CAR T-Cell Therapies New Standard of Care
New York, NY—Treatment with chimeric antigen receptor (CAR) T-cells is becoming mainstream, with the 2 different CAR T-cell drugs, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah), approved by the FDA, for the treatment of patients with leukemia and lymphoma. At the 2018 National Comprehensive Cancer Network (NCCN) Hematologic Malignancies Congress, Frederick L. Locke, MD, Program Co-Leader, Immunology, Moffitt Cancer Center, Tampa, FL, provided a historical perspective on this novel approach to therapy and discussed the classification and management of associated key adverse events, specifically cytokine release syndrome (CRS) and neurologic events.
There are now 3 generations of CAR T-cell therapies. Second-generation CAR T-cell therapies have a costimulatory domain, either CD28 or 41bb. Currently, it takes approximately 3 weeks to manufacture CAR T-cells, which are derived from the patient’s own cells and are genetically engineered ex vivo before being reinfused into the patient. CAR T-cells are typically delivered in the hospital, but in a very few centers they are being given as outpatient therapy.
The first responses to CAR T-cell therapy were described approximately 8 years ago, and were quite dramatic in a small number of children and adults with leukemia who had no other treatment options. The responses were durable, and a few of the first patients treated with CAR T-cell therapies achieved an apparent cure. Pivotal clinical trials led to the initial FDA approval of axicabtagene ciloleucel and tisagenlecleucel in 2017, and a third CAR T-cell drug is close to being submitted for FDA approval. Many other CAR T-cell agents are still in clinical trials.
With experience, toxicities associated with CAR T-cell therapies have been characterized. The 2 main concerns are CRS and neurologic events, including encephalopathy, confusion, tremor, and frank psychosis.
“These 2 categories of adverse events have different temporal characteristics. They are mediated by similar pathophysiology that we don’t completely understand, and they are described separately,” Dr Locke said.
“The current version of Common Terminology Criteria for Adverse Events [CTCAE] toxicity grading system is inadequate and irrelevant for CAR T,” he added.
The NCCN has developed toxicity criteria for CAR T-cell drugs and has a group of CAR T-cell investigators, but these 2 systems do not match up. Toxicities associated with CAR T-cell therapies are graded differently by each of these systems. CTCAE 5 is an attempt to standardize the toxicity grading.
Dr Locke expects CTCAE 5 to become a gold standard for grading CRS in the future, “but we are not there yet,” Dr Locke told listeners at the meeting.
Neurotoxicity grading is complicated by various terms for neurologic symptoms; for example, one system uses “encephalopathy” whereas another system uses “confusion” for the same manifestation, he noted.
The CAR-T Related Encephalopathy System uses a 10-point neurologic scale to define neurologic symptoms and to assess day-to-day changes.
The CAR T-Cell Therapy–Associated TOXicity (CARTOX) Working Group comprising investigators from multiple institutions and medical disciplines with experience in treating patients with CAR T-cell drugs also provides recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients who receive CAR T-cell therapy.
Management of CRS and Neurotoxicity
Severe adverse effects of CAR T-cell therapy are managed by immunosuppression. For grade 3 CRS, the interleukin-6 inhibitor tocilizumab (Actemra) is used with corticosteroids. This strategy reduces the likelihood of CRS progression. Patients continue to respond to CAR T-cell therapy while receiving tocilizumab.
“We feel confident that we can treat early, and they will respond and benefit from CAR T,” Dr Locke said. “It took 30 years to develop CAR T-cells. But with second-generation CAR T-cell therapy, the field has rapidly advanced, and now we give this as standard of care. ASCO named CAR T-cell immunotherapy advance of the year,” he noted.
“CAR T-cell is not the only cell therapy in development. About 750 cell therapies are in development, and about half are CAR T,” Dr Locke pointed out. Others include tumor-infiltrating lymphocytes and natural-killer cells.
“The next advance will be earlier use of these therapies,” Dr Locke predicted.
Clinical trials for CAR T-cell therapy in aggressive B-cell lymphoma and multiple myeloma are encouraging, and CAR T-cell therapies will probably soon have a role for the treatment of these malignancies.