Ovarian cancer: Effective immunotherapy steps closer with new T cell study

At a scientific meeting this week, researchers report some progress in developing an immunotherapy for ovarian cancer. However, they also outline the considerable challenges that remain before the treatment can be made effective for this and other cancers that have solid tumors.

The researchers – from the Fred Hutchinson Cancer Research Center (Fred Hutch) in Seattle, WA – presented the findings at the annual meeting of the American Association of Cancer Research in Washington, D.C.

Estimates from the American Cancer Society suggest that, in the United States, around 22,440 women will be diagnosed with ovarian cancer and approximately 14,000 will die from the disease during 2017.

The cancer begins in cells of the ovaries – reproductive glands found only in women. Each woman normally has two ovaries, situated on each side of the uterus inside the pelvis. The ovaries produce eggs that travel to the uterus through the fallopian tubes. If an egg is fertilized by male sperm, it develops into a fetus.

Dr. Kristin Anderson, an immunotherapy researcher at Fred Hutch who presented the findings at the meeting, says that while ovarian cancer is not as common in the U.S. as other cancers with solid tumors, it has a low rate of survival and a high rate of relapse. The main reason is that the cancer does not cause obvious symptoms and is often advanced by the time it is diagnosed.

Immunotherapy is a relatively new area of medicine that is showing promising results in the treatment of cancer. The approach uses the patient’s own immune system to fight disease.

Adoptive T cell transfer lessons for solid tumors

The new study concerns a method called adoptive T-cell transfer. In this approach, immune cells called T cells are taken from the patient’s own blood and trained to target and destroy cancer cells. Then, after multiplying in the laboratory, the primed cells are returned to the patient’s body. Sometimes donor cells are used instead.

Fred Hutch has several teams researching immunotherapy cancer treatments. In particular, Dr. Anderson and colleagues have reported success in using adoptive T cell transfer to treat blood cancers.

In her meeting presentation, Dr. Anderson reported progress on applying lessons learned from that work to the treatment of solid tumors.

The researchers found that ovarian cancer cells overproduce two proteins – WT1 and mesothelin – and showed that T cells engineered to target them can kill mouse and human ovarian cancer cells in the laboratory.

They also found that the engineered T cells significantly increased survival in a mouse model of ovarian cancer.

However, Dr. Anderson cautions that there is still some way to go before adoptive T cell transfer is ready for clinical trials in human patients.

The team discovered that, compared with treating blood cancers, it is much harder to apply T cell therapy to solid tumors like breast, ovarian, lung, and pancreatic cancers.

In leukemia and lymphoma, the engineered T cells can be infused directly into the bloodstream to target the blood cancer. However, access to solid tumors that are tucked away inside the body poses some major challenges. Among these are issues concerning the tumor microenvironment – a mixture of noncancerous cells, molecules, and extracellular matrix in and around the tumor.

Tumor microenvironment challenges to overcome

Dr. Anderson outlines three particular challenges posed by the tumor microenvironment that they are working on. One is the fact that there are cells and proteins in the tumor microenvironment that send signals to the T cells that tell them to shut down or simply ignore the tumor cells.

The team suggests that there are some existing drugs called checkpoint inhibitors that they could explore to tackle this problem. Another approach could be to engineer the T cells to block these particular signals.

The second challenge is that ovarian tumor cells and neighboring blood vessels send self-destruct signals to the T cells, causing them to commit suicide before they can attack cancer cells.

The Fred Hutch team is already working on a solution to this second challenge in the form of a fusion protein that boosts the T cells’ anticancer activity when they receive these self-destruct signals.

The third challenge that the researchers have identified in the solid tumor microenvironment is the problem of low sugar. To grow as rapidly as they do, ovarian cancer cells devour sugar, which they get from their environment.

However, the engineered T cells also need this sugar to fuel their journey to, and attack on, the cancer cells. The researchers at Fred Hutch are looking for a way to engineer the T cells so that they use a different source of energy.

Dr. Anderson says that while they are currently focusing on ovarian cancer, they believe that these solutions will also help to make progress on using adoptive T cell transfer with other solid tumors.

“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 explains, as she concludes:

“Tumor microenvironment issues come hand-in-hand with working on solid tumors.”

The team hopes to start a human clinical trial of adoptive T cell transfer for ovarian cancer in the next few years.

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