Chronic Myeloid Leukemia Cell Derived Multi Antigen Vaccines

Heat Shock Protein Vaccines

Heat shock proteins (HSPs) are ubiquitous protective intracellular molecules induced by cellular stress, which act as chaperones for peptides. HSPs isolated from tumor cells carry an array of tumor-specific peptides capable of inducing immune responses. In fact, purified HSP-peptide complexes have been demonstrated to activate CD8+ and CD4+ lymphocytes to induce innate immune responses, including natural killer (NK) cell activation, cytokine secretion, and induce maturation of DCs (33). In a phase I trial, vaccinations with patient-specific autologous leukocyte-derived HSP70 peptide complexes were given to 20 CML patients who had cytogenetic or molecular evidence of disease despite ongoing treatment with imatinib (34). In each patient entering this study, HSP70 was purified from the leukapheresed peripheral blood mononuclear cells and administered in eight-week intervals as intradermal injections without immunological adjuvant. The vaccine produced no adverse effects and was associated with a reduction in Ph-positive cells and/or BCR-ABL expression in 13/20 patients. Immunologic responses, measured as increased IFN-y expression in T cells against pre-vaccination leukocyte targets, were observed in 9/16 patients analyzed (34). A significant correlation between clinical responses and immunologic responses was observed. Phase II clinical trials are currently underway.

Other Vaccine Candidates

Although not yet tested in clinical trials, several other molecules that are either CML-specific or preferentially expressed by CML cells are under evaluation as potential targets for immunotherapy. These include CML66 and CML28 tumor-associated antigens found both in leukemias and in a variety of solid tumor cell lines, but not in normal hematopoietic tissue (35). Other potential immunothera-peutic targets in CML are survivin, an antiapoptotic molecule up-regulated in CML cells (36), telomerase, thought to be involved in disease progression and potentially linked to imatinib resistance (37), and RHAMM/CD168 expressed in about 83% of CML cells and able to mediate a specific T cell response in CML patients (38).

Cell-Based Vaccines

An additional approach of inducing a CML-specific immune attack against MRD exploits the capacity of DCs to efficiently process and present antigens, which leads to effective sensitization of naive T lymphocytes (39). Human DCs can be obtained from CD34+ bone marrow cells and from human peripheral monocytes in the presence of cytokine combinations. As the majority of CML DCs carry t(9;22), the immune response induced by an "unprimed DCs"-based vaccine approach relies on presentation of leukemic antigens inherently expressed by the leukemic DC. Autologous BCR-ABL-positive DCs have been safely used for vaccinations in CP patients with an insufficient response to imatinib and have been shown to induce CML-specific T-cell responses in association with a decrease in tumor cell burden/circulating BCR-ABL-positive cells (40). The feasibility of this patient-specific vaccine approach in the setting of MRD after imatinib needs further evaluation, as imatinib treatment dramatically reduces Ph-positive DCs and it could be difficult to generate an adequate amount for vaccination. Additionally, the immunologic efficiency may be reduced if imatinib adversely affected DC function (41,42). An alternative approach is to generate more efficient targeted immune responses by loading (or "priming") Ph-positive or Ph-negative DCs with tumor-specific antigens (i.e., BCR-ABL, PR3 or WT-1 derived peptides, and HSPs or autologous tumor lysates). In this setting, peptide-specific immune responses, but no clinical improvement, were observed in three patients vaccinated with b3a2 fusion peptide-primed DCs (43). A different cell-based vaccine approach is underway in a pilot clinical trial in which irradiated K562 cells genetically modified to secrete GM-CSF (K562/GM-CSF) are administered subcutaneously to CML patients undergoing therapy with imatinib (44).

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