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.”
Species: general tox
None; no toxicology studies (no relevant animal model)
“Single-dose toxicology studies in animals were not performed by the Applicant due to the lack of a relevant animal model.”
Species: DART
Not conducted
“Developmental and Reproductive Toxicology Studies (DART) No DART studies were conducted.”
Species: carcinogenicity
Not conducted
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted.”
Surrogate used in
Yes: anti-murine CD19 CAR (1D3 scFv) T cells
“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.”
Genotox: Ames
Not conducted
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted.”
Genotox: in vitro mammalian
Not conducted
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted.”
Genotox: in vivo
Not conducted
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted.”
Carcinogenicity model
Not conducted; literature review suggests T cells relatively resistant to retroviral malignant transformation
“To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors. The data suggest that T cells are relatively resistant to malignant transformation by retroviral vectors.”
Carcinogenicity timing
Not conducted; literature review on retroviral-vector T-cell transformation submitted instead
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted. To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies were conducted.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Yescarta don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL; surrogate mice: no overt toxicity, persistent on-target B-cell aplasia to Day 209 (FDA pharmacology/toxicology review, p. 16)
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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Screening ELISA positives occurred, but a confirmatory cell-based assay found all of them antibody-negative
“Results of a confirmatory cell-based assay, leveraging a properly folded and expressed extracellular portion of the CAR (ScFv, hinge and linker) demonstrated that all patients treated with YESCARTA that had a positive result in the screening ELISA were antibody negative at all time points tested.”
Label warnings
Boxed warning: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES and SECONDARY HEMATOLOGICAL MALIGNANCIES
- Cytokine Release Syndrome
- Neurologic Toxicities
- Hypersensitivity Reactions
- Serious Infections
- Prolonged Cytopenias
- Hypogammaglobulinemia
- Secondary Malignancies
CytopeniasCytokine release syndromeNeurotoxicitySecondary malignancyHypersensitivity & infusion reactionsInfections
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; initial dose-finding study NCI 09-C-0082 in patients with advanced B-cell malignancies
“Dosing of the conditioning chemotherapy agents and Yescarta was based on the results NCI study 09-C0082, a Phase 1 open label study of the safety and feasibility of anti-CD 19 CAR T-cells in subjects with advanced B-cell malignancies.”
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Yescarta don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL; surrogate mice: no overt toxicity, persistent on-target B-cell aplasia to Day 209 (FDA pharmacology/toxicology review, p. 16)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No toxicology studies with the product; surrogate mouse CAR-T pharmacology study only
“No toxicology studies with KTE-C19 were conducted.”
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.”
DART package
Species: DART
Not conducted
“Developmental and Reproductive Toxicology Studies (DART) No DART studies were conducted.”
Reproductive & developmental
Not conducted
“Developmental and Reproductive Toxicology Studies (DART) No DART studies were conducted.”
PPND / ePPND: when
No fertility/reproduction/development studies; acceptable given product type, target expression and lack of a relevant animal model
“No studies have been conducted to evaluate the effects of YESCARTA on fertility, reproduction and development. This is acceptable based on the type of product, the expression pattern of the target antigen and the lack of a relevant animal model.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted.”
Carcinogenicity model
Not conducted; literature review suggests T cells relatively resistant to retroviral malignant transformation
“To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors. The data suggest that T cells are relatively resistant to malignant transformation by retroviral vectors.”
Carcinogenicity timing
Not conducted; literature review on retroviral-vector T-cell transformation submitted instead
“No in vitro and in vivo genotoxicity and carcinogenicity assessments for KTE-C19 were conducted. To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors.”
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Published surrogate anti-murine CD19 CAR T cells in lymphodepleted syngeneic CD19+ B-cell lymphoma mice
“To evaluate CD19-specific anti-tumor activity in vivo, an analogous murine CAR construct recognizing the murine CD19 molecule was evaluated in a lymphodepleted syngeneic mouse model of CD19+ B cell lymphoma.”
Why that model
FMC63 scFv recognizes human but not murine CD19, so an anti-murine CD19 CAR was used
“The scFv construct used to manufacture KTE-C19 recognizes human, but not murine CD19. Therefore, the NCI investigators developed an anti-murine CD19 CAR construct to administer in a syngeneic mouse model of B cell lymphoma in proof-of-concept experiments that also evaluated general safety.”
Reviewer's view of the efficacy data
EMA: package limited by animal models but adequate
“The non-clinical development package provided for KTE-C19 was limited due to the type of product and the limitations of animal models available for investigating pharmacodynamics, pharmacokinetics, and toxicity aspects of KTE-C19, but it was considered adequate.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No toxicology studies with the product; no relevant animal model, murine surrogate CAR-T used for pharmacology
Why: Type of product and limitations of available animal models · No relevant species
“Single-dose toxicology studies in animals were not performed by the Applicant due to the lack of a relevant animal model.”
“The non-clinical development package provided for KTE-C19 was limited due to the type of product and the limitations of animal models available for investigating pharmacodynamics, pharmacokinetics, and toxicity aspects of KTE-C19, but it was considered adequate.”
DARTAcceptedBeyond the letter
No fertility, reproduction or development studies
Why: Type of product, target antigen expression pattern and lack of a relevant animal model · No relevant species · Pharmacology or kinetics
“No studies have been conducted to evaluate the effects of YESCARTA on fertility, reproduction and development. This is acceptable based on the type of product, the expression pattern of the target antigen and the lack of a relevant animal model.”
BiodistributionAccepted
Germline transmission risk of the CAR construct not addressed nonclinically
Why: EMA germline transmission guideline considers the risk low for genetically modified human cells · Within the guideline · Low-risk modality
“The risk of inadvertent germline transmission of the CD19 CAR construct has not been addressed; however, the Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors (EMEA/273974/2005) indicates that the risk of germline transmission associated with the administration of genetically modified human cells is considered to be low”
CarcinogenicityVerdict not stated
No genotoxicity or carcinogenicity/tumorigenicity studies; published literature review on retrovirally transduced T cells instead
Why: Literature suggests T cells are relatively resistant to malignant transformation by retroviral vectors · Weight of evidence · Human data
“To address the risk of retroviral vector insertional mutagenesis and potential carcinogenicity/tumorigenicity the applicant performed a review of published nonclinical and clinical information reported for T cells transduced with retroviral vectors. The data suggest that T cells are relatively resistant to malignant transformation by retroviral vectors.”
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