CAR T-cell Drug Makers Race Toward FDA Approval
By Julie Monroe
When people think of cancer treatment, they usually envision brutal regimens of chemotherapy or radiation. These two treatments attack cancers by disrupting their division mechanisms or chemical processes at the cellular level.
In many cases, chemotherapy and radiotherapy produce very good results. However, for reasons not completely understood, certain cancer cells are just more resistant to traditional methods of attack.
But with some very promising immunotherapy research in recent years, additional cancer fighting tools may soon be included in the broader oncology arsenal.
One immunotherapy that has created a stir within the pharmaceutical and biotech industries over the last decade is Chimeric Antigen Receptor T-cell Therapy (CAR-T).
T-cells, lymphocytes that play a pivotal role in cell-mediated immunity, are extracted from a patient, or donor if necessary, and modified to express CARs, which direct the T-cells to recognize specific protein target sites on cancer cells.
These modified T-cells are allowed to multiply into the billions ex vivo, and then are infused back into the patient. If the infusion is successful, the CAR T-cells will continue to multiply in the body, and recognize and attack tumor cells.
CAR-T therapy has sparked an explosion of interest by companies to invest in research and pursue FDA approval of related immunotherapy drugs.
While dozens of players are either directly or indirectly involved, three institutions in particular have edged their way to the forefront of the race to bring the first of this type of drug to market: Kite Pharma, Novartis, and Juno Therapeutics. The sprint toward FDA approval of CAR T-cell drugs has not been without obstacles.
This type of drug tends to elicit an extreme immune response in patients, referred to as a “cytokine storm.” Neurotoxicity and unwanted targeting of healthy cells has also been documented. Finally, the bulk of CAR T-cell success thus far has been limited to various blood-related cancers.
Kite incorporated in 2009 as a clinical-stage drug development company. Since that time, they have partnered with dozens of research institutions to develop their drug, KTE-C19. KTE-C19 targets the CD19 antigen on many B-cell cancers, including certain lymphomas and leukemias.
In September 2016, Kite released interim results from a Phase II clinical trial using KTE-C19 on advanced diffuse large B-cell lymphoma (DLBCL) patients who were preconditioned with chemotherapy. Initially, 76% of the patients responded to the treatment.
After three months, the overall response rate dropped to 39% due to relapse, with a third of patients in the trial entering complete remission. Kite has argued that despite the drop in response, KTE-C19 is still a valid treatment for lymphoma patients who have stopped responding to traditional cancer therapies.
Novartis shocked the industry late in 2016 with plans to reorganize and eliminate key components of its cell and gene therapy group.
This surprise came as Novartis maintained its neck and neck race with Kite and Juno to get its CT019 drug, designed to treat pediatric acute lymphoblastic leukemia (ALL) by also targeting CD19, approved by the FDA in early 2017. It’s product development pipeline also includes additional trials to prove the efficacy of CT019 in treating DLBCL.
Despite a lay-off of 120 people, Novartis released promising data in December 2016 from ELIANA, the first global pediatric CAR T-cell trial. The Phase II study showed that CT019 elicited an 82% response for complete remission or remission with incomplete blood count recovery after three months.
Juno has had a tough year. With it’s stocks in steady decline since July, it is a far different picture than when Juno exploded onto the public market in 2014 as the hopeful collaborative spin-off of three major U.S. cancer research centers.
In June of 2014, Juno was confident that it would have it’s ALL drug, JCARO15, ready for market in early 2017. However, their trials were abruptly halted by the FDA in the following month because of the death of trial patients from cerebral edema.
The FDA lifted their restrictions several days later when Juno promised to reformulate its preconditioning regimen, but in November 2016, more patients died from the same type of complications.
Juno voluntarily paused the trial and has suspended its timeline for its formerly leading CAR T-cell candidate surrounding concerns that it was JCAR015, and not the preconditioning, to blame for the deaths. Now Juno appears to be switching its focus to the CD17 antigen using their drug JCARO17, whose Phase I results offered a 60% response rate in a small sample of DLBCL patients.
Juno also announced in late December 2016 that it is suing Kite Pharma for potential patent infringement from it’s KTE-C19 drug.
Juno’s patent, focused on T-cells modified to target the CD19 antigen using a CD28 co-stimulatory molecule, was reviewed and upheld by the U.S. Patent and Trademark Office following a challenge from Kite in mid-2015.