First CAR-T Approval Begins New Era in Modern Medicine

Specialists in the field of immunotherapy were strongly encouraged by the FDA’s approval of the first CAR-T therapy for cancer patients last month.

“This is an exciting time for patients, for the scientific fields of gene and cell therapies, and for cancer in general,” says Marcela Maus, MD, PhD, Director of Cellular Immunotherapy at the Mass General Cancer Center. “It’s not every day that an entirely new platform of treatment comes along, especially one that is so potent and offers the chance of durable remission.”
The recently approved therapy, called Kymriah, was developed by Novartis for pediatric and young adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). ALL is a blood-based, or liquid cancer, that results in the overproduction of cancerous immature white blood cells. It is the most common type of cancer in children, according to the National Cancer Institute.

The safety and efficacy of Kymriah were demonstrated in a multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL where the overall remission rate was 83 percent.

“It’s really clinical and regulatory validation of a development that has been going on for the better part of 25 years,” says Pat Fortune, PhD, Vice President of Market Sectors for Partners Innovation. “This is the first approval, and its performance based on clinical trial results is quite remarkable.”

Fortune noted that more CAR-T treatments are in the development pipeline and should be heading to the FDA for approval soon. “By last count, conservatively, there are 40 individual CAR-T therapies in the stage of clinical trials moving to approval, and this is just the beginning of that process.”

“Since the therapy, at least in the way it has been used so far, is so remarkably successful, this is really a seminal event with respect to the outlook for cancer patients—initially for hematological cancers and hopefully for solid tumors, although that has yet to be proven.”

The basic concept behind CAR-T is to take a patient’s own T-cells, which are responsible for directing the body’s immune response to invading agents, and reengineer them in the lab to detect and respond to antigens produced by tumor cells.

One way that cancer cells spread unchecked throughout the body is by mimicking the proteins expressed by “safe” cells in the body, thereby avoiding detection and elimination by the immune system.

Once the T-cells have been reprogrammed to identify and attack a protein expressed by the tumor cells, they are replicated in the lab and injected back into the patient. If all goes according to plan, the T-cells will attack the tumor cells and send the cancer into remission.

Partners HealthCare is contributing to the development of CAR-T and other immunotherapies for cancer, both as a host site for clinical trials at BWH and MGH, and in developing new CAR-T treatments via the Cellular Immunotherapy Program run by Dr. Maus, Fortune said.

Immune-based therapies being tested in clinical trials include CAR-T therapies and first-in-man studies for oncolytic viruses (viruses that have been reengineered to attack and kill cancer cells instead of healthy cells), among others.

In CAR-T therapies specifically, Dr. Maus has an active development program and will be moving some of her discoveries into clinical trials within the next 12 to 18 months.

While the initial results from CAR-T are promising, significant hurdles remain. For one, it has yet to be determined what the long-term outcomes of treatment will be—if and when the blood cancers will recur for patients down the line. Since the therapies are new, it is too early to determine the long-term prognosis.

There is also the challenge of managing cytokine release syndrome, which is a complication of CAR-T treatment where cytokines (proteins that induce an immune response) released by the modified T-cells once they are injected back into the body produce a systemic inflammatory response similar to that of a severe infection.

More work also needs to be done to determine which patients will respond to CAR-T therapies and which will not.

Lastly, there is the question of affordability. The pricing for Kymriah is estimated at $450,000 for treatment. “One would think that as more therapies come out, the price will come down,” Fortune says. “But these are very expensive therapies to develop; which of them will be affordable in the end still has to be sorted out.”

“Right now, the manufacturing process is complex, labor-intensive and requires expensive reagents that make it difficult to treat large numbers of patients,” adds Maus. “I think improvements in manufacturing or in equipment that allow individual hospitals to manufacture the cells could be revolutionary.”

Finally, while there are clinical trials testing CAR-T therapies on solid tumors in the clinic, solid and liquid tumors don’t look quite alike, and it may be more challenging to produce the same kind of dramatic results, Fortune notes.

While challenges remain, Maus is optimistic that the field will make significant advances over the next few years.

“We are going to see genes introduced with different levels of precision to make CAR-T cells, to make other engineered cells, and that will include the use of gene-editing techniques that make T cells safer, more potent and more widely available, including ‘off-the-shelf’ T cells that don’t have to be personalized for every patient.”