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By Lee Greenberger, PhD, Chief Scientific Officer, The Leukemia & Lymphoma Society  |  Aug 19, 2020

The Evolution of CAR-T Therapy

Over the past two decades there’s been tremendous progress in understanding how to harness the body’s immune system to fight cancer. Today, immunotherapy is a mainstay of cancer treatment. One of the most exciting areas of immunotherapy is CAR (chimeric antigen receptor) T-cell therapy. This treatment involves purifying a special type of white blood cell, called a T cell, which is isolated from a cancer patient’s blood and then genetically engineering in the laboratory to find and kill cancer cells. Once complete, the re-programmed T cells are reintroduced to the patient’s body to fight their cancer. It’s now very clear that this method works!

Early CAR T Development

Lee Greenberger

Lee Greenberger, PhD, The Leukemia & Lymphoma Society

The first CAR T cells were created more than 30 years at the Wiezmann Institute of Science in the laboratory of Dr. Zelig Eshhar.  It took more than two decades to learn how to super-activate the CAR T cells, mass produce them and understand how to use them to control cancer. The Leukemia & Lymphoma Society (LLS) recognized the great promise of this treatment for blood cancer patients and has been supporting research and development of CAR T cells since the 1990s. LLS has awarded grants to many researchers dedicated to immunotherapy including Dr. Carl June of the University of Pennsylvania, who is considered a pioneer of immunotherapy. The nonprofit not only funded research and development in academic laboratories, but used its venture philanthropy effort, known as the Therapy Acceleration Program (TAP), to partner with industry to speed up the clinical development of CAR T-cell therapy for blood cancer patients.

LLS’s investment of more than $50 million in cutting-edge gene therapies for blood cancer patients has yielded tremendous returns in progress. Tisagenlecleucel, the first-ever CAR T-cell therapy approved by the U.S. Food & Drug Administration (FDA) in 2017, was developed by Dr. June and his team with LLS support. This ground-breaking treatment is used to treat pediatric and young adults patients with B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma, (DLBCL), the most common type of non-Hodgkin lymphoma (NHL), and several more rare types including primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma or tFL).

Axicabtagene ciloleucel is approved for the treatment of certain lymphomas.  The clinical results have been stunning.  When used in many cancer patients who have relapsed or did not respond to all other therapies, CAR T-cell therapy has eliminated the disease for years after a single dose of cells.  Nevertheless, CAR T-cell therapy does have significant, but manageable side-effects (most are transient) that require careful monitoring.

Supporting CAR-T Research

LLS continues to support scientists dedicated to advancing CAR-T including Dr. June and his team as they work to develop CAR-T targeting a different molecule, CD38, to work on different blood cancers including adult and pediatric acute myeloid leukemia (AML), T-cell ALL and multiple myeloma.

Significant progress has been made in CAR-T for myeloma targeting the B-cell maturation antigen (BCMA), which is close to FDA approval. LLS is also supporting new work at Dr. Mahdav Dhodapkar at Emory University to further improve BCMA CAR T-cell therapy. Plus, there is convincing clinical data for the use of CAR-T to treat two other types of lymphoma – follicular and mantle cell – that will support FDA filings for approval in the near future.

Safe, Effective Treatment

The next generation of CAR T-cell therapy is focusing on making the treatment safer, more effective, less costly, and accessible to patients with other types of cancers. Expanding on its original concepts, innovations in development will propel CAR-T to new levels. And there are exciting breakthroughs on the horizon – LLS is funding new work under the guidance of Dr. Renier Brentjens (Memorial Sloan Kettering Cancer Center) to develop “armored” CARs – a two-pronged approach to unleashing a patient’s immune system to fight cancer, which will not only target cancer cells, but will release a chemical that knocks out proteins that block the immune system from activating. Off-the-shelf CAR-T, where the T cells can be reprogrammed from healthy donors and used immediately as needed, promises to be less costly and labor-intensive option for patients. In this case, scientists are working to remove the mechanism that will cause donor T cells to attack a patient’s own cells.

Beyond blood cancer, the future of CAR T-cell therapy is promising. Multiple studies are under way to target cancers of the brain, lung, breast and other solid tumors. Laboratory studies have also demonstrated that CAR T-cell therapy can be used to control cardiac fibrosis and other inflammatory diseases in mice. In short, the full potential of CAR T-cell therapy has yet to be realized.

About the Leukemia & Lymphoma Society

The Leukemia & Lymphoma Society® (LLS) is a global leader in the fight against cancer. The LLS mission: cure leukemia, lymphoma, multiple myeloma, and improve the quality of life of patients and their families. LLS funds lifesaving blood cancer research around the world, provides free information and support services, and is the voice for all blood cancer patients seeking access to quality, affordable, coordinated care. Founded in 1949 and headquartered in Rye Brook, NY, LLS has chapters throughout the United States and Canada. To learn more, visit www.LLS.org. Patients should contact the Information Resource Center at (800) 955-4572, Monday through Friday, 9 a.m. to 9 p.m., ET.

About the Author

As the chief scientific officer of The Leukemia & Lymphoma Society (LLS) since 2013, Dr. Lee Greenberger is responsible for planning and executing the strategy for all LLS research programs. This effort includes a grant portfolio with more than 250 active research projects worldwide, as well as the Therapy Acceleration Program, a venture philanthropy initiative currently with 16 assets – three of which have earned FDA-approval in the past two years. Dr. Greenberger holds a BA from the University of Rochester and a Ph.D. from Emory University.

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