Tisagenlecleucel

Tisagenlecleucel is an autologous, immunocellular cancer therapy which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19 expressing cells. The CAR is comprised of a murine single chain antibody fragment which recognises CD19 and is fused to intracellular signalling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and antitumour activity, while 4-1BB enhances the expansion and persistence of tisagenlecleucel. Upon binding to CD19-expressing cells, the CAR transmits a signal promoting T-cell expansion and persistence of tisagenlecleucel.

Following infusion of tisagenlecleucel into paediatric and young adult r/r B-cell ALL and r/r DLBCL patients, tisagenlecleucel typically exhibited an initial rapid expansion followed by a slower bi-exponential decline.

Cellular kinetics in paediatric and young adult B-cell ALL patients

A summary of cellular kinetic parameters of tisagenlecleucel in paediatric and young adult B-cell ALL patients is provided in Table 7 below. The maximal expansion (C_max) was approximately 2-fold higher in CR/CRi patients (n=79) compared with non-responding (NR) patients (n=10) as measured by qPCR.

Table 7. Cellular kinetic parameters of tisagenlecleucel in paediatric and young adult r/r B-cell ALL (Studies B2202 and B2205J):

^‡ A total of 5 patients had an early T_max (<1 days), the next lowest T_max occurs at 5.7 days. Early T_max may not be representative of the true maximal expansion, rather the amount of transgene present in the catheter from which sample was collected.

Cellular kinetics in adult DLBCL patients

A summary of cellular kinetic parameters of tisagenlecleucel in DLBCL patients is provided in Table 8 below.

Table 8. Cellular kinetic parameters of tisagenlecleucel in r/r DLBCL patients by clinical response at month 3:

Distribution

In paediatric and young adult B-cell ALL patients, tisagenlecleucel has been shown to be present in the blood and bone marrow beyond 2 years (study B2101J). The blood to bone marrow partitioning of tisagenlecleucel in bone marrow was 47.2% of that present in blood at day 28 while at months 3 and 6 it distributes at 68.3% and 69%, respectively (Studies B2202 and B2205J). Tisagenlecleucel also traffics and persists in cerebrospinal fluid in paediatric and young adult B-cell ALL patients (Study B2101J) for up to 1 year.

In adult DLBCL patients (Study C2201), tisagenlecleucel has been detected for up to 2 years in peripheral blood and up to month 9 in bone marrow for complete responder patients. The blood to bone marrow partitioning in bone marrow was nearly 70% of that present in blood at day 28 and 50% at month 3 in both responder and non-responder patients.

Elimination

The elimination profile of tisagenlecleucel includes a bi-exponential decline in peripheral blood and bone marrow.

Linearity/non-linearity

There is no apparent relationship between dose and AUC0-28d or C_max.

Special populations

Elderly

The scatter plots of cellular kinetic parameters versus age (22-76 years) revealed no relevant relationship between cellular kinetic parameters (AUC_0-28d and C_max) with age.

Gender

Gender is not a significant characteristic influencing tisagenlecleucel expansion in B-cell ALL and DLBCL patients. In Study B2202, 43% female and 57% male patients and in Study C2201 39% female and 61% male patients received tisagenlecleucel.

Race/ethnicity

There is limited evidence that race/ethnicity impact the expansion of tisagenlecleucel in paediatric and young adult ALL and DLBCL patients. In Studies B2202 and B2205J there were 79.8% Caucasian, 7.7% Asian and 12.5% other ethnic patients. In Study C2201 there were 88% Caucasian, 5% Asian, 4% Black or African American patients, and 3 patients (3%) of unknown race.

Body weight

In DLBCL patients, across the weight ranges (38.4 to 186.7 kg), the scatter plots of qPCR cellular kinetic parameters versus weight revealed no apparent relationship between cellular kinetic parameters with weight.

Prior transplantation

Prior transplantation did not impact the expansion/persistence of tisagenlecleucel in paediatric and young adult B-Cell ALL patients or DLBCL patients.

Non-clinical safety assessment of tisagenlecleucel addressed the safety concerns of potential uncontrolled cell growth of transduced T cells in vitro and in vivo as well as dose-related toxicity, biodistribution and persistence. No such risks were identified based on these studies.

Carcinogenicity and mutagenicity

Genotoxicity assays and carcinogenicity studies in rodents are not appropriate to assess the risk of insertional mutagenesis for genetically-modified cell therapy products. No alternative adequate animal models are available.

In vitro expansion studies with CAR-positive T cells (tisagenlecleucel) from healthy donors and patients showed no evidence for transformation and/or immortalisation of T cells. In vivo studies in immunocompromised mice did not show signs of abnormal cell growth or signs of clonal cell expansion for up to 7 months, which represents the longest meaningful observation period for immunocompromised mouse models. A genomic insertion site analysis of the lentiviral vector was performed on tisagenlecleucel products from 14 individual donors (12 patients and 2 healthy volunteers). There was no evidence for preferential integration near genes of concern or preferential outgrowth of cells harbouring integration sites of concern.

Reproductive toxicity

No non-clinical reproductive safety studies were conducted as no adequate animal model is available.

Juvenile animal studies

Juvenile toxicity studies were not conducted.