Generation of cytotoxic donor CD8+ T cells against relapsing leukemic cells following allogeneic transplantation by stimulation with leukemic cell- or leukemic lysate pulsed donor cell-derived dendritic cells

Lee, Je‐Jung; Nam, Chan-Eun; Nam, Jong Hee; Lee, Hyun Chul; Chung, Ik‐Joo; Park, Myong-Suk; Choi, Bo-Hwa; Song, Won-Hyun; Lee, Il-Kwon; Park, Kyeong-Soo; Kook, Hoon; Hwang, Tai-Ju; Takei, Masao; Takaue, Yoichi; Kim, Hyeoung-Joon

doi:10.1016/j.leukres.2003.08.018

Cited by 20 publications

(12 citation statements)

References 24 publications

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“…The cells were seen to increase in size, and they developed cytoplasmic protrusion. Also, we confirm the origin of the leukemic DCs as being the leukemic clones themselves using interphase fluorescence in situ hybridization analysis, as described previously [16]. When the leukemic cells were cultured with 1 · 10 7 cells per 5 mL of the medium, the median number of leukemic-DCs harvested from group A, group B, and group C was 1.2 · 10 6 cells (range, 0.8-1.9 · 10 6 cells), 1.5 · 10 6 cells (0.7-2.2 · 10 6 cells), and 1.3 · 10 6 cells (1.2-2.0 · 10 6 cells), respectively (Table I).…”

Section: Generation Of Leukemic Dcs In Vitrosupporting

confidence: 76%

“…In addition, DCbased vaccination may be used as a potential alternative tool to augment the effect of donor lymphocyte infusion for treating leukemic patients who relapse after allogeneic transplantation [16,25].…”

Section: Discussionmentioning

confidence: 99%

“…The purity of isolated cells was >90% for CD3+ cells. The CD3+ T cells (1 · 10 6 cells) were co-cultured as autologous effector cells at a ratio of 2:1 with autologous leukemic DCs (2 · 10 5 cells) in 2 ml of medium (RPMI 1640:AIM-V at 1:1) that contained 10% FCS (Sigma, St Louis, MO), 1% penicillinstreptomycin (Gibco-BRL), and 0.1 mM/L nonessential amino acids, which was supplemented with 10 ng/mL IL-2 (R&D Systems) and 5 ng/mL IL-7 (R&D Systems), representing a slight modification of the medium used in our previous report [15,16]. The cultures were fed every 3 days with a halfvolume of fresh medium that contained IL-2 and IL-7.…”

Section: Ifn-c Release Elispot Assaymentioning

confidence: 99%

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The generation of leukemic dendritic cells from acute myeloid leukemia cells is potentiated by the addition of CD40L at the terminal maturation stage

Lee

Choi

Nam

et al. 2004

J of Clinical Apheresis

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Leukemic dendritic cells (DCs) that are derived from acute myeloid leukemia (AML) cells display low-level expression of several key molecules. We investigated the optimal combination of cytokines needed to generate potent leukemic DCs from AML cells in vitro. AML cells were cultured in the presence of the following combinations of cytokines: Group A, granulocyte-macrophage colony-stimulating factor (GM-CSF) + interleukin-4 (IL-4) + tumor necrosis factor-alpha (TNF-alpha); Group B, GM-CSF + IL-4 + CD40L; and Group C, CD40L addition at the terminal maturation point of cells that were grown as for Group A. The AML cells showed clear upregulation of CD80, CD83, CD86, CD40, and HLA-DR expression under all culture conditions, without significant differences between these groups. However, the addition of CD40L (as in Group C) showed a slight upregulation in the expression of CD83 and CD86 on leukemic DCs. The leukemic DCs in Groups A and B had higher allogeneic T-cell stimulatory capacities than untreated AML cells, and the addition of CD40L (Group C) enhanced this effect. The function of the cytotoxicity-stimulating autologous T cells was also augmented by the addition of CD40L (Group C). These results suggest that AML cells may be used to generate leukemic DCs using various cytokine combinations, and that the most potent, mature leukemic DCs are generated by the addition of CD40L to terminal-stage AML cultures that are grown in the presence of conventional cytokine combinations.

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Section: Generation Of Leukemic Dcs In Vitrosupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Ifn-c Release Elispot Assaymentioning

confidence: 99%

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The generation of leukemic dendritic cells from acute myeloid leukemia cells is potentiated by the addition of CD40L at the terminal maturation stage

Lee

Choi

Nam

et al. 2004

J of Clinical Apheresis

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“…13,43,44 Another potential approach is adoptive immunotherapy using ex vivo-generated cytotoxic donor T lymphocytes stimulated by donor dendritic cells pulsed with minor histocompatibility antigens or leukemic lysates. 45,46 In addition, it may also be important to minimize the leukemic cell burden before the application of DLI, since the GVL effect of DLI would be more effective when the disease is minimal. To achieve this goal, several cycles of chemotherapy and/or addition of new therapeutic agents into usual chemotherapy regimen could be tried before and/or after DLI with careful monitoring of minimal residual disease.…”

Section: Discussionmentioning

confidence: 99%

Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study

Choi

Lee

Kim

et al. 2005

Bone Marrow Transplant

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Summary:Donor leukocyte infusion (DLI) alone has very limited efficacy for patients with acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic bone marrow transplantation (BMT). We, therefore, prospectively tested the efficacy of cytoreductive chemotherapy (intermediate-dose cytarabine þ idarubicin þ etoposide) followed immediately by G-CSF-primed DLI (Chemo-DLI) in 10 relapsed ALL patients after allogeneic BMT. Seven achieved complete remission (CR) at a median of 25 days (19-73 days) after DLI. Of these seven CR patients, only one remains alive in CR 907 days after DLI. Two CR patients died in CR of graft-versus-host disease. The remaining four CR patients relapsed at a median of 153 days (120-991 days) after DLI. One is alive with leukemia at post-DLI day 1217. The median survival duration after DLI was 175 days (15-1217 days). In summary, although Chemo-DLI for relapsed ALL after allogeneic BMT induced a relatively high CR rate, durable remissions were rare. Although our data should be interpreted cautiously considering the small number of patients, these results suggest that poor outcome of DLI in relapsed ALL may be primarily due to intrinsic resistance to graft-versus-leukemia effect rather than to the rapid pace of the disease. For patients with acute lymphoblastic leukemia (ALL) receiving allogeneic bone marrow transplantation (BMT), relapse remains the major cause of treatment failure and is associated with a very poor prognosis. The optimal salvage treatment for patients with ALL who relapse after allogeneic BMT has not yet been established, since most therapies are of limited benefit. While reinduction chemotherapy can induce remission in about 40-60% of patients, most of these patients eventually relapse and die of uncontrolled leukemia, with a 3-year disease-free survival (DFS) rate of less than 10%. 1-4 A second BMT results in long-term event-free survival in only 10-20% of patients with relapsed ALL. 5-7 However, even these poor results may be an overestimate because only a small proportion of relapsed patients is suitable for second BMT, and hence the results may reflect the positively biased outcome of a highly selected group of patients. Only 7-20% of patients has been reported to reach the stage of a second BMT after relapse according to the performance and remission status after salvage chemotherapy. 2,8 Moreover, second BMT is associated with extremely high treatment-related mortality, ranging from 40% to 50%. [6][7][8] Another approach to the treatment of ALL patients who relapse after allogeneic BMT is donor leukocyte infusion (DLI), which may induce a graft-versus-leukemia (GVL) effect. DLI has been shown to be highly effective in patients with chronic myelogenous leukemia (CML) who relapse into the chronic phase, achieving complete and durable remission in 70-80% of these patients. 9,10 In contrast, DLI for relapsed ALL has been much less effective. Although there have been many case reports showing that patients with ALL respond to DLI, [11][12][13][14][15][16][17][18][...

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“…Autologous CD3+ T cells were isolated by positive selection using MACS (Miltenyi Biotec) from the peripheral blood of patients who had achieved CR. The CD3+ T cells (1 3 10 6 cells) were co-cultured as autologous effector cells at a ratio of 5:1 with leukemic DCs (2 3 10 5 cells) in 2 ml of medium (RPMI 1640:AIM-V at 1:1) containing 10% FCS (Sigma, St Louis, MO), 1% penicillin-streptomycin (GIBCO-BRL), 0.1 mM non-essential amino acids supplement, 10 ng/mL IL-2 (R&D Systems), and 5 ng/mL IL-7 (R&D Systems), as described in our previous report [23,24]. The cultures were fed every 3 days with a half-volume of fresh medium containing IL-2 and IL-7.…”

Section: Ifn-g Release Enzyme Linked Immunospot (Elispot) Assaymentioning

confidence: 99%

Optimization of the concentration of autologous serum for generation of leukemic dendritic cells from acute myeloid leukemic cells for clinical immunotherapy

et al. 2006

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Clinical application of immunotherapy for acute myeloid leukemia (AML) requires the efficient induction of dendritic cells (DCs) from AML blast cells using in vitro culture. We examined the effect of autologous serum on the properties of leukemic DCs derived from leukemic cells of AML patients by culture in AIM-V medium with GM-CSF, IL-4, TNF-alpha, and 0, 2, 5, or 10% human autologous serum. The expressions of CD80, CD83, CD86, and HLA-DR were upregulated under all culture conditions; however, 10% autologous serum induced the highest expression levels of several molecules. The capacity of leukemic DCs to stimulate allogeneic T cells increased with increasing serum concentration. Stimulation of autologous CD3(+) T cells with leukemic DCs grown in the presence of various concentrations of autologous serum resulted in induction of more IFN-gamma-secreting cells than was the case for unprimed CD3(+) T cells. Leukemic DCs cultured with 10% autologous serum induced the highest numbers of IFN-gamma-secreting cells and CD8(+)CD56(+) T cells from autologous T cells. These results suggest that culture of AML blast cells in the presence of autologous serum could be used to generate leukemic DCs for immunotherapy against AML. The highest serum concentration appeared optimal for generating the most potent leukemic DCs.

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Generation of cytotoxic donor CD8+ T cells against relapsing leukemic cells following allogeneic transplantation by stimulation with leukemic cell- or leukemic lysate pulsed donor cell-derived dendritic cells

Cited by 20 publications

References 24 publications

The generation of leukemic dendritic cells from acute myeloid leukemia cells is potentiated by the addition of CD40L at the terminal maturation stage

The generation of leukemic dendritic cells from acute myeloid leukemia cells is potentiated by the addition of CD40L at the terminal maturation stage

Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study

Optimization of the concentration of autologous serum for generation of leukemic dendritic cells from acute myeloid leukemic cells for clinical immunotherapy

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