Yescarta
axicabtagene ciloleucel
Species
no relevantMouse
Longest study
30 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
No relevant species; syngeneic mouse lymphoma model with murine surrogate CAR-T (published, non-GLP)
“Single-dose toxicology studies in animals were not performed by the Applicant due to the lack of a relevant animal model.”
Why that species
FMC63 scFv recognizes only human CD19; engineered human T cells not modelable in animals
“Since the anti-CD19 scFv utilized for KTE-C19 does only recognize human CD19, a murine surrogate was engineered for non-clinical proof-of-concept studies in immune competent mice.”
Surrogate molecule
Yes: anti-murine CD19 CAR (1D3 scFv) in murine T cells, syngeneic lymphoma mice
“This surrogate model used an anti-murine CD19 CAR construct that was similar to KTE-C19 with the exception of the scFv, which has been derived from the 1D3 mAb recognizing murine CD19.”
Study lengthopen answer page →
Longest pivotal study
30 weeks
“Some mice were followed out to Day 209. The publication reported no overt toxicity, but normal B cells were decreased (i.e., B cell aplasia).”
Pivotal GLP studies
No toxicology studies; published surrogate CAR-T study in lymphodepleted syngeneic tumor-bearing mice (Kochenderfer 2010)
“No toxicology studies with KTE-C19 were conducted.”
Route in tox
Intravenous (after total body irradiation lymphodepletion in mice)
“Following intravenous injection of murine T cells expressing the anti-murine CD19 CAR into the mice, tumors were eliminated (i.e., lymphoma cells were undetectable) and animal survival was extended.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; literature review of retroviral-transduced T-cell transformation risk instead
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted.”
Carcinogenicity
Not conducted; literature suggests T cells resistant to retroviral transformation
“The data suggest that T cells are relatively resistant to malignant transformation by retroviral vectors.”
Reproductive & developmental
Not conducted
“Developmental and Reproductive Toxicology Studies (DART) No DART studies were conducted.”
Safety pharmacology
Not conducted
“No safety pharmacology studies were conducted.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
No NOAEL; surrogate mice: no overt toxicity, persistent on-target B-cell aplasia to Day 209
“B cell aplasia was observed, but no overt toxicity was exhibited (Experiment E).”
Risksopen answer page →
Immune & cytokine safety
CRS, TLS, MAS deemed not investigable nonclinically; CD19-dependent cytokine release in vitro
“These toxic effects cannot be investigated in non-clinical studies as they are general effects of CAR T cells and the extent of expected toxicities are largely based on patient-specific parameters such as the individual tumour load.”
Biodistribution & persistence
No biodistribution studies; surrogate CAR-T in spleen Day 8, undetectable Day 63
“No biodistribution studies with KTE-C19 were conducted.”
Modality-specific risk
Insertional oncogenesis from gamma-retroviral vector with full-length LTRs; on-target B-cell aplasia; RCR
“The combination of both the use of a γ-retroviral vector with full-length viral LTRs and the high proliferative potential of the transduced T cells provides a certain risk of insertional oncogenesis.”