in Cancer Research Scholar Awards, a travel award given to female early-career cancer researchers presenting at the meeting.
She 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.
In her presentation, Anderson outlined three types of tumor microenvironment 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 heading 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 to instead boost their anti-tumor activity in response to the death signal.
• 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 [the solutions] to cancers that have fewer of these hurdles,” she said.
The researchers are hoping to launch a clinical trial of the engineered T cells for patients with ovarian cancer in the next few years, Anderson said.
Paying it forward
For Anderson, the work is not just academic. Five years ago, while she was completing her doctorate research, Anderson was diagnosed with triple negative breast cancer when she was just 28. After her diagnosis, she learned she carried a mutation in the breast cancer–linked gene BRCA1, a mutation which also increases her risk for ovarian cancer.
An immunologist by training, Anderson’s own experience with cancer spurred her to look for research opportunities where she could one day have a direct impact on other cancer patients. She wasn’t particularly looking to study breast or ovarian cancer, she said, but she was very interested in the burgeoning field of immunotherapy. It seemed a prime research area where she could use her background to make a difference.
When Anderson met with Greenberg, who’s long been a leader in the field of T-cell therapy, to discuss research options for her postdoctoral fellowship, he proposed the ovarian cancer project to her. Anderson jumped at the chance.
“Someone did a lot of research to come up with the drug that got rid of my cancer. Part of the reason that I wanted to go into cancer therapy was so I could pay it forward and do that for someone else,” she said. “It just so happened coincidentally to be [a cancer] that is close to my heart.”