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The oncology world achieved an incredible gain last month, when the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) unanimously recommended approval of Novartis’ CTL019 (tisagenlecleucel), a groundbreaking chimeric antigen receptor T cell (CAR-T) therapy for the treatment of relapsed or refractory pediatric lymphoblastic leukemia (ALL).

This investigational therapy gained global attention in 2012 after successfully treating a pediatric ALL patient, seven-year-old Emily Whitehead, who had a resistant, life-threatening form of the disease. After facing two relapses and showing no response to chemo and radiation, Emily became the first pediatric patient to use the experimental therapy. Three weeks after receiving the treatment she was in remission and has been ever since.

The therapy involves removing T-cells from the patient and genetically engineering them to produce “Chimeric Antigen Receptors” on the surface of the T cells (“CAR-T cells”) that recognize a specific antigen on tumor cells and attack them. Once infused back into the patient’s body, the altered T cells actually multiply, travel all through the body, and will find and kill the cancer cells that harbor the antigen on their surfaces, and will remain in the patient ready to attack if the cancer returns.  In this case the antigen is CD19, but in the future, many other antigens could be used to kill other kinds of cancer.

A new era for oncology

This is the first recommended approval for a CAR-T therapy, and it has enormous implications for oncology research. Unlike precision medicines, which are targeted therapies that attack very specific tumor mutations, CAR-T therapies could conceivably be engineered to address all types of cancers.

The recommended approval is likely to generate a flood of new CAR-T products, first in other leukemias and lymphomas, then targeting other tumor antigens, including BCMA (found on all Multiple Myeloma cancer cells), CD20, CD30, and others. Along with Novartis, Kite Pharma, Juno Therapeutics, and researchers at the First Affiliated Hospital of Zhejiang University in China, have also shown positive results in trials of CAR-T therapies, and many more are likely to follow. This first generation of CAR-T therapies have focused on hematologic or liquid tumors, which are more accessible, though over time researchers will likely find ways to engineer versions of CAR-T therapy that can attack solid tumors and other kinds of molecular target antigens.

These approvals will also likely begin to move up the sequence of treatment for certain cancers. Currently Novartis’ therapy is only approved as a last resort in the most desperately ill patients who have failed all other therapies. But as these therapies generate results, and physicians are better able to manage and minimize negative side effects, these or similar CAR-T products will be used earlier in the natural progression of the disease, and eventually may become a “first line” option for ALL, instead of chemotherapy or Bone Marrow Transplant, which is unpleasant, dangerous, and has long term complications.

There are still risks

However for CAR-T therapies to become a primary first line of defense for cancer patients, there are still obstacles to overcome, including rare, dangerous and sometimes fatal side effects. The most common serious side effect is cytokine-release syndrome (CRS), which leads to high fevers, joint pain, and a dramatic drop in blood pressure. In some cases, these side effects are mild enough to be managed, however about three-quarters of the patients who experience CRS require admission to an intensive care unit.

Researchers have found that treatments for inflammatory conditions like juvenile arthritis can ease the symptoms of CRS in response to CAR-T cell therapy, however these treatments are very expensive and thus only used reactively. Another solution could come from Bellicum Pharmaceuticals, which is exploring use of its Chemical Induction of Dimerization (CID) technology as a complimentary “safety-switch” to reduce the activity of the CAR-T cells, when needed to protect the patient.

The need for customization of each treatment also causes some industry leaders to argue that CAR-T therapy will be too expensive to use as a first line treatment. There are also concerns about the ability to safely handle the logistics of custom engineering each patients’ cells. But these are common problems that often arise with any groundbreaking therapy – or other innovations.  Over time the ability to generate efficiencies in the engineering and logistics process will likely drive down costs while demonstrating the ability to safely manage and monitor patients’ cells throughout the treatment lifecycle.

These are obstacles that can be overcome. As newer and more complicated CAR-T products are designed and tested, these treatments will become safer and easier to manufacture and more effective over time.

We may still be years away from seeing CAR-T therapy as a first line of defense in all cancers, but this historic approval paves the way. This may be “the first” CAR-T to win FDA support but it will certainly not be the last.