Universal artificial antigen presenting cells to selectively propagate T cells expressing chimeric antigen receptor independent of specificity.
T cells genetically modified to stably express immunoreceptors are being assessed for therapeutic potential in clinical trials. T cells expressing a chimeric antigen receptor (CAR) are endowed with a new specificity to target tumor-associated antigen (TAA) independent of major histocompatibility complex. Our approach to nonviral gene transfer in T cells uses ex vivo numeric expansion of CAR T cells on irradiated artificial antigen presenting cells (aAPC) bearing the targeted TAA. The requirement for aAPC to express a desired TAA limits the human application of CARs with multiple specificities when selective expansion through coculture with feeder cells is sought. As an alternative to expressing individual TAAs on aAPC, we expressed 1 ligand that could activate CAR T cells for sustained proliferation independent of specificity. We expressed a CAR ligand (designated CARL) that binds the conserved IgG4 extracellular domain of CAR and demonstrated that CARL aAPC propagate CAR T cells of multiple specificities. CARL avoids technical issues and costs associated with deploying clinical-grade aAPC for each TAA targeted by a given CAR. Using CARL enables 1 aAPC to numerically expand all CAR T cells containing the IgG4 domain, and simplifies expansion, testing, and clinical translation of CAR T cells of any specificity.
*Division of Pediatrics, Children's Cancer Hospital, The University of Texas MD Anderson Cancer Center ‡Department of Biostatistics, The University of Texas MD Anderson Cancer Center †The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX.
David
D
Rushworth
Bipulendu
B
Jena
Simon
S
Olivares
Sourindra
S
Maiti
Neima
N
Briggs
Srinivas
S
Somanchi
Jianliang
J
Dai
Dean
D
Lee
Laurence J N
LJ
Cooper
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D016219:Immunotherapy, Adoptive; D020014:K562 Cells; D051379:Mice; D011946:Receptors, Antigen / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D018941:Antigens, CD19; D011946:Receptors, Antigen; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins