Abecma
idecabtagene vicleucel · BCMA CAR-TCountry not stated; first-in-human dose-finding study in patients with relapsed/refractory multiple myeloma (CRB-401)
Tecelra: what was done before first-in-human, and what came after?
afamitresgene autoleucel · MAGE-A4 TCR-T
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.”
Same question, other cell therapies
Carvykti
ciltacabtagene autoleucel · BCMA CAR-TCountry not stated; first clinical trial in patients with relapsed/refractory multiple myeloma (LEGEND-2)
MACI
autologous cultured chondrocytes on porcine collagen membrane · Autologous chondrocytesOutside the United States: all clinical studies ex-US (countries not named)
Yescarta
axicabtagene ciloleucel · CD19 CAR-TCountry not stated; initial dose-finding study NCI 09-C-0082 in patients with advanced B-cell malignancies
Zemcelpro
dorocubicel · UM171-expanded cord blood CD34+Canada: dose de-escalation study (Study 001) at 2 sites in patients needing allogeneic stem cell transplant
Alofisel
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Amtagvi
lifileucel · TIL therapyNot stated in public reviews
Aucatzyl
obecabtagene autoleucel · CD19 CAR-TNot stated in public reviews
Breyanzi
lisocabtagene maraleucel · CD19 CAR-TNot stated in public reviews
ChondroCelect
characterised viable autologous cartilage cells · Autologous chondrocytesNot stated in public reviews
Ebvallo
tabelecleucel · EBV-specific allogeneic T cellsNot stated in public reviews
Encelto
revakinagene taroretcel · CNTF (encapsulated RPE cell implant)Not stated in public reviews
Gintuit
allogeneic cultured keratinocytes and fibroblasts in bovine collagen · Allogeneic keratinocytes + fibroblastsNot stated in public reviews
Holoclar
autologous corneal epithelial cells containing limbal stem cells · Autologous limbal stem cellsNot stated in public reviews
Kymriah
tisagenlecleucel · CD19 CAR-TNot stated in public reviews
Lantidra
donislecel · Allogeneic pancreatic isletsNot stated in public reviews
Laviv
azficel-T · Autologous fibroblastsNot stated in public reviews
Omisirge
omidubicel · Expanded cord blood HPCNot stated in public reviews
Provenge
sipuleucel-T · PAP-GM-CSF (autologous APC)Not stated in public reviews
Rethymic
allogeneic processed thymus tissue · Allogeneic thymus tissueNot stated in public reviews
Ryoncil
remestemcel-L · Allogeneic BM-MSCNot stated in public reviews
Spherox
spheroids of autologous matrix-associated chondrocytes · Autologous chondrocyte spheroidsNot stated in public reviews
StrataGraft
allogeneic cultured keratinocytes and dermal fibroblasts in murine collagen · Allogeneic keratinocytes + fibroblastsNot stated in public reviews
Tecartus
brexucabtagene autoleucel · CD19 CAR-TNot stated in public reviews
Tregzi
allogeneic Treg immunotherapy with HSPC and T cells (Orca-T) · Allogeneic Treg + HSPC + TconNot stated in public reviews
Zalmoxis
allogeneic T cells modified with HSV-TK / dLNGFR (nalotimagene carmaleucel) · HSV-TK suicide-gene T cellsNot stated in public reviews