Tecelra
afamitresgene autoleucel
Species
no relevantMouse
Longest study
none
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; in vitro cross-reactivity/alloreactivity and murine xenograft pharmacology only
“Standard in vivo single-dose or repeat-dose toxicity studies were not conducted with afamitresgene autoleucel due to the lack of appropriate animal models for testing of human TCR engineered T-cells.”
Why that species
HLA-restricted human TCR: MHC mismatch with animals; humanized mice develop lethal xeno-GvHD within 8 weeks
“Because afamitresgene autoleucel is an autologous engineered-TCR T-cell therapy, there is a mismatch of MHC antigens between animal and human TCRs, so specificity cannot be assessed.”
Surrogate molecule
No surrogate; engineering an animal TCR judged uninformative for human TCR specificity/safety
“Engineering an animal TCR for use in animal model testing would also not reflect the specificity/safety profile of the human TCR, and therefore would be uninformative.”
Species: general tox
None; no in vivo toxicity studies (no appropriate animal model for human TCR-engineered T cells)
“Standard in vivo single-dose or repeat-dose toxicity studies were not conducted with afamitresgene autoleucel due to the lack of appropriate animal models for testing of human TCR engineered T-cells.”
Species: DART
Not conducted; acceptable based on product characteristics and safety profile
“No animal reproductive and developmental toxicity studies were conducted with TECELRA which is acceptable based on the product characteristics and safety profile.”
Species: carcinogenicity
Not conducted (no relevant animal models)
“Afamitresgene autoleucel is a human TCR engineered T-cell product, therefore conventional carcinogenicity studies were not performed due to the lack of relevant animal models.”
Surrogate used in
No surrogate used; an animal TCR was judged uninformative
“Engineering an animal TCR for use in animal model testing would also not reflect the specificity/safety profile of the human TCR, and therefore would be uninformative.”
Study lengthopen answer page →
Longest pivotal study
0 (no in vivo tox study)
“Standard in vivo single-dose or repeat-dose toxicity studies were not conducted with afamitresgene autoleucel due to the lack of appropriate animal models for testing of human TCR engineered T-cells.”
Pivotal GLP studies
No in vivo tox; in vitro X-scan/MAGE-family peptide cross-reactivity, alloreactivity, normal/iPSC cell co-culture; murine xenograft efficacy
“A comprehensive analysis of cross-reactivity was performed using a peptide library screen with single amino-acid substitutions at each position of the antigenic peptide sequence (X-scan) and peptides from MAGE family member proteins.”
Route in tox
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.
Skipped studiesopen answer page →
Genotoxicity
Not conducted (no test models or relevant species); integration site analysis showed polyclonal products, no selective insertion
“Conventional genotoxicity studies were not conducted with afamitresgene autoleucel, due to the lack of appropriate test models and pharmacologically relevant species.”
Carcinogenicity
Not conducted (no relevant animal models for human TCR-engineered T cells)
“Afamitresgene autoleucel is a human TCR engineered T-cell product, therefore conventional carcinogenicity studies were not performed due to the lack of relevant animal models.”
Instead of genotoxicity
Genomic insertion site analysis on products from five patients; no preferential integration near genes of concern
“A genomic insertion site analysis was performed on TECELRA products from five patients. There was no evidence for preferential integration near genes of concern.”
Reproductive & developmental
Not conducted; theoretical testis/placenta risk (MAGE-A4 expression) judged mitigated by immune privilege, labeling, pharmacovigilance
“MAGE-A4 is known to be expressed in testes and placenta, and so there is a theoretical risk of embryotoxicity or toxicity to the testes.”
Safety pharmacology
Not conducted; no relevant animal models
“No safety pharmacology studies were conducted, as there are no relevant animal models for the nonclinical safety assessment of afamitresgene autoleucel.”
Genotox: Ames
Not conducted
“Conventional genotoxicity studies were not conducted with afamitresgene autoleucel, due to the lack of appropriate test models and pharmacologically relevant species.”
Genotox: in vitro mammalian
Not conducted
“Conventional genotoxicity studies were not conducted with afamitresgene autoleucel, due to the lack of appropriate test models and pharmacologically relevant species.”
Genotox: in vivo
Not conducted
“Conventional genotoxicity studies were not conducted with afamitresgene autoleucel, due to the lack of appropriate test models and pharmacologically relevant species.”
Carcinogenicity model
Not conducted; vector integration site profile similar to other lentiviral products, no greater insertional oncogenesis risk expected
“However, vector integration site analysis demonstrated that the insertion site profile for the product was similar to other lentiviral vector products and was not expected to represent a greater risk for the development of insertional oncogenesis.”
Carcinogenicity timing
Not conducted; no relevant animal models for a human TCR-engineered T-cell product
“Afamitresgene autoleucel is a human TCR engineered T-cell product, therefore conventional carcinogenicity studies were not performed due to the lack of relevant animal models.”
hERG / QT
Not conducted (no relevant animal models for safety pharmacology)
“No safety pharmacology studies were conducted, as there are no relevant animal models for the nonclinical safety assessment of afamitresgene autoleucel.”
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 Tecelra 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; in vitro alloreactivity against HLA-A*02:05 (contraindication); cross-reactivity to MAGE-A8/MAGE-B2 (cancer/germline-restricted) (FDA multi-discipline review, p. 39)
NOAEL / key findings
No NOAEL; in vitro alloreactivity against HLA-A*02:05 (contraindication); cross-reactivity to MAGE-A8/MAGE-B2 (cancer/germline-restricted)
“An alloreactivity screen against a panel of cells expressing a range of HLA alleles indicated in vitro alloreactivity against HLA-A*02:05. Therefore, afamitresgene autoleucel is contraindicated for adults who are heterozygous or homozygous for HLA-A*02:05P.”
Risksopen answer page →
Immune & cytokine safety
In vitro cytokine-release assay for cytokine-storm risk, no concerns; no immunogenicity studies (wild-type human TCR)
“No immunogenicity studies have been performed on afamitresgene autoleucel, as there are no suitable animal models for assessment of the immunogenicity of human TCRs.”
Biodistribution & persistence
No PK/ADME studies; not considered relevant for autologous T-cell product
“Afamitresgene autoleucel, cell suspension for infusion is an autologous T-cell product. Therefore, traditional pharmacokinetic and ADME studies are not considered relevant to this product.”
Modality-specific risk
TCR off-target cross-reactivity and HLA alloreactivity; LV insertional oncogenesis (integration profile similar to other LV products)
“However, vector integration site analysis demonstrated that the insertion site profile for the product was similar to other lentiviral vector products and was not expected to represent a greater risk for the development of insertional oncogenesis.”
Anti-drug antibodies: animals
Not studied; no suitable animal models for immunogenicity of human TCRs
“No immunogenicity studies have been performed on afamitresgene autoleucel, as there are no suitable animal models for assessment of the immunogenicity of human TCRs.”
Anti-drug antibodies: patients
Not evaluated in clinical studies (low expected immunogenicity)
“Given the low expected immunogenicity risk, the immunogenicity of afamitresgene autoleucel has not been evaluated in clinical studies.”
Label warnings
Boxed warning: Cytokine release syndrome
- Cytokine Release Syndrome
- Immune Effector Cell-associated Neurotoxicity Syndrome
- Prolonged Severe Cytopenia
- Infections
- Secondary Malignancies
- Hypersensitivity Reactions
- Potential for HIV Nucleic Acid Test False-Positive Results
Cytokine release syndromeNeurotoxicityCytopeniasInfectionsSecondary malignancyHypersensitivity & infusion reactions
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human dose-escalation and expansion study in HLA-A*02 patients with MAGE-A4-positive advanced tumors
“a Phase 1, first-in-human, cell dose escalation and expansion study (ADP-0044-001) in HLA-A*02 patients with MAGE-A4-positive unresectable locally advanced or metastatic tumors.”
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 Tecelra 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; in vitro alloreactivity against HLA-A*02:05 (contraindication); cross-reactivity to MAGE-A8/MAGE-B2 (cancer/germline-restricted) (FDA multi-discipline review, p. 39)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No single- or repeat-dose toxicity studies (no appropriate animal model for human TCR-engineered T cells)
“Standard in vivo single-dose or repeat-dose toxicity studies were not conducted with afamitresgene autoleucel due to the lack of appropriate animal models for testing of human TCR engineered T-cells.”
Pivotal GLP studies
No in vivo tox; in vitro X-scan/MAGE-family peptide cross-reactivity, alloreactivity, normal/iPSC cell co-culture; murine xenograft efficacy
“A comprehensive analysis of cross-reactivity was performed using a peptide library screen with single amino-acid substitutions at each position of the antigenic peptide sequence (X-scan) and peptides from MAGE family member proteins.”
DART package
Species: DART
Not conducted; acceptable based on product characteristics and safety profile
“No animal reproductive and developmental toxicity studies were conducted with TECELRA which is acceptable based on the product characteristics and safety profile.”
Reproductive & developmental
Not conducted; theoretical testis/placenta risk (MAGE-A4 expression) judged mitigated by immune privilege, labeling, pharmacovigilance
“MAGE-A4 is known to be expressed in testes and placenta, and so there is a theoretical risk of embryotoxicity or toxicity to the testes.”
PPND / ePPND: when
No reproductive/developmental studies; acceptable given product characteristics and safety profile
“No animal reproductive and developmental toxicity studies were conducted with TECELRA which is acceptable based on the product characteristics and safety profile.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no relevant animal models)
“Afamitresgene autoleucel is a human TCR engineered T-cell product, therefore conventional carcinogenicity studies were not performed due to the lack of relevant animal models.”
Carcinogenicity model
Not conducted; vector integration site profile similar to other lentiviral products, no greater insertional oncogenesis risk expected
“However, vector integration site analysis demonstrated that the insertion site profile for the product was similar to other lentiviral vector products and was not expected to represent a greater risk for the development of insertional oncogenesis.”
Carcinogenicity timing
Not conducted; no relevant animal models for a human TCR-engineered T-cell product
“Afamitresgene autoleucel is a human TCR engineered T-cell product, therefore conventional carcinogenicity studies were not performed due to the lack of relevant animal models.”
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; in vitro alloreactivity against HLA-A*02:05 (contraindication); cross-reactivity to MAGE-A8/MAGE-B2 (cancer/germline-restricted)
“An alloreactivity screen against a panel of cells expressing a range of HLA alleles indicated in vitro alloreactivity against HLA-A*02:05. Therefore, afamitresgene autoleucel is contraindicated for adults who are heterozygous or homozygous for HLA-A*02:05P.”
Efficacy evidenceopen answer page →
Efficacy evidence
Murine tumor xenograft studies showing dose-dependent tumor control
“Murine in vivo xenograft studies demonstrated dose-dependent TECELRA-mediated tumor control.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: xenograft studies demonstrate in vivo activity against MAGE-A4-expressing systemic or local tumors
“These studies demonstrate in vivo ADP-A2M4 activity against MAGE-A4 expressing systemic or local tumors when administered via the IV route of administration.”
Test articleopen answer page →
Test article vs clinical lot
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.
Genetically modified?
Autologous TCR-T (affinity-enhanced MAGE-A4 TCR), lentiviral vector
“TECELRA consists of autologous T cells that are genetically modified with the lentiviral vector (LVV) MAGE-A4-c1032 to constitutively express an affinity-enhanced T cell receptor (TCR) specific for human MAGE-A4.”
First approval
2024 (FDA)
“Summary Basis for Regulatory Action Date: August 1, 2024”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
No in vivo single- or repeat-dose toxicity studies; no appropriate animal model for human TCR-engineered T cells
Why: No appropriate animal model for human TCR-engineered T cells · No relevant species
“Standard in vivo single-dose or repeat-dose toxicity studies were not conducted with afamitresgene autoleucel due to the lack of appropriate animal models for testing of human TCR engineered T-cells.”
DARTAccepted with a conditionBeyond the letter
No reproductive and developmental toxicity studies despite MAGE-A4 expression in testes and placenta
Why: Product characteristics and safety profile; risk mitigated via labelling and routine pharmacovigilance · No relevant species · Human data
“No animal reproductive and developmental toxicity studies were conducted with TECELRA which is acceptable based on the product characteristics and safety profile.”
“In the post-marketing setting, this risk can be mitigated via labelling, and monitored via routine pharmacovigilance measures (follow-up and thorough evaluation of any reported pregnancy cases in the post-marketing setting).”
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology studies
Why: No relevant animal models · No relevant species
“No safety pharmacology studies were conducted, as there are no relevant animal models for the nonclinical safety assessment of afamitresgene autoleucel. The FDA’s Assessment: [FDA concurs with the Applicant.]”
CarcinogenicityAcceptedBeyond the letter
No genotoxicity or carcinogenicity studies; lentiviral vector integration site analysis instead
Why: Insertion site profile similar to other lentiviral vector products; no greater insertional oncogenesis risk expected · Class precedent · Weight of evidence
“Traditional in vitro and in vivo genotoxicity and carcinogenicity assessments were not conducted using TECELRA. However, vector integration site analysis demonstrated that the insertion site profile for the product was similar to other lentiviral vector products and was not expected to represent a greater risk for the development of insertional oncogenesis.”
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