Tisagenlecleucel leading the CAR T-cell race
Tisagenlecleucel, now US FDA approved, made history as the first ever chimeric antigen receptor (CAR) T-cell therapy for B-cell precursor acute lymphoblastic leukaemia (ALL) – a breakthrough that has the potential to transform treatment for blood cancers that have not responded to standard therapies.
“Not only does tisagenlecleucel provide patients with a novel treatment option where very limited options exist, it has also shown promising remission and survival rates in clinical trials,” said Dr Peter Marks, director of FDA’s Center for Biologics Evaluation and Research. “It is a first-of-its-kind treatment approach that fills an important unmet need for patients with this serious disease.”
The FDA’s Oncologic Drugs Advisory Committee, in July 2017, voted unanimously to recommend tisagenlecleucel’s approval. In August 2017, the FDA took the committee’s advice and gave the cell-based gene therapy the green light for use in paediatric and young adults (up to age 25) with relapsed or refractory B-cell ALL who currently have few – if any – therapeutic options.
Changing the course of cancer care
The approval drew excitement from the oncology and haematology community. Dr Kenneth Anderson from the Dana-Farber Cancer Institute in Haematology said the approval of CAR T-cell therapy for paediatric leukaemia marks an important shift in the blood cancer treatment paradigm. “This is a potentially curative therapy in patients whose leukaemia is unresponsive to other treatments and represents the latest milestone in the shift away from chemotherapy toward precision medicine.”
“[Finally, here’s] a brand-new way of treating cancer,” said ELIANA* lead investigator Dr Stephan Grupp from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, Pennsylvania, US. The first patient he treated using CAR T-cell therapy is now cancer-free for 5 years and counting.
First global CAR T-cell trial in ALL
The approval was based on results of the first global CAR T-cell trial, the phase II ELIANA study, in patients with CD19-positive, relapsed/refractory B-cell ALL. The study was conducted across 25 centres in the US, Europe, Canada, Australia, and Japan. Patients (n=68) were infused a single dose of CTL019 (tisagenlecleucel) –2.0–5.0 x 106 cells/kg for those ≤50 kg and 1.0–2.5 x 108 cells/kg for those >50 kg). Three months after infusion, 83 percent of patients achieved the primary endpoint of complete remission (CR) or CR with incomplete haematologic recovery (CRi). [EHA 2017, abstract S476]
The estimated relapse-free rate postremission onset was 75 percent at 6 months and 64 percent at 12 months. The estimated survival rate was 89 percent at 6 months and 79 percent at 1 year. Seven patients (13 percent of responders) in remission subsequently underwent allogeneic stem cell transplantation (alloSCT) within 6 months, but many did not and stayed in remission. At a median follow-up of 6.9 months, median overall survival had not been reached.
The therapy, while highly effective, is not without risks. Of the 63 patients who underwent infusion, 48 percent experienced grade 3 or 4 cytokine-release syndrome (CRS) and 15 percent developed grade 3 neurotoxicity. “The majority of adverse events occurred in the first 8 weeks and then subsided,” said Grupp.
Another expected side effect of CAR T-cell therapy is B-cell aplasia (low or absent B-cells) as a result of the destruction of not only the cancer cells but the normal B cells as well, predisposing the patient to infection. Tumour lysis syndrome, a life-threatening sequela, may also occur post-therapy and may require hospitalization.
Amid the toxicity concerns, tisagenlecleucel will carry a boxed warning for CRS and neurological events. A Risk Evaluation and Mitigation Strategy (REMS) was also approved by the FDA to ensure that tisagenlecleucel’s benefits outweigh the risks. Meanwhile, the agency also expanded the indication for tocilizumab to include treatment of CAR T-cell-induced CRS in patients 2 years and older.
How CAR T-cell therapy works
The CAR T-cell procedure is relatively intensive. T-cells are extracted from the patient via apheresis, separated out, and shipped to a laboratory where they are modified and grown to target cancer cells. The reengineered cells are then expanded in vitro and reinfused into the patient to fight and kill the leukaemic cells and guard against recurrence.
Critics say the treatment is not only complicated – it also comes with a USD475,000 price tag. With severe side effects in patients with high disease burden, relapses, and nonresponses, it is still early days for CAR T-cell therapy. Yet for patients and their families who run out of options and hope, tisagenlecleucel holds great promise and may offer the only chance for a cure.