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 anti-tumour 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, r/r DLBCL and r/r FL patients, tisagenlecleucel typically exhibited an initial rapid expansion followed by a slower bi-exponential decline. High inter-subject variability was associated with the in vivo exposure metrics (AUC0-28d and Cmax) across all indications.
A summary of cellular kinetic parameters of tisagenlecleucel in paediatric and young adult Bcell- ALL patients is provided in Table 1 below. The maximal expansion (Cmax) was approximately 1.5-fold higher in CR/CRi patients (n=114) compared with non-responding (NR) patients (n=10) as measured by qPCR. Delayed and lower expansion was observed in NR patients compared to CR/CRi patients.
Table 1. Cellular kinetic parameters of tisagenlecleucel in paediatric and young adult r/r B-cell ALL (Studies B2202 and B2205J):
| Parameter | Summary statistics | Responding patients (CR/CRi) N=114 | Non-responding patients (NR) N=12 |
|---|---|---|---|
| Cmax (copies/μg) | Geometric mean (CV%), n | 32 900 (173.8), 114 | 21 900 (80.7), 10 |
| Tmax‡ (day) | Median [min;max], n | 9.85 [5.70; 54.8], 114 | 20.1 [12.6; 62.7], 10 |
| AUC0-28d (copies/μg*day) | Geometric mean (CV%), n | 286 000 (194.9), 114 | 232 000 (104.5), 8 |
| T½ (day) | Geometric mean (CV%), n | 40.0 (436.8), 72 | 3.78 (222.0), 4 |
| Tlast (day) | Median [min;max], n | 190 [17.8; 1 860], 114 | 28.8 [13.9; 888], 11 |
A summary of cellular kinetic parameters of tisagenlecleucel in DLBCL patients is provided in Table 2 below.
Table 2. Cellular kinetic parameters of tisagenlecleucel in r/r DLBCL patients:
| Parameter | Summary statistics | Responding patients (CR and PR) N=44 | Non-responding patients (SD/PD/Unknown) N=71 |
|---|---|---|---|
| Cmax (copies/μg) | Geometric mean (CV%), n | 6 070 (256.8), 44 | 5 000 (391.7), 67 |
| Tmax (day) | Median [min;max], n | 9.02 [5.78; 27.7], 44 | 8.84 [0.994; 26.7], 67 |
| AUC0-28d (copies/μg*day) | Geometric mean (CV%), n | 63 000 (177.7), 43 | 52 300 (321.4), 62 |
| T½ (day) | Geometric mean (CV%), n | 151 (487.5), 31 | 11.6 (196.2), 49 |
| Tlast (day) | Median [min;max], n | 930 [17.1; 1 830], 44 | 41.9 [0.994; 1 480], 67 |
A summary of cellular kinetic parameters of tisagenlecleucel in FL patients by BOR is provided in Table 3 below.
The geometric mean AUC0-28d value of responders was 2.9 fold higher compared to non-responders, while the geometric mean Cmax value was 2.1 fold higher in responders compared to non-responders.
Table 3. Cellular kinetic parameters of tisagenlecleucel in r/r FL patients:
| Parameter | Summary statistics | Responding patients (CR and PR) N=81 | Non-responding patients (SD/PD) N=12 |
|---|---|---|---|
| Cmax (copies/micrograms) | Geometric mean (CV%), n | 6 280 (331), 67 | 3 000 (1 190), 8 |
| Tmax (day) | Median [min;max], n | 9.92 [2.62; 28.0], 67 | 13.0 [7.73; 16.0], 8 |
| AUC0-28d | |||
| Geometric mean (CV%), n | 57 500 (261), 66 | 20 100 (18 100), 7 | |
| T½ (day) | Geometric mean (CV%), n | 43.8 (287), 43 | 24.4 (180), 6 |
| Tlast (day) | Median [min;max], n | 191 [19.9; 558], 73 | 107 [18.7; 366], 10 |
In paediatric and young adult B-cell ALL patients, tisagenlecleucel has been shown to be present in the blood and bone marrow for up to 5 years and 6 months, respectively. The blood to bone marrow partitioning of tisagenlecleucel in bone marrow was 50% of that present in blood at day 28 while at both months 3 and 6 it distributes at 67% (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 5 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.
In adult FL patients (Study E2202), tisagenlecleucel has been detected for up to 18 months in peripheral blood and up to month 3 in bone marrow for complete responder patients. The blood to bone marrow partitioning in bone marrow was nearly 54% of that present in blood at month 3 in both responder and non-responder patients.
The elimination profile of tisagenlecleucel includes a bi-exponential decline in peripheral blood and bone marrow.
There is no apparent relationship between dose and AUC0-28d or Cmax.
The scatter plots of cellular kinetic parameters versus age (22 to 76 years in DLBCL patients and 29 to 73 years in FL patients) revealed no relevant relationship between cellular kinetic parameters (AUC0-28d and Cmax) with age.
Gender has not been identified as a significant characteristic influencing tisagenlecleucel expansion in B-cell ALL, DLBCL and FL patients. In Study B2202, there were 43% female and 57% male patients, in Study C2201 38% female and 62% male patients and in Study E2202 34% female and 66% male patients who received tisagenlecleucel. Further, in Study E2202, the geometric means of the exposure parameters (Cmax and AUC0-28d) were shown to be 111% and 106% higher, respectively, in female patients compared to male patients. Although the interpretation of expansion in relation to gender is difficult due to overlapping ranges and high inter-subject variability.
There is limited evidence that race/ethnicity impact the expansion of tisagenlecleucel in paediatric and young adult ALL, DLBCL and FL patients. In Study B2202 there were 73.4% Caucasian, 12.7% Asian and 13.9% other ethnic patients. In Study C2201 there were 85% Caucasian, 9% Asian, 4% Black or African American patients, and 3 patients (3%) of unknown race. In Study E2202, there were 75% Caucasian, 13% Asian, 1% Black or African American patients, and 10% of unknown race.
In ALL, DLBCL and FL patients, across the weight ranges (ALL; 14.4 to 137 kg; DLBCL: 38.3 to 186.7 kg; FL: 44.3 to 127.7 kg), the scatter plots of qPCR cellular kinetic parameters versus weight revealed no apparent relationship between cellular kinetic parameters with weight.
Prior transplantation did not impact the expansion/persistence of tisagenlecleucel in paediatric and young adult B-cell ALL patients, adult DLBCL or adult FL 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.
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 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.
No non-clinical reproductive safety studies were conducted as no adequate animal model is available.
Juvenile toxicity studies were not conducted.
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