Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors.
We present a strategy for adoptive immunotherapy using T-lineage committed lymphoid precursor cells generated by Notch1-based culture. We found that allogeneic T-cell precursors can be transferred to irradiated individuals irrespective of major histocompatibility complex (MHC) disparities and give rise to host-MHC restricted and host-tolerant functional allogeneic T cells, improving survival in irradiated recipients as well as enhancing anti-tumor responses. T-cell precursors transduced to express a chimeric receptor targeting hCD19 resulted in significant additional anti-tumor activity, demonstrating the feasibility of genetic engineering of these cells. We conclude that ex vivo generated MHC-disparate T-cell precursors from any donor can be used universally for 'off-the-shelf' immunotherapy, and can be further enhanced by genetic engineering for targeted immunotherapy.
Zakrzewski
Johannes L
JL
Department Immunology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Suh
David
D
Markley
John C
JC
Smith
Odette M
OM
King
Christopher
C
Goldberg
Gabrielle L
GL
Jenq
Robert
R
Holland
Amanda M
AM
Grubin
Jeremy
J
Cabrera-Perez
Javier
J
Brentjens
Renier J
RJ
Lu
Sydney X
SX
Rizzuto
Gabrielle
G
Sant'Angelo
Derek B
DB
Riviere
Isabelle
I
Sadelain
Michel
M
Heller
Glenn
G
Zúñiga-Pflücker
Juan Carlos
JC
Lu
Chen
C
van den Brink
Marcel R M
MR
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D014162:Transfection / Q000379:methods*; D014184:Transplantation, Homologous