FDA Announcement on Cancer Drug Creates Critical Role for Engineers

The FDA recently announced an exciting new class of cancer drug made from a patient’s own cells, and it is clear that engineers will play a key role in fulfilling its promise.

by Michael MacRae
September 18, 2017

Cancer research advocates are hailing the U.S. Food & Drug Administration’s recent approval of Novartis’s new anti-leukemia drug Kymriah as a true watershed moment in cancer medicine. As the first of an entirely new class of immunocellular drugs and the first gene therapy of any kind approved for use in the U.S., Kymriah is the first in a coming wave of patient-specific drugs based on what is known as chimeric antigen receptor (CAR) T therapy – a highly personalized approach to treatment in which a patient’s own immune cells are used as the active ingredient.

Kymriah is for people under age 26 with a specific form of acute lymphoblastic leukemia (ALL). With current therapies, only about 10% of patients with this form of ALL survive five years after diagnosis. However, the new drug achieved complete and prolonged remission in 83% of patients enrolled in a 25-center global clinical trial.

According to its chief developers at Novartis, the University of Pennsylvania, and the Children’s Hospital of Philadelphia (CHOP), this unprecedented debut is only the beginning. “We've never seen anything like this before and I believe this therapy may become the new standard of care for this patient population," said Stephan Grupp, M.D., Ph.D., a Penn professor of pediatrics and director of CHOP’s Cancer Immunotherapy Frontier Program.

As effective as Kymriah appears to be against ALL, scientists and regulators alike are most excited by the future potential of its unique approach for other, more common diseases. By reprogramming a patient’s own immune system to attack cancer cells in the same way it would fight an infection, such drugs have enormous potential to treat other blood cancers, solid-tumor cancers and even autoimmune diseases like Type 1 diabetes. “We’re entering a new frontier in medical innovation,” said FDA Commissioner Scott Gottlieb in a statement. Such treatments, he said, “hold out potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses.”

But as is true with every major advance in cancer research, success comes with qualifications. And in the case of Kymriah-like drugs, engineers will play a key role in scaling up the complex and delicate process of transforming each patient’s cells into a personalized cure.

Production and Scale-Up

CAR-T therapies begin with the collection of T cells from a patient’s blood. These white blood cells, also known as lymphocytes, are involved in the immune system’s defense against invading pathogens. In CAR-T therapies, the patient’s isolated T-cells are shipped to a manufacturing facility, where they are augmented with a new gene that expresses a specific CAR protein that binds to leukemia cells with a hallmark CD19 antigen expressed on their surfaces. In effect, the CAR protein turns the T-cells into targeted leukemia killing machines.

Kymriah is designed as a one-time treatment with an initial price of $475,000 for a single infusion. Industry analysts say that price is justifiable given the drug’s long-term cost, efficacy, and quality-of-life advantages over the current standard treatment, a bone marrow transplant.

Novartis will supply the U.S. market for Kymriah from its Morris Plains, NJ, facility. The 3-4 week manufacturing process involves a number of complicated steps, and quality control testing is integrated throughout.

The process begins in the clinic with a step known as leukapheresis, in which blood is removed from a patient, processed to remove the white blood cells, and then reinfused. The leukapheresis product is then shipped to the manufacturing center where it is first enriched to remove anticoagulants and other unwanted components using blood recovery equipment such as the Haemonetics Cell Saver (Haemonetics Corporation, Braintree, MA).

Activation of the T-cells is the next critical step. The CAR protein is introduced into the patient’s T-cells via an engineered viral vector, which enters the cell and delivers a payload of genetic material. During a several-day incubation period, copies of this RNA material permanently alter the T-cell’s genome, giving it the ability to express the CD19-targeted CAR protein. Once activated, the cell culture must next be expanded to produce a batch large enough for clinical use. This step is performed in a bioreactor, where cells are subjected to precise conditions that enable them to divide and replicate until volumes of up to 5 liters are produced. Cells within the batch are then washed and concentrated down into the volume required for the patient’s infusion. Cryopreservation protects cell viability while the treatment is transported back to the clinic and thawed prior to administration.

Several available bioreactor culture systems are geared toward CAR T cells with varying requirements for gas-exchange and culture mixing performance. For Kymriah, Novartis has used the rocking-platform-equipped Xuri bioreactor (formerly WAVE bioreactor, GE Healthcare Bio-Sciences, Marlborough, MA). The G-Rex system from Wilson Wolf (St. Paul, MN) features gas-permeable membranes designed to expand cells from low seeding densities. And as opposed to systems that require separate machinery for each step, the CliniMACS (Miltenyi Biotec, Cologne, Germany) integrates cell preparation, enrichment, activation, transduction, expansion, final formulation and sampling in one device. With Kymriah’s approval, bioreactor companies are expected to invest heavily in innovative new systems that further automate the manual steps of this process to meet the production needs for both clinical trials and post-approval patient care.

Of the 3,100 people under 20 annually diagnosed with ALL, only about 600 new patients per year will be eligible for Kymriah therapy. Consequently, the established protocols for producing clinical-quality CAR T cell therapies have only been used and tested in a few hundred patients to date. For this treatment approach to live up to its full potential, however, these protocols must be expanded to cover larger patient populations and larger clinical trials in multiple trial sites. Scaling up the process also entails considerations such as global regulatory issues, consistency of viral vector quality, and the long-term safety of gene therapy. Although the T-cells on which each treatment is based must be patient specific, it is possible to produce the viral vectors used to transduce the CAR into these cells in bulk and store them at minus 80 celsius for several years. Sterility of these vector components is essential because the finished T cells can’t be further sterilized through filtration. Vectors are made in Good Manfuacturing Practice facilities under controlled, clean room conditions with minimal open processing.

To ensure that each batch of vector meets defined standards before it is used to make CAR T cells, the batch is quality-tested throughout the process. The FDA has produced guidance documents for testing safety, sterility, purity, potency, identity, and titer.

Novartis and several other pharmaceutical companies have more CAR-T therapies in the development pipeline. The farthest along, like Kymriah, target blood and bone marrow cancers, but many early-stage investigational drugs are aimed at solid-tumor cancers. Other research is aimed at developing off-the-shelf therapies that achieve similar effectiveness without using a patient’s own cells. For now, however, the spotlight is on Kymriah and the economic, logistical, and manufacturing complexities of scaling up an efficient, quality-assured process for producing a drug of which no two batches are alike.

Michael MacRae is an independent technical writer based in Portland, OR.