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CAR-T: The Designer Tumor Therapy Frontier

Dec 4, 2017 8:00:25 AM / by Stacy Matthews Branch, DVM, PhD

 Cancer immunotherapy research concept cancer gene therapy with cancer cell and test tubePersonalized medicine is taking new and powerful forms in the field of immunotherapy. The technology behind making customized tumor-destroying cells, thought of not long ago as science-fiction, is now a reality. [1,2] Chimeric Antigen Receptor T cells, or CAR-T cells, are designer, precision built personal immunotherapeutic agents that target an individual’s tumor. The use of CAR-T cells is a means of using the body’s own immune system arsenal to attack cancer cells.

CAR-T cells have the specificity of antibodies, combined with the toxicity and memory capacity of T cells. To create this novel therapeutic, a patient’s own T cells are collected, then genetically modified to express patient tumor-antigen–specific receptors on their outer surface. These modified cells are expanded until their numbers are sufficient to mount a strong immune response, at which point they are injected back into the patient. The CAR-T cell strategy doesn’t stop at the cell surface level, however. These “designer” cells are also modified to incorporate internal activation domains, which direct the T cells to activate and launch their attack once they bind to the tumor targets.

The exciting and promising remission rates, over 90% in some cases, are not without some drawbacks. Neurotoxic effects and even mortality in some CAR-T trials have obliged scientists to rethink and modify the technology to strive for better safety profiles. For example, UCART19 is a CAR-T therapeutic that is only activated in the presence of the drug rapamycin, while a similar CAR-T cell therapy, GoCAR-T, is activated in the presence of rimiducid. Another approach to built-in safety precautions is the use of CAR-T therapy in combination with checkpoint inhibitors [3]. Checkpoint inhibitors are drugs which overcome the mechanisms used by tumor cells to circumvent, or hide from the immune system.

There is a catch to this fascinating new therapy. It takes several weeks to generate treatment-ready CAR-T cells, and due to very high development costs, it is considerably expensive. One answer to this dilemma is to have cells that can be stored and accessed when needed, in other words, “off-the-shelf” CAR-T cells. These are cells obtained from healthy donors that are at least partially prepared ahead of time, then stored in a frozen state. Such cells could then be thawed as needed for more immediate application. HemaCare is working with many CAR-T collaborators and understands that developing commercialized therapies using this type of approach will necessitate having a reliable/recallable donor pool; using healthy donors instead of patients for starting material will allow medical personnel to quickly generate a sufficient number of cells for each treatment.

At present, the US FDA has only approved CAR-T cell therapy for the treatment of some types of adult B-cell lymphoma, but applications for the technology are ever-growing. Future CAR-T cell therapeutics will no doubt provide wider patient population options, and hope where none has previously existed.
References:

[1] FDA approves gene therapy to treat a rare cancer. Science News. August 30, 2017.

https://www.sciencenews.org/blog/science-ticker/fda-approves-gene-therapy-treat-rare-cancer

[2] Beavis PA, et al. A Novel Target Antigen for the Treatment of Acute Myeloid Leukemia by CAR T Cells. Molecular Therapy. 25(9), 1997–1998. September 6, 2017.

[3] Immune checkpoint inhibitors to treat cancer. American Cancer Society. May 2017.

https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html

Topics: Cancer Immunology, cancer immunotherapy, CAR-T, car

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