ABSTRACT
Analyzing the regenerative compartment in the blast cell population of patients with acute myeloid leukemia (AML) may yield important insights into the mechanisms of disease progression. Here we present findings with a human AML cell line (AML-SP1), initiated from leukemic precursor cells and consecutively propagated by serial xenotransplantation in vivo. AML-SP1 maintained the characteristics of a human AML, consistently exhibiting a small leukemic side population (SP) of blast cells with high Hoechst 33342 exclusion. In the AML-SP1 line, an increased expression of the ABC transporters MDR1, MRP, ABCG2 and ABCA3 was found in the SP cells. The detection of ABCA3 in leukemic progenitor cells merits further investigation with regard to intracellular drug transport in AML blast cells. In vivo propagation of leukemias, such as AML-SP1 is a model system of maintaining the populational heterogeneity of AML disease, especially the unique characteristics of leukemic SP cells.
Subject(s)
ATP-Binding Cassette Transporters/biosynthesis , Leukemia, Myelomonocytic, Acute/pathology , Neoplasm Proteins/biosynthesis , ATP-Binding Cassette Transporters/genetics , Adolescent , Animals , Biological Transport , Bone Marrow Transplantation , Cell Line, Tumor/cytology , Cell Line, Tumor/metabolism , Cell Line, Tumor/transplantation , Female , Humans , Leukemia, Myelomonocytic, Acute/metabolism , Leukemia, Myelomonocytic, Acute/therapy , Mice , Neoplasm Proteins/genetics , Neoplasm Recurrence, Local , Neoplasm TransplantationABSTRACT
In murine models, transgenic chemokine-cytokine tumor vaccines overcome many of the limitations of single-agent immunotherapy by producing the sequence of T-cell attraction followed by proliferation. The safety and immunologic effects of this approach in humans were tested in 21 patients with relapsed or refractory neuroblastoma. They received up to 8 subcutaneous injections of a vaccine combining lymphotactin (Lptn)- and interleukin-2 (IL-2)-secreting allogeneic neuroblastoma cells in a dose-escalating scheme. Severe adverse reactions were limited to reversible panniculitis in 5 patients and bone pain in 1 patient. Injection-site biopsies revealed increased cellularity caused by infiltration of CD4+ and CD8+ lymphocytes, eosinophils, and Langerhans cells. Systemically, the vaccine produced a 2-fold (P =.035) expansion of CD4+ T cells, a 3.5-fold (P =.039) expansion of natural killer (NK) cells, a 2.1-fold (P =.014) expansion of eosinophils, and a 1.6-fold (P =.049) increase in serum IL-5. When restimulated in vitro by the immunizing cell line, T cells collected after vaccination showed a 2.3-fold increase (P =.02) of T-helper (TH2)-type CD3+IL-4+ cells. Supernatant collected from restimulated cells showed increased amounts of IL-4 (11.4-fold; P =.021) and IL-5 (8.7-fold; P =.002). Six patients had significant increases in NK cytolytic activity. Fifteen patients made immunoglobulin G (IgG) antibodies that bound to the immunizing cell line. Measurable tumor responses included complete remission in 2 patients and partial response in 1 patient. Hence, allogeneic tumor cell vaccines combining transgenic Lptn with IL-2 appear to have little toxicity in humans and can induce an antitumor immune response.
