Vaccines for Chronic Myeloid Leukemia CML

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CML is characterized by a t(9;22) translocation that results in the expression of chimeric bcr/abl fusion oncoproteins necessary for oncogenesis. Like AML cells, CML-derived DCs show potential as tools for therapy. Leukemia cells of patients with CML will undergo substantial differentiation toward DCs and may be used to drive autologous T cells to acquire antileukemic cytotoxicity (for a review, see ref. 126). Early studies showed that both CD34+ bone marrow cells (127) and peripheral blood cells (128) could be differentiated into DCs after culturing with GM-CSF, TNF-a, and IL-4. These cells contained the CML-specific t(9;22) translocation as revealed by in situ hybridization, indicating that they were leukemic in origin. These leukemic DCs were able to stimulate the generation of specific CTLs that lysed autologous CML cells, but not normal blood or bone marrow cells (128). Addition of IFN-a to the culture may further improve the differentiation of CML cells into leukemic DCs (129). In a clinical study involving one patient with CML, infusion of leukemic DCs induced a vigorous CTL response in vivo that was accompanied by a decrease in the number of tumor cells in the peripheral blood and bone marrow (130). Nevertheless, two recent studies have shown that leukemic DCs from CML patients were functionally abnormal. Compared with DCs from normal donors, CML DCs had altered actin organization, reduced antigen processing, and impaired migration capacity (131). Furthermore, CML DCs displayed a reduced endocytotic capacity and deficiency in ex vivo maturation (132). These defects may be related to underlying cytoskeletal changes induced by the p210 (bcr-abl) fusion protein (131,132).

In CML, more than 90% of patients express the 210-kDa chimeric fusion proteins bcr2/abl2 or bcr3/abl2. Because bcr/abl chimeric protein is expressed only in CML cells, not in normal cells, the fusion sequence may act as a potential target for a T-cell-mediated immune response to CML. Within the fusion region of the bcr3/abl2 protein, different peptides have been identified that bind to HLA-A2, -A3, -A11, and -B8 (133,134). As CML DCs share a common progeny with leukemia cells, bcr/abl is constitutively expressed in these cells (135). The finding by Yasukawa and coworkers (136) that bcr/abl fusion protein-derived, peptide-specific CD4+ T-cell clones were able to augment colony formation by CML cells in a bcr/abl type-specific and HLA class II-restricted manner without addition of exogenous antigen suggests that CML cells can naturally process and present endogenous bcr/abl fusion protein to CD4+ T cells. Their subsequent study confirmed this finding (137). Thus, leukemia-derived DCs can be used as a vaccine to stimulate bcr/abl-specific CTLs. Alternatively, one can also prepare DC vaccines by transducing normal DCs with a virus vector expressing the fusion protein (138) or by pulsing DCs with bcr/abl peptides (139). Both strategies were efficient at stimulating specific CTL activities in vitro. Further studies are needed to evaluate their potential and efficacy as vaccines for treating CML patients.

As fusion proteins offer a good target for immunotherapy, vaccination with bcr/abl peptides has been explored in CML patients. Pinilla-Ibarz and coworkers (140) completed a phase I/II clinical trial to evaluate the safety and immunogenicity of peptide vaccination in 12 CML patients. Cohorts of three patients each received either 50 |g, 150 |g, 500 |g, or 1500 |g of total peptides (a mixture of equal amounts of four class I-restricted CML peptides and one class II-restricted peptide) mixed with 100 |g of QS-21 as an immunological adjuvant. The vaccines were well tolerated. In three of the six patients treated at the two highest dose levels, peptide-specific T-cell proliferative responses (three patients) and/or skin DTH reactions (two patients) were generated. Clinical response was not assessed because all patients remained on their current therapy while receiving the vaccine.

Leukemia cells also express other tumor-associated antigens that can be targeted for immunotherapy (for a review, seeref. 141). One antigen, proteinase 3, a serine proteinase present in the primary granules of neutrophils (142), can elicit a specific immune response in nonimmunized CML patients (143). PR1, a nine-amino-acid HLA-A2-restricted peptide derived from proteinase 3, is highly immunogenic (144). PRl-specific CTLs effectively lysed fresh, autologous CML blasts, and T-cell immunity to PR1 correlated with cytogenetic remission in CML patients treated with IFN-a or allogeneic marrow transplantation (145). On the basis of these observations, a phase I vaccine study was initiated at the M.D. Anderson Cancer Center to determine whether PR1 peptide could elicit CTL immunity in refractory leukemia patients (146). Nine patients were treated in cohorts of three at one of three dose levels of PR1 (0.25, 0.5, or 1.0 mg) in incomplete Freund's adjuvant and 70 |g of GM-CSF every 3 wk in three subcutaneous injections. One patient with myelodysplastic syndrome (MDS), four with AML, and four with CML were enrolled, and two patients were in hematological or cytogenetic remission before the study. After vaccination, antineutrophil cytoplasmic antibodies did not develop in any of the patients, and there was no evidence of vasculitis. Two AML patients died of progressive disease. At each escalating dose level, none, one, and three of three patients, respectively, were in complete remission. PRl-specific CTLs were elicited in all four patients in complete remission. Three of these patients were induced into complete remission, including one patient with overt leukemia. Two patients with relapsed AML before vaccination attained cytogenetic remission after the second injection at dose levels 2 and 3. Thus, this study demonstrated that (PR1) peptide vaccination of leukemia patients could elicit highly active specific immunity against leukemia cells, inducing remission, and merits further studies to confirm the clinical efficacy of such an approach.

5. perspective and conclusion

Id protein has been used for the past 10 yr as the major antigen for immunotherapy in B-cell malignancies. As Id protein is a weak antigen, various strategies have been developed to enhance its immunogenicity, including the addition of or conjugation to KLH or GM-CSF and the use of other cytokines, such as IL-2, as immunomodulators and DCs as APCs (16,17,40,91). These approaches have shown immunological activity, but most of the treated patients did not benefit clinically. This may suggest that the elicited or enhanced immunity following Id vaccination is still too weak to cause significant tumor destruction, or alternatively immunization may generate a nonbeneficial immune response (e.g., a type 2 T-cell response; 147) that might enhance tumor B-cell growth and facilitate differentiation into plasma cell tumors (148,149). Ideally, a tumor-specific immunotherapy should induce or expand only the beneficial immune responses mediated by CTLs (Thl and Tcl subsets) that have sufficient cytotoxic effects toward tumor cells. Further studies are warranted to examine the interaction between B-cell tumors and Id-specific T-cell subsets so that a better understanding of the immune regulation mechanism in B-cell malignancies can be obtained. Furthermore, for B-cell malignancies and in particular, other hematologic malignancies, the discovery of other tumor antigens is needed. For example, the Wilms tumor gene WT1 has been identified as a possible antigen in some leukemias.

The timing of immunotherapy is also crucial for its success. It is a consensus that immunotherapy may work better in immunocompetent patients with minimal tumor burden. In most, if not all, of the studies reported thus far, however, vaccination is administrated to patients shortly after high-dose chemotherapy when the immune system has not yet recovered. Although these patients are able to mount KLH-specific immune responses, it is highly possible that the responses are weak and not durable, compared with the same responses induced in immunocompetent individuals. This may partly explain the inability of the same patients to mount a tumor antigen-specific immune response to immunotherapy (tumor antigens are much less immunogenic than KLH), even with tumor antigen-pulsed DCs as the vaccine. Hence, it may be preferable to immunize patients up-front before chemotherapy to generate specific T cells in vivo, collect and freeze the primed T cells, and reinfuse them into the patients after the completion of high-dose therapy to partially restore the immune system and provide specific T cells. Additional vaccination can then be given to further expand tumor-specific immune responses in these patients.

DCs may be the best natural adjuvant for immunotherapy in human malignancies. Despite the success in animal and preclinical studies (30,31), however, the clinical evaluation of DC vaccination remains in its early phases, with a large number of technical variables awaiting in vivo testing before this approach is optimized. It is encouraging that early attempts at DC vaccination for tumor immunotherapy have demonstrated efficacy against several human tumors, including hematological malignancies. Further understanding of fundamental tumor immunology gained from well-designed clinical trials of DC-based vaccinations will improve the methods for inducing an effective antitumor immunity that will ultimately benefit clinically treated patients.

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