Vaccines for Acute Myeloid Leukemia AML

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AML cells can be made into cell vaccines for the disease. A strategy that has been extensively pursued is the differentiation or maturation of leukemia cells into DCs, which reflects the knowledge of DC development from primitive myeloid cells (32-34). A representative study by Choudhury and coworkers (113) demonstrated that the cytokine combination of GM-CSF and IL-4 together with CD40L or TNF-a induced primary AML cells from 18 of 19 patients to differentiate into DC-like cells that were able to effectively stimulate the generation of leukemia-specific CTLs, when cocultured with autologous T cells. These CTLs lysed autologous leukemia cells but not normal cells. A more recent study from Harrison and coworkers (114) confirmed these results. In their study, blast samples from 24 of 40 patients with AML were differentiated into DC-like cells in the presence of GM-CSF, IL-4, and TNF-a. Most of the DC-like cells were able to activate allogeneic T cells and stimulate autologous T cells. Other reagents, such as stem-cell factor (115,116), transforming growth factor-P (116,117), FLT3 ligand (115), and cytokines IL-3 and IL-6 (118), have been used to optimize the conditions of generating AML DCs. As AML is a heterogeneous disease, further studies are required to predict the potential of leukemia cells from individual patients to differentiate into DC-like cells.

An alternative method is direct gene transfer of immunomodulators into AML cells as a means of improving their immunogenicity. These could be the costimulatory molecules and IL-12, which can facilitate T-cell priming; cytokines such as GM-CSF and IL-2, which trigger inflammation and recruit high numbers of professional APCs to the vaccination site; or GM-CSF, IL-4, and CD40L, which promote differentiation and maturation of leukemia cells into effective APCs (105). In murine models of AML, vaccination with irradiated leukemia cells transduced with CD80 (119); with GM-CSF, but not CD86-, IL-4-, or TNF-a-transduced AML cells (120); or with IL-12 elicited leukemia-specific protective and therapeutic immunity (121). Immunized mice showed no sign of systemic IL-12 toxicity, and their spleen histology was comparable with that of naïve mouse spleen (121). In a preclinical study, Koya and coworkers (122) transduced human ALL cells with third-generation self-inactivating lentivirus vectors expressing CD80 and GM-CSF. GM-CSF transduction and expression were associated with higher proliferation and cell viability, as well as enhanced capacity to induce allogeneic and autologous T-cell activation by transduced AML cells. Hence, these approaches might be feasible and applicable to immunotherapy in human disease.

In addition to blast-derived DCs, functional DCs can also be obtained from nonleukemic sources in patients with AML. Spisek and coworkers (123) recently reported on their experience with generating such cells from AML patients. In their study, mature, tumor-pulsed nonleukemic DCs were successfully generated from remission samples of all (n = 10) tested patients. These cells were used as APCs to induce leukemia-specific CTLs, which showed significant cytotoxic activity against autologous AML cells similar to that of CTLs stimulated by leukemic DCs. Thus, the induction of a leukemia-specific cytotoxic response by nonleukemic DCs cross-presenting apoptotic leukemic blasts offers a complementary approach to immunotherapy and has led to clinical trials. In their pilot study, Lee and coworkers (124) treated two patients with AML that had relapsed after autologous stem cell transplantation with DC vaccination. The vaccines were autologous CD14+ monocyte-derived DCs pulsed with AML tumor lysate. Patients received a mean of 7.8 x 106 DCs and 9 x 106 DCs, respectively. After vaccination, a positive DTH skin reaction and T-cell proliferation to tumor lysate-pulsed DCs were seen, although no improvement in patients' clinical status was observed. Further studies are needed to determine the appropriate dose of DCs and the most effective means of tumor antigen loading and presentation. Indeed, a recent study showed that DC-leukemia cell hybrids might be more potent at inducing specific CTL activity in vitro than DCs pulsed with either apoptotic leukemia cells or tumor-cell lysate (125).

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