Selective elimination of a chemoresistant side population of B-CLL cells by cytotoxic T lymphocytes in subjects receiving an autologous hCD40L/IL-2 tumor vaccine.
Side-population (SP) analysis identifies precursor cells in normal and malignant tissues. Cells with this phenotype have increased resistance to many cytotoxic agents, and may represent a primary drug-resistant population in malignant diseases. To discover whether drug-resistant malignant SP cells are nonetheless sensitive to immune-mediated killing, we first established the presence of a malignant CD5(+)CD19(+) SP subset in the blood of 18/21 subjects with B-cell chronic lymphocytic leukemia (B-CLL). We examined the fate of these cells in six of these individuals who received autologous human CD40 ligand and interleukin-2 (hCD40L/IL-2) gene-modified tumor cells as part of a tumor vaccine study. Vaccinated patients showed an increase in B-CLL-reactive T cells followed by a corresponding decline in circulating CD5(+)CD19(+) SP cells. T-cell lines and clones generated from vaccinated patients specifically recognized B-CLL SP tumor cells. Elimination of SP cells is likely triggered by their increased expression of target antigens, such as receptor for hyaluronan-mediated motility (RHAMM), after stimulation of the malignant cells by hCD40L, as CD8(+) RHAMM-specific T cells could be detected in the peripheral blood of immunized patients and were associated with the decline in B-CLL SP cells. Hence, malignant B cells with a primary drug-resistant phenotype can be targeted by T- cell-mediated effector activity after immunization of human subjects.
Foster
A E
AE
Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA. aefoster@txccc.org
Okur
F V
FV
Biagi
E
E
Lu
A
A
Dotti
G
G
Yvon
E
E
Savoldo
B
B
Carrum
G
G
Goodell
M A
MA
Heslop
H E
HE
Brenner
M K
MK
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000032:analysis; D023201:CD40 Ligand / Q000276:immunology*; D018956:CD5 Antigens / Q000032:analysis; D019496:Cancer Vaccines / Q000276:immunology*; D019008:Drug Resistance, Neoplasm; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D007114:Immunization; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018941:Antigens, CD19; D018956:CD5 Antigens; D019496:Cancer Vaccines; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; C098946:hyaluronan-mediated motility receptor; D023201:CD40 Ligand; D014740:Vidarabine; C024352:fludarabine