In 2012, seven-year-old Emily Whitehead became an unsuspecting celebrity in the world of oncology research. She had already been fighting acute lymphoblastic leukemia (ALL) for more than a year, and her prognosis was grim. She had a disease type resistant to most intense chemotherapy regimens, and had already relapsed twice. There were no other treatments available that had any possibility of controlling her disease. As a last effort, Emily’s physician enrolled her in an ongoing clinical trial that had already enrolled adult patients at Children’s Hospital of Philadelphia (CHOP). She was the first pediatric patient in the trial, using an experimental T-cell therapy for B-cell Acute Lymphoblastic Leukemia (ALL) patients who were resistant to, or relapsed after, the usual chemotherapeutic treatments.

Three weeks after receiving the treatment she was in remission, and has been ever since.

Emily is inspiring example of the revolutionary impact that Chimeric Antigen Receptor T-Cell Therapy (CAR T) is having in the fight against cancer, and has received so much attention lately in the public media. The therapy involves removing T-cells from the patient and genetically engineering them to produce CAR receptors that recognize a specific antigen on tumor cells and can therefore attach to cancer cells and kill them. Once infused back in the patient’s body, the altered T-cells can kill the cancer cells that have that specific antigen on their surfaces; and in this process of killing cancer cells, generate circulating factors that cause these T cells to further grow in numbers. The CAR-T cells are a “living therapy” that will expand its own numbers until it has destroyed all tumor cells, then decrease to a low background population, but persist in the patients, and prevent any future regrowth or relapse of the tumor in the future. This is similar to getting “immunized” against a bacterial or viral illness. The patient has become “immunized” against a recurrence of their deadly leukemia.

When it works, the impact is astonishing. In the CHOP trial, conducted by Novartis sponsorship in collaboration with researchers from the University of Pennsylvania, all signs of cancer disappeared (a complete response) in 27 of the 30 ALL patients treated. And unlike “molecular targeted” oncology treatments that may only work on a very specific genetic mutation in one type of cancer, CAR-T cell therapy may become much more generally applicable. Although most effective now in a kind of B cell leukemia, the technique is now being extended to clinical trials in other kinds of leukemias and lymphomas, and also to “solid” tumors such as lung, brain, liver, sarcomas, etc.  Because the therapy focuses on “redesigning” the patient’s own immune system to fight cancer cells, rather than killing a tumor cell directly, they may be designed to work against multiple types of cancers.

Deadly side effects

But it’s not (yet) a perfect solution. One of the biggest challenges with CAR-T cell therapy is the dangerous, and sometimes fatal, side effects that occur with the treatment. The most common serious adverse event is Cytokine Release Syndrome (CRS), where a massive release of cytokines into the bloodstream leads to high fever, joint pain, respiratory problems, or a dramatic drop in blood pressure. In some cases, these side effects are mild; however about three-quarters of the patients who experience CRS require admission to an intensive care unit. The research team at CHOP noticed that CRS severity was correlated with higher blood levels of IL-6, and that this inflammatory interleukin might be causing most of the symptoms. Also they noted that CRS was actually a sign that the therapy was working to kill cancer cells.

Therefore, researchers are looking for ways to treat or avoid the CRS without interfering with the therapy itself. The Penn researchers were the first to try tocilizumab (Actemra®), a specific blocker of IL-6, and this works quite well, dramatically reducing fatality rates from CRS in ongoing CAR-T studies. Another anti-inflammatory drug that may also be useful is etanercept (Enbrel®). Both treat inflammatory conditions such as juvenile arthritis and have been shown to ease the symptoms of CRS in response to CAR-T cell therapy. However these treatments are very expensive and used after a patient shows signs of severe reaction. It’s a good first step, but for CAR-T cell therapy to be uniformly available as a viable treatment for cancer, we need more cost effective approaches.

Several trials are underway to identify laboratory markers (e.g., a blood test) that can predict who will get CRS, so that drugs may be administered prophylactically, and researchers are also exploring other therapy options that could be used to reduce or prevent the most dangerous side effects of CRS. One possible solution could come from Bellicum Pharmaceuticals, exploring use of its Chemical Induction of Dimerization (CID) technology that can be used as a “suicide safety switch” to switch off genetically engineered CAR-T if the side effects in a patient are getting dangerous. But then, the longer term therapeutic effects may be turned off also. “Modulation” of the CAR-T functions to tune in just the right amount of therapeutic activity at the right times, is an active area of innovation at many companies designing new CAR-Ts, as they seek to improve efficacy, reduce side effects for patients, and to improve the efficiency of manufacturing these complicated “living” therapies.

The trouble with scale

Developers also need to consider the overall cost and infrastructure challenges that come with this treatment. Unlike most drugs, these precision medicines cannot be mass produced and distributed from a factory, because CAR-T cells are custom-made using the patient’s own cells. That means treatment centers may need to create their own CAR-T cell labs to process and genetically alter cells from each new patient; which is expensive, labor intensive, and has significant quality control issues.

Nonetheless, some industry entrepreneurs are optimistic that further research will deliver a more cost-effective, scalable solution. Juno Therapeutics in Seattle, Kite Pharma in Santa Monica, and Novartis (working with U Penn investigators) are the three leading clinical-stage companies developing novel cellular immunotherapies based on CAR-T cell technologies that could make these therapies easier and less expensive to access. And in Paris, the biopharma company Cellectis is partnering with Pfizer to create CAR-T technology that could enable them to create a universal cell line that would use engineered T-cells from a single donor in multiple patients. If it works, it could lead to a more cost-effective and saleable treatment option, especially for patients who don’t have enough T-cells to undergo an autologous CAR-T therapy.

These solutions may still be years away, but they offer hope, and a clear path forward. I believe that one day in the not too distant future, CAR-T cell therapy will provide a safe, effective and affordable therapy for many of the cancers that we now consider terminal diseases.