• California’s stem cell agency has awarded $5.8 million to UC San Diego researchers to develop a new variation of cancer immunotherapy.

    The California Institute for Regenerative Medicine, or CIRM, . These deadliest of cancer cells have stem cell-like properties that enable them to survive treatments against them and grow profusely. One surviving cell can re-create an entire tumor.

    , pioneered by Dr. Carl June at the , has been used against blood cancers. While not all of those gravely ill patients have survived, a number have experienced dramatic and long-lasting remissions.

    UC San Diego Moores Cancer Center physicians led by Ezra Cohen will experiment with the therapy to deal with a variety of hard-to-treat solid tumors. These include head and neck squamous cell carcinoma, , pancreatic cancer and ovarian cancers. The preliminary research that yielded this potential treatment was funded by the San Diego-based .

    Here’s how CAR T-cell therapy works: Doctors genetically engineer a patient’s T cells, part of the immune system, to recognize a protein, called an , on cancer cells so they can destroy them.

    The T cells are given what is called a , or CAR. This is an artificial construct that can recognize the antigen on cancer cells, signaling the immune system to attack. The antigen targeted varies with different versions of the technology.

    The T cells are removed from the patient, given the cancer-fighting receptor construct, grown to sufficient numbers, then re-infused into the patient. The cells act as living drugs. They tend to stick around in the patient, ready to grow and attack again if the cancer recurs.

    While this has been demonstrated in blood cancers, solid tumors pose a more difficult problem, because immune cells have more limited access to the interior of these tumors.

    Cohen, associate director for translational science at UC San Diego Moores Cancer Center, is a specialist in head and neck cancer. Among his patients: Ricki Rockett, the drummer from the band Poison.

    Rockett, facing amputation of his tongue when he met Cohen, was given another kind of cancer immunotherapy, two drugs called checkpoint inhibitors that remove a molecular cloak that cancer cells use to hide from the immune system.

     The cancer disappeared, and Rockett’s tongue was saved.

    ”It’s one year after his complete response, and he’s still cancer-free,” Cohen said. Rockett also went on tour with the band.

    Building on past research

    Cohen said the newly funded work with CAR T cells builds on earlier UC San Diego research that identified a receptor on some cancer cells as a promising new target. It’s made in both solid tumors and blood cancers, but not in normal cells.

    The receptor, tyrosine kinase-like orphan receptor or ROR1, is the target of a drug now being tested by Cohen’s colleague Dr. Thomas Kipps in patients with relapsed or refractory chronic lymphocytic leukemia. The drug, a monoclonal antibody called , is named after CIRM, which funded the research that produced the drug.

    ROR1 is produced almost exclusively in the embryonic and early fetal stage, and helps the nascent tissues migrate to the right parts of the body, Cohen said. It appears to have virtually no use after that stage. So it appears to be a safe target. That’s been a challenge to find with cancer stem cells, because their genetic activity somewhat resembles that of normal stem cells.

    “For obvious reasons you don’t want to eliminate all the stem cells in a person’s body,” Cohen said.

    There’s some hints ROR1 might be produced in certain precursors to B cells, which are immune cells that make antibodies, he said. It’s possible to live without B cells, as in the case where drugs destroy B cells to stop B-cell lymphoma.

    The new project was sparked by Kipps’ research indicated that ROR1 was produced in high amounts in the hard-to-treat cancers. Cohen began thinking of how this knowledge could be applied with CAR T-cell technology

    Cohen said preclinical research has already been performed for the new project. In cell culture tests, CAR T cells with the ROR1 receptor kill cancer stem cells with the receptor in those difficult cancers.

    Funding for that research came from , created by San Diego philanthropists Ralph and Fernanda Whitworth in 2015 after Ralph Whitworth was diagnosed with cancer. .

    Christina Martinez, the Immunotherapy Foundation’s executive director, said Whitworth met with Cohen after his diagnosis, and became personally interested in advancing the research.

    “It was a serendipitous encounter, but he really saw the potential for a lasting partnership in his ability to be able to make a long-term contribution to the area of immunotherapy,” Martinez said. “This project was just one that fell under kind of an umbrella of projects that he was interested in and funding at UCSD. So he and Fernanda seeded that initial investment.”

    Results maturing

    To further improve cancer immunotherapy, the Whitworths established the Immunotherapy Foundation. Fernanda Whitworth, president and co-founder, said she’s pleased with the progress.

    “Ralph and I liked that these projects were designed to be tightly interconnected to leverage information and allow efficient movement into the clinic,” she said. “Today, I am proud to see this rational, focused approach is working.”

    Aside from his work at the Moores Cancer Center, Cohen is co-director of the San Diego Center for Precision Immunotherapy, a collaboration with the La Jolla Institute for Allergy and Immunology.

    Cohen said the new CIRM grant will fund work to generate more data on safety and efficacy needed before the therapy can be tried in people.

    CIRM was created in 2004 by California voters with $3 billion in funding to accelerate stem cell research and treatments. UC San Diego researchers have received at least 95 CIRM awards, totaling more than $177 million.

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