Researchers at the Weizmann Institute of Science announced Tuesday they have discovered, in a world first, that specialized immune cells known as memory B cells can recognize and attack ovarian cancer tumors.

Ovarian cancer is the deadliest gynecological cancer worldwide, with a five-year survival rate below 50 percent.

The peer-reviewed study, conducted in Prof. Ziv Shulman’s lab in Weizmann’s Department of Systems Immunology, challenges the scientific assumption that immune memory B cells only respond to external invaders such as viruses and bacteria.

The research, led by Dr. Nachum Nathan, appeared in Immunity. It identified memory cells that zeroed in on ovarian tumors and produced effective antibodies against them.

The findings pave the way for the development of vaccines and therapies that harness immune memory to fight cancer.

“If we suggest that there are memory cells, antibody-forming cells that remember the tumor, and we can activate them with a vaccine, then we can make cancer vaccines that stimulate these cells,” said Shulman, who supervised the research. “I’m very excited. It’s a new idea, a totally new approach to vaccines for cancer patients.”

Ovarian cancer

Contrary to what was formerly believed, scientists now recognize that the most common ovarian cancer, high-grade serous ovarian carcinoma, or HGSOC, does not begin in the ovaries but in the fallopian tubes close to the ovaries, Shulman explained.

Inherited BRCA1 and BRCA2 gene mutations are the most significant known risk factors for ovarian cancer. Jewish women of Ashkenazi descent face a significantly higher lifetime risk of developing ovarian cancer since they are about 10 times more likely to carry these faulty genes than the general population.

When there is a mutation in the BRCA gene, it can no longer produce the essential proteins needed to repair cellular DNA damage, thereby triggering aggressive tumor growth.

Currently, there is no reliable screening test to diagnose ovarian cancer, and a cervical cancer smear test, or a Pap test, cannot detect it.

Its symptoms, which include persistent abdominal bloating and pelvic pain, are often confused with less severe illnesses. Most women are diagnosed only after the cancer has already advanced and spread.

There were 492 new cases of ovarian cancer in Israel in 2022, and 353 deaths from the disease, according to World Health Organization statistics.

Enhancing the immune system to kill cancer cells

“I’m an immunologist, I’m not a cancer guy,” Shulman said of his research, adding that he studies B cells and antibody-mediated immune responses to pathogens and infectious diseases.

“This is my expertise, what I know how to do best,” Shulman said.

He said he went into cancer research from the field of “studying the B cell and antibody side, rather than from the cancer side.”

“I want to understand how we can boost the immune system to allow it to enhance its ability to kill tumor cells, and this is what we do with immunotherapy,” Shulman said.

He started studying the role of B cells fighting cancer in 2015 on a hunch.

“Back then, people were more interested in T cells,” another form of lymphocytes that fight cancer, Shulman said. “Nobody really cared about B lymphocyte cells,” a type of white blood cell that tracks down and destroys cancer cells.

However, Shulman was still intrigued. When a physician whose mother died from ovarian cancer came to do a PhD in his lab, “he only wanted to study ovarian cancer, so we got to work,” Shulman said.

“We found that B cells infiltrate tumors and produce antibodies against cancerous ovarian tumors,” Shulman said.

He published a study to that effect in 2022.

In the most recent study, the research team analyzed samples collected from 11 patients with the most common type of ovarian cancer, HGSOC, in collaboration with Prof. Ram Eitan and Dr. Oded Raban from Rabin Medical Center.

They looked for B cells in the lymph node and tumor of the same patient.

“Each cell has its own unique antibody with its own sequence. It’s like a barcode,” Shulman said. “We found the same barcode in both the lymph node and the tumor.”

This means, he said, that they both had the same ancestor, which “gave rise to these cells, perhaps in the lymph node, and then the cells migrated and moved to the tumor.”

This provides “very strong evidence” that memory cells can move from the lymph node to the tumor, secreting antibodies that can be beneficial to the patient, he said.

The researchers produced the antibodies artificially in the lab.

“We were amazed to find that more than a third of these antibodies bound strongly to ovarian cancer cells,” Shulman said. “The memory cells can be a targeted weapon against ovarian cancer. This is something that nobody ever did before.”

Immunotherapy, which harnesses the immune system to fight cancer, “has transformed oncology and shown major success in many cancer types, but in ovarian cancer it has so far been only minimally effective,” said Dr. Ruth Perets, head of early phase clinical trials and the Women’s Cancers Research Lab at the Rambam Health Care Campus in Haifa.

Perets was not involved in the study.

She said that Shulman’s latest research “shows that ovarian cancer patients naturally produce B lymphocytes that can recognize their tumors, but these cells remain inactive. These findings suggest that in the future, activating these naturally occurring anti-cancer B lymphocytes could offer a new and potentially effective immunotherapy strategy for ovarian cancer.”

Shulman said that he hopes the next step will be clinical trials for a B lymphocyte vaccine.

“This puts a new therapeutic option out there for people to use in clinical trials,” he said.

Story by:  Diana Bletter | Times of Israel