In vitro engagement of CD3 and CD28 corrects T cell defects in chronic lymphocytic leukemia.
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells concomitant with immunological abnormalities and depressed immune responses. The T cell abnormalities found in CLL patients are thought to increase the risk of infection and hamper immune recognition and elimination of leukemic cells. We evaluated whether providing signals through CD3 and CD28 would correct some of these T cell defects. PBMC were incubated with anti-CD3 and anti-CD28 mAbs conjugated to superparamagnetic beads for 12-14 days. This resulted in a 1400-fold increase in T cell numbers. Activated T cells expressed high levels of CD25, CD54, CD137, and CD154, and produced IFN-gamma, TNF-alpha, and GM-CSF. The mean T cell composition of cultures increased from approximately 6% to >90% and leukemic B cells decreased from a mean of approximately 85% to 0.1% or less. Leukemic B cells up-regulated expression of CD54, CD80, CD86, and CD95. Receptor up-regulation required direct cell contact with the activated T cells and could be blocked with anti-CD154 mAb, suggesting that the CD40-CD40L pathway helped mediate these effects. Poor T cell responses to allostimulation were corrected by the activation and expansion process. The skewing in the TCR repertoire returned to normal, or near normal following the culture process in eight of nine patients with abnormal TCR repertoires. Activated T cells had potent in vitro antileukemic effects in contrast to nonactivated T cells. Based upon these findings, a clinical trial has been initiated to test the potential therapeutic effects of T cells activated using this approach in patients with CLL.
Bonyhadi
Mark
M
Xcyte Therapies, Inc., Seattle, WA 98104, USA. mbonyhadi@xcytetherapies.com
Frohlich
Mark
M
Rasmussen
Angela
A
Ferrand
Christophe
C
Grosmaire
Laura
L
Robinet
Eric
E
Leis
Jose
J
Maziarz
Richard T
RT
Tiberghien
Pierre
P
Berenson
Ronald J
RJ
D000911:Antibodies, Monoclonal / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism*; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods*; D016130:Immunophenotyping; D007519:Isoantigens / Q000276:immunology; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D007519:Isoantigens; D016693:Receptors, Antigen, T-Cell, alpha-beta