A new twist on immunotherapy

Research team reports on a method for altering B cells to create a new anticancer weapon

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SAN DIEGO—New advances at the University of California, San Diego (UCSD) School of Medicine suggest that the manipulation of B cells can be harnessed to create tumor-suppressing microRNAs to battle specific cancers. In a new twist to traditional immunotherapy, the novel methodology works from inside the cell to arrest tumor growth. Results of their research using lab testing and mouse experiments were published in the December 4 issue of Scientific Reports.
B cells, also known as B lymphocytes, are a type of white blood cells that secrete antibodies, antigens and cytokines to boost the immune system. B cells activate when they encounter foreign antigens on the outside of bacteria cells during an infection. These cells then differentiate into antibody-producing plasma cells, which produce antibodies, or microRNAs, that attach to the surface of foreign agents. While scientists have known for decades that B cells produce the antibody microRNAs (also called miRNAs), the UCSD team was exploring how they could drive them to create very specific miRNAs.
“This is the tradition of the laboratory,” said senior author Dr. Maurizio Zanetti, professor of medicine at the UC San Diego School of Medicine and head of the Laboratory of Immunology at the UC San Diego Moores Cancer Center. “We knew that B cells are easy to manipulate, and so we started with an initial ambitious goal: can we instruct the them to make the exact miRNA we want? Can we regulate immunity?”
Traditional immunotherapy relies on two other classes of lymphocytes, T cells and natural killer cells, which target cells from the outside. T cells recognize antigens on the surface of a cancer cell, which triggers an immune response to try and kill the cell. While advances in immunotherapy have been dramatic, it doesn’t work for everyone, and some types of immunotherapy can cause serious side effects. In this new approach, the researchers are utilizing the B cells to fight the disease from inside the cell—slowing, stopping and sometimes even reversing the internal processes of the cancer cells.
“Once further developed, we envision this method could be used in situations where other forms of immunotherapy don’t work,” noted Zanetti. “The advantages are that this type of treatment is localized, meaning potentially fewer side effects. It’s long-lasting, so a patient might not need frequent injections or infusions. And it would likely work against a number of different tumor types, including breast cancer, ovarian cancer, gastric cancer, pancreatic cancer and hepatocellular carcinoma.”
In the study, Zanetti and his team used miR-335, a microRNA that specifically dampens SOX4, a transcription factor that promotes tumor growth. They added a miR-335 precursor to B cells in the lab, which spurred the cells to convert the precursor into mature, active miR-335 and package it into membrane-coated vesicles that bud off from the cell. Each B cell can produce 100,000 miR-335-containing vesicles per day—enough to treat 10 cancer cells.
“We were surprised to find that even small changes in cancer cell gene expression after miR-335 treatment were associated with specific down-regulation of molecules key to tumor growth,” commented study co-author Dr. Hannah Carter, assistant professor of medicine at UC San Diego School of Medicine.
The researchers initially targeted human breast cancer cells with miR-335-containing vesicles and transplanted the cancer cells to mice. After 60 days, 100 percent (five out of five) of the mice with mock-treated cancer cells had large tumors. In contrast, 44 percent (four of nine) of the mice with miR-335 vesicle-treated cancer cells had tumors. On average, the tumors in the treated mice were more than 260 times smaller than those in the mock-treated mice (7.2 vs. 1,896 mm3). And the treatment was long-lasting—miR-335 levels were still elevated in the treated mice 60 days after the vesicles and cancer cells were transplanted.
According to Zanetti, the next step for this research is to find cancers that are most susceptible to miRNAs and develop the capacity to attach the vesicles in an extremely targeted way. It is not enough, he asserts, to produce the miRNAs—they will focus on getting it to the right location. The team envisions two potential mechanisms for the therapy: harvesting vesicles from B cells in a lab and administering them as they did in this study, or administering the B cells themselves.
“I think harvesting the vesicles is a better solution,” remarked Zanetti. “B cells are quite fragile, while the vesicles are more durable. Injecting the vesicles is a more stable process, allowing more time for us to work, and thus, more precision in getting the reagent as close to a tumor as possible. Ideally, in the future we could test patients to see if they carry a deficiency in miR-335 and have an overabundance of SOX4. Then we’d treat only those patients, cases where we know the treatment would most likely work. That’s what we call personalized, or precision, medicine. We could also apply this technique to other microRNAs with other targets in cancer cells and in other cell types that surround and enable tumors.”

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