True Chronic Myeloid Leukemia Specific Antigen Vaccines

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The BCR-ABL-derived p210 protein and particularly the alternative b3a2 or b2a2 peptide epitope at its fusion point is the most obvious CML-specific target, and thus was first explored for a vaccine strategy. p210 is exclusive to the CML clone, and the sequences of amino acids contained in the b3a2 and b2a2 junctional regions represent unique tumor-specific determinants, which can be exploited for an immunological attack against the tumor cell (11). Recent data support the hypothesis that peptides binding HLA with moderate-to-high affinity are capable of stimulating T-cells after natural processing and cell surface presentation within the cleft of the appropriate HLA molecule. Within the p210 b3a2 breakpoint sequence, five junctional peptides were found to be capable of binding to certain HLA class I and class II molecules and were shown to elicit in vitro a specific T-cell response both in normal donors (12) and in CML patients (13). After these initial observations, p210 b3a2 breakpoint peptides have also been shown to induce cytotoxic T cells (CTLs) and CD4+ cells able to induce cell death and to inhibit proliferation of leukemia cells, respectively (14). Finally, the relevance of these peptides as truly immunogenic tumor antigens has been confirmed by their capability to be "endogenously" presented within class I and class II molecules

Tumor Associated Antigen Definition

FIGURE 1 Tumor-associated antigens that are now under evaluation for vaccine therapy in chronic myeloid leukemia (CML) (bcr-abl-derived P210; myeloblastin (PR-3), Wilm's Tumor protein (WT-1); Heat shock proteins. In CML cells, peptides derived by these antigens may be presented on the cell surface both through the MHC class I and class II pathway, thus inducing both CD8+ and CD4+ T cell antitumor response. Abbreviations: CML, chronic myeloid leukemia; MHC, major histocompatibility complex; TCR, T cell receptor; HSP, heat shock protein.

FIGURE 1 Tumor-associated antigens that are now under evaluation for vaccine therapy in chronic myeloid leukemia (CML) (bcr-abl-derived P210; myeloblastin (PR-3), Wilm's Tumor protein (WT-1); Heat shock proteins. In CML cells, peptides derived by these antigens may be presented on the cell surface both through the MHC class I and class II pathway, thus inducing both CD8+ and CD4+ T cell antitumor response. Abbreviations: CML, chronic myeloid leukemia; MHC, major histocompatibility complex; TCR, T cell receptor; HSP, heat shock protein.

of CML blasts and CML dendritic cells (DCs) (15,16). All these findings provided powerful scientific support for a b3a2-breakpoint peptides vaccine approach.

"Native" BCR-ABL Breakpoint-Derived Vaccines

The first phase I/II vaccine trials employing a mixture of five or more b3a2-derived peptides plus the immunological adjuvant QS-21 included CML patients in CP during conventional treatment (17,18). These trials have documented for the first time the capability of CML breakpoint peptides to elicit peptide-specific CD8+ and CD4+ T cell responses in CML patients with a relatively large tumor burden. However, despite some decrease in the proportion of Ph-positive metaphases observed in some patients, a clear relationship between clinical responses and vaccination could not be established in these studies.

As it is more likely that effective vaccination strategies will target patients with MRD, a similar phase II b3a2-derived peptide vaccine multicenter trial was conducted at the Department of Hematology in Siena, Italy, and included patients with b3a2-positive CML, proper HLA restriction, and a major or complete cytoge-netic response to imatinib or IFN-a (19). The vaccine (CMLVAX100) consisted of five b3a2 breakpoint-derived peptides plus QS-21. To increase peptide immuno-genicity and possibly antitumor effect, low doses of GM-CSF as co-immunoadju-vant were also included. Sixteen CML patients with stable cytogenetic or molecular residual disease for at least six months on treatment with imatinib or IFN-a were vaccinated. After six planned vaccinations of 10 patients on imatinib, all 10 patients improved their responses. In particular, five of nine patients with cytogenetic disease before the vaccination reached CCyR and 4/9 reduced the

TABLE 1 Current Approaches for Immunotherapy of Chronic Myeloid Leukemia

Antigen

Method of delivery

Advantages

Peptides

CML-derived material

CML-specific b3a2 and b2a2 bcr-abl fusion "native" peptides b3a2 and b2a2 fusion "heteroclitic" peptides

Tumor associated PR3-derived peptides WT-1 -derived peptides

HSP complexes

Subcutaneous vaccine with adjuvants

Subcutaneous vaccine with adjuvants

Subcutaneous vaccine

Specific targeting Simple, rapid, and inexpensive production Unlimited availability Best GMP compliance Easy to monitor response Specific targeting3 Simple, rapid, and inexpensive production3 Unlimited availability3 Best GMP compliance3 Easy to monitor response All CML Ags available Specific mechanism for uptake

Disadvantages

Stage of development

Certain HLA type may have better response than others Single Ag targeting may lead to tumor escape mechanism

Phase I

Ags also expressed on other tissues

Preclinical and phase I and II studies

Complex preparation for individual patient

Phase II

Cell-based

Non specific immuno-stimulators

Ph-positive DC DC loaded with CML-derived peptides or genetically modified CML cell lines

IFN-a IL-2

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