Brief Introduction of CAR-T Cell Therapy Kymriah (Tisagenlecleucel)

Brief Introduction of CAR-T Cell Therapy Kymriah (Tisagenlecleucel)

Kymriah is a CD19-directed genetically modified autologous T-cell immunocellular therapy, in which the CD19 chimeric antigen receptor (CAR) is fixed on the T-cells. These T-cells, when infused into the body, can recognize B-cell-related hematological malignancies and kill them through direct or indirect actions. CD19 is an antigen protein expressed on the surface of various hematological malignant cells, including B-cell lymphomas and leukemia cells.

Mechanism of Action

The patient’s T-cells are genetically modified to express a chimeric antigen receptor (CAR) targeting the CD19 antigen, which is used to treat tumors. CD19 is an antigen protein expressed on the surface of various hematological malignant cells, including B-cell lymphomas and leukemia cells.

Development History

2012: Co-developed by Novartis and the University of Pennsylvania.

August 2017: Approved by the U.S. FDA for the treatment of relapsed or refractory acute lymphoblastic leukemia (r/r ALL).

2018: The U.S. FDA approved the expanded indication for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).

2018: Approved by the European Union for the treatment of relapsed or refractory acute lymphoblastic leukemia (R/R ALL) and relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL).

October 2020: Obtained approval from the NMPA to enter clinical trials.

2022: The U.S. FDA and the European Union approved the expanded indication for the treatment of relapsed or refractory follicular lymphoma (r/r FL).

Clinical Data

In the open-label, single-arm, multicenter Phase II TARMAC trial, patients with relapsed or refractory follicular lymphoma who had measurable disease by imaging or histology and had received at least one prior line of therapy were included. The primary endpoint was the CR rate assessed by the investigator at 4 months after Kymriah infusion; secondary endpoints included ORR, progression-free survival (PFS), duration of response (DOR), overall survival (OS), safety, and MRD negativity at 1, 4, 6, 9, and 12 months.

At baseline, the median age of patients was 66 years; most patients were male (75%), and 68% had Stage IV disease; the median number of prior therapies was 2.

The study results showed that the study met its primary endpoint. In patients evaluable for efficacy (n=20), the complete response rate (CR) at 4 months after CAR-T cell infusion was 80%. The overall objective response rate (ORR) at this time was 80%. Among the 16 CR patients, 14 were found to be minimal residual disease (MRD) negative by flow cytometry, with an overall MRD negativity rate of 70%.

Other study results showed that at a median follow-up time of 13 months, the median progression-free survival (PFS) had not been reached; the estimated 12-month PFS and OS rates were 75% and 100%, respectively.

Safety

In terms of safety, all patients experienced adverse events (AEs) of any grade, and 75% of patients reported Grade 3 or 4 AEs. The most common treatment-related AEs of any grade included: cytokine release syndrome (CRS; 75%), neutropenia (50%), diarrhea (30%), rash (20%), and thrombocytopenia (15%).

Dosage and Administration

(1) Prior to treatment, premedicate with acetaminophen and an H1-antihistamine;

(2) Ensure availability of tocilizumab prior to treatment;

(3) The dose depends on the number of CAR-positive viable T-cells;

(4) For patients ≤50 kg, the recommended dose is 0.2 to 5.0 x 106 CAR-positive viable T-cells/kg, administered intravenously;

(5) For patients >50 kg, the recommended dose is 0.1 to 2.5 x 108 CAR-positive viable T-cells, administered intravenously.

Adverse Reactions

Common adverse reactions (≥20%) with Kymriah (tisagenlecleucel) include cytokine release syndrome, hypogammaglobulinemia, infections of unspecified pathogen, fever, decreased appetite, headache, encephalopathy, hypotension, bleeding, tachycardia, nausea, diarrhea, vomiting, viral infectious disorders, hypoxia, acute kidney injury, and delirium.