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CAR-T

Fighting Cancer with Next-Gen Cell Engineering

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Kole Roybal
Credit: Susan Merrell

Researchers continue to make progress with cancer immunotherapy, a type of treatment that harnesses the body’s own immune cells to attack cancer. But Kole Roybal wants to help move the field further ahead by engineering patients’ immune cells to detect an even broader range of cancers and then launch customized attacks against them.

With an eye toward developing the next generation of cell-based immunotherapies, this synthetic biologist at University of California, San Francisco, has already innovatively hacked into how certain cells communicate with each other. Now, he and his research team are using a 2018 NIH Director’s New Innovator Award to build upon that progress.

Roybal’s initial inspiration is CAR-T therapy, one of the most advanced immunotherapies to date. In CAR-T therapy, some of a cancer patient’s key immune cells, called T cells, are removed and engineered in a way that they begin to produce new surface proteins called chimeric antigen receptors (CARs). Those receptors allow the cells to recognize and attack cancer cells more effectively. After expanding the number of these engineered T cells in the lab, doctors infuse them back into patients to enhance their immune systems’s ability to seek-and-destroy their cancer.

As helpful as this approach has been for some people with leukemia, lymphoma, and certain other cancers, it has its limitations. For one, CAR-T therapy relies solely on a T cell’s natural activation program, which can be toxic to patients if the immune cells damage healthy tissues. In other patients, the response simply isn’t strong enough to eradicate a cancer.

Roybal realized that redirecting T cells to attack a broader range of cancers would take more than simply engineering the receptors to bind to cancer cells. It also would require sculpting novel immune cell responses once those receptors were triggered.

Roybal found a solution in a new class of lab-made receptors known as Synthetic Notch, or SynNotch, that he and his colleagues have been developing over the last several years [1, 2]. Notch protein receptors play an essential role in developmental pathways and cell-to-cell communication across a wide range of animal species. What Roybal and his colleagues found especially intriguing is the protein receptors’ mode of action is remarkably direct.

When a protein binds the Notch receptor, a portion of the receptor breaks off and heads for the cell nucleus, where it acts as a switch to turn on other genes. They realized that engineering a cancer patient’s immune cells with synthetic SynNotch receptors could offer extraordinary flexibility in customized sensing and response behaviors. What’s more, the receptors could be tailored to respond to a number of user-specified cues outside of a cell.

In his NIH-supported work, Roybal will devise various versions of SynNotch-engineered cells targeting solid tumors that have proven difficult to treat with current cell therapies. He reports that they are currently developing the tools to engineer cells to sense a broad spectrum of cancers, including melanoma, glioblastoma, and pancreatic cancer.

They’re also engineering cells equipped to respond to a tumor by producing a range of immune factors, including antibodies known to unleash the immune system against cancer. He says he’ll also work on adding engineered SynNotch molecules to other immune cell types, not just T cells.

Given the versatility of the approach, Roybal doesn’t plan to stop there. He’s also interested in regenerative medicine and in engineering therapeutic cells to treat autoimmune conditions. I’m looking forward to see just how far these and other next-gen cell therapies will take us.

References:

[1] Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors. Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, Thomson M, Lim WA. Cell. 2016 Feb 11;164(4):780-91.

[2] Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors. Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, Walker WJ, McNally KA, Lim WA. Cell. 2016 Oct 6;167(2):419-432.e16.

Links:

Car-T Cells: Engineering Patients’ Immune Cells to Treat Cancers (National Cancer Institute/NIH)

Synthetic Biology for Technology Development (National Institute of Biomedical Imaging and Bioengineering/NIH)

Roybal Lab (University of California, San Francisco)

Roybal Project Information (NIH RePORTER)

NIH Support: Common Fund; National Cancer Institute


FDA Approves First CAR-T Cell Therapy for Pediatric Acute Lymphoblastic Leukemia

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Emily Whitehead

Caption: Cancer survivor Emily Whitehead with her dog Lucy.
Credit: Emily Whitehead Foundation

Tremendous progress continues to be made against the Emperor of All Maladies, cancer. One of the most exciting areas of progress involves immunotherapy, a treatment strategy that harnesses the natural ability of the body’s own immune cells to attack and kill tumor cells. A lot of extremely hard work has gone into this research, so I was thrilled to learn that the Food and Drug Administration (FDA) just announced today its first approval of a promising type of immunotherapy called CAR-T cell therapy for kids and young adults with B-cell acute lymphoblastic leukemia (ALL)—the most common childhood cancer in the U.S.

ALL is a cancer of white blood cells called lymphocytes. Its treatment with chemotherapy drugs, developed with NIH support, has transformed ALL’s prognosis in kids from often fatal to largely treatable: about 90 percent of young patients now recover. But for those for whom the treatment fails, the prognosis is grim.

In the spring of 2012, Emily Whitehead of Philipsburg, PA was one such patient. The little girl was deathly ill, and her parents were worried they’d run out of options. That’s when doctors at Children’s Hospital of Philadelphia gave Emily and her parents new hope. Carl June and his team had successfully treated three adults with their version of CAR-T cell therapy, which is grounded in initial basic research supported by NIH [1,2]. Moving forward with additional clinical tests, they treated Emily—their first pediatric patient—that April. For a while, it was touch and go, and Emily almost died. But by May 2012, her cancer was in remission. Today, five years later, 12-year-old Emily remains cancer free and is thriving. And I’ve had the great privilege of getting to know Emily and her parents over the last few years.