Outlining the Risks That Go Along With the Benefit of CAR T-Cell Therapy

Though chimeric antigen receptor (CAR) T-cell therapy has been largely touted as one of the most important advances in cancer care in recent years, the therapy comes with the risk of severe toxicities as well as increased financial burden due to the high cost of the drugs.

During the American Society of Clinical Oncology’s Annual Meeting held in Chicago, Illinois, May 31-June 4, 2019, data was presented regarding “the other side of CAR T-cell therapy,” namely, cytokine release syndrome (CRS), neurologic toxicity, and financial burden.

“[CAR T-cell therapy] is truly now the 4th arm of treatment for cancer patients and has allowed our patients to get great therapeutic rewards. However, about half of the patients included in the study that was the basis of approval for Yescarta needed ICU [intensive care unit] management. In 3 of the published studies to date [for the therapies], almost all the patients developed some grade of cytokine release syndrome,” said Elizabeth Shpall, MD, of MD Anderson Cancer Center.

The authors of the study concluded that there are several factors that can predict the onset of CRS, such as a high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, and administering a higher CAR T-cell dose. Thrombocytopenia also seemed to be a predictor.

“So how can we ameliorate CRS? We need to focus on the identification of predictive biomarkers, prompt and correct use of anti-IL6 [interleukin-6] and steroid therapy, and educate our physicians extensively,” she said.

However, once a patient has hopefully overcome the week or so that CRS usually lasts, according to Shpall, the next challenge is to identify whether or not the patient has signs of neurotoxicity, which can often occur after CRS is completed resolved.

“The immediate first fever happens early. That’s usually the first sign, if a patient develops a fever early on. Overwhelmingly, though, neurotoxicity is reversible and usually subsides within 7 days,” said Bianca Santomasso, PhD, MD, of Memorial Sloan Kettering Cancer Center.

Historically, Santomasso explained, neurotoxicity used to be included in CRS. But when studying the toxicity, it began to be identified by different characteristics, such as global encephalopathy and aphasia, among others.

“We’ve definitely learned some lessons and figured out what to look for when it comes to neurotoxicity. We know that we need to do a baseline MRI [magnetic resonance imaging], watch a patient's vitals and electrolytes, and definitely a declining level of consciousness without another cause is concerning,” said Santomasso.

Putting aside the physical cost of the therapies, the actual price of the therapies can be cause for patient concern as well, considering the price of the 2 FDA-approved therapies currently on the market are $495,000 and $373,000.

“Currently, there are 475 cell and gene therapy companies in North America. In 2018, there were about $20 billion worth of cell therapy deals, IPOs [initial public offerings] of nearly $1 billion, and $750 million in company series funding. And yet, if you take out the university programs and big cancer centers, there are only 17 community institutions left that administer CAR T-cell therapy,” said Carlos Bachier, MD, of the Sarah Canon Center for Blood Cancer.

It is important to note that while the cost to the patient is significant, the cost to the institution is also substantial. In order to be able to administer the therapy, the institution must have a triage CAR T nurse or coordinator, train its medical staff on CAR Ts, have the proper collection/shipping/storage containers for the product, and ensure proper reporting to the FDA in order to allow for proper regulation.

“Best practices of experienced centers include building a multidisciplinary team that not all institutions are prepared or capable of implementing…[and] financial barriers for both the patient and the institution providing the therapies can prevent wide use of the treatments,” said Bachier.

Of note, to date, reimbursement has not been finalized for these products, and is currently being discussed by CMS.