Ciltacabtagene autoleucel

Ciltacabtagene autoleucel is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. The ciltacabtagene autoleucel CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3-zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells.

Pharmacodynamic effects

In vitro co-culture experiments demonstrated that ciltacabtagene autoleucel-mediated cytotoxicity and cytokine release (interferon-gamma, [IFN-γ], tumour necrosis factor alpha [TNF-α], interleukin [IL]-2) were BCMA-dependent.

Ciltacabtagene autoleucel pharmacokinetics (PK) was assessed in 97 patients with multiple myeloma receiving a single ciltacabtagene autoleucel infusion at the median dose of 0.71 × 106 CAR-positive viable T cells/kg (range: 0.51 × 10⁶ to 0.95 × 10⁶ cells/kg).

Following a single infusion, ciltacabtagene autoleucel exhibited an initial expansion phase followed by a rapid decline and then a slower decline. However, high interindividual variability was observed.

Pharmacokinetic parameters of ciltacabtagene autoleucel in patients with multiple myeloma:

After the cell expansion, the persistence phase of the ciltacabtagene autoleucel was observed for all patients. At the time of analysis (n=65), the median time for CAR transgene levels in peripheral blood to return to the pre-dose baseline level was approximately 100 days (range: 28-365 days) post-infusion.

Detectable ciltacabtagene autoleucel exposures in bone marrow indicate a distribution of ciltacabtagene autoleucel from systemic circulation to bone marrow. Similar to blood transgene levels, bone marrow transgene levels declined over time and exhibited high interindividual variability.

Special populations

The pharmacokinetics of ciltacabtagene autoleucel (C_max and AUC_0-28d) were not impacted by age (range: 43-78 years, including patients <65 years of age (n=62; 63.9%), 65-75 years (n=27; 27.8%) and >75 years of age (n=8; 8.2%).

Similarly, the pharmacokinetics of ciltacabtagene autoleucel (C_max and AUC_0-28d) were not impacted by gender, body weight, and race.

Renal impairment

Renal impairment studies of ciltacabtagene autoleucel were not conducted. Ciltacabtagene autoleucel C_max and AUC_0-28d were similar in patients with mild renal dysfunction (60 mL/min ≤ creatinine clearance [CRCL] <90 mL/min) and patients with normal renal function (CRCL ≥90 mL/min).

Hepatic impairment

Hepatic impairment studies of ciltacabtagene autoleucel were not conducted. Ciltacabtagene autoleucel C_max and AUC_0-28d were similar in patients with mild hepatic dysfunction [(total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase > ULN) or (ULN < total bilirubin ≤ 1.5 times ULN)] and patients with normal hepatic function.

Ciltacabtagene autoleucel comprises engineered human T cells; therefore, there are no representative in vitro assays, ex vivo models, or in vivo models that can accurately address the toxicological characteristics of the human product. Hence, traditional toxicology studies used for medicinal product development were not performed.

Carcinogenicity and mutagenicity

No genotoxicity or carcinogenicity studies have been performed.

The risk for insertional mutagenesis occurring during the manufacturing of ciltacabtagene autoleucel following transduction of autologous human T cells with an integrating lentiviral vector (LV) was assessed by evaluating the integration pattern of the vector in pre-infusion ciltacabtagene autoleucel. This genomic insertional site analysis was performed on ciltacabtagene autoleucel products from 7 samples from 6 multiple myeloma patients and from 3 samples from 3 healthy donors. There was no evidence for preferential integration near genes of concern.

Reproductive toxicology

No reproductive and developmental toxicity animal studies have been conducted with ciltacabtagene autoleucel. No studies have been conducted to evaluate the effects of ciltacabtagene autoleucel on fertility.