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Beyond conventional adoptive T cell therapy
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DOI：10.1016/j.jaci.2025.08.004.png)
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Abstract
En 中文
Reconstitution of the T cell compartment is essential in the treatment of several immune disorders. Similarly, individuals with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation experience prolonged T cell deficiencies, which increase the risk of infections and relapses. Various strategies for addressing T cell deficiencies are based on adoptive T cell therapies. However, challenges related to specificity, safety, scalability, and manufacturing have yet to be overcome. Human T lymphoid progenitor (HTLP)-based immunotherapy might be a valuable, complementary approach for increasing the effectiveness of current treatments for T cell deficiencies. We developed a feeder-free culture system that leverages a human DLL4-Fc fusion protein (Notch ligand) to generate HTLP from CD34+ hematopoietic stem and progenitor cells within 7 days. The cell product, called ProTcell, is mainly constituted of cells expressing CD7, chemokine receptor proteins (e.g. CCR9) and adhesion molecules (e.g. L-selectin). After injection in NSG mice, ProTcell can differentiate and be educated in the thymus to generate simple positive T-cells. Here, we summarize the current state of preclinical and clinical research using this approach, highlighting its potential advantages and current limitations for immune reconstitution therapies.
Keywords:
Hematopoietic stem cell transplantation
T cell progenitor
T lymphocyte
Lymphopoiesis
Immune reconstitution
Thymus
DLL4
ATO
artificial thymic organoids
CAR
chimeric antigen receptor
CB
cord blood
cTECs
cortical TECs
DLL1/4
delta-like ligand 1/4
EC
ethics committee
GMP
good manufacturing practice
GvHD
graft-versus-host disease
HCT
hematopoietic cell transplant
HLA
human leukocyte antigen
HSCT
hematopoietic stem cell transplantation
HSPCs
hematopoietic stem/progenitor cells
HTLP
human T-lymphoid progenitor
ICIs
immune checkpoint inhibitors
iPSCs
induced pluripotent stem cells
LTA
lymphotoxin alpha
MAIT
mucosal-associated invariant T
mPB
mobilized peripheral blood
mRNA
messenger ribonucleic acid
mTEC
medullary TEC
NSG
Nod SCID gamma
PTCy
post-transplantation cyclophosphamide
RANKL
receptor activator of nuclear factor kappa-B ligand
RNA
ribonucleic acid
TCEs
T-cell engagers -TCR
T cell receptor
TEC
thymic epithelial cell
TECs
thymic epithelial cells
TNFα
tumor necrosis factor alpha
Treg: regulatory T
TSPs
thymus-seeding progenitors
VCAM1
vascular cell adhesion molecule 1
Vα
variable alpha chain
Vδ
variable delta chain
αβ
alpha beta
γδ
gamma delta
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