With Bcrablderived Peptide Vaccines

As discussed above, many clinicians still consider allo-geneic stem cell transplantation to be the "gold standard" for curative therapy in CML by virtue of the long-term survival achieved and the ability of this modality to render the patient BCR/ABL negative using PCR-based assays. The importance of the immunologic properties of the graft has received a great amount of attention, with attempts to recapitulate a GvL effect while separating it from the side effects of conventional transplantation regimens undertaken by a number of investigators. The potential to induce and then employ specific antileukemic immune effectors is attractive and has seen realization in the formulation of a vaccine strategy for this disease.

The unique amino acid sequences encompassing the b3a2, b2a2, or e1a2 in BCR/ABL breakpoints can be considered truly tumor-specific antigens because they contain sequences that are not expressed in any normal cellular protein. Despite the intracellular location of these proteins, short peptides produced by cellular processing of the fusion protein products can be presented on the cell surface within the cleft of HLA molecules, and in this form, they can be recognized by T cells.52-54 Several investigators have demonstrated the immunogenicity from fusion-region-derived peptides of p210-b3a2 in the context of MHC class I and class II. By screening large numbers of fusion peptides from the junctional sequences of CML, several peptides have been derived from the b3a2 CML breakpoint that bind with high, intermediate, or low affinity to HLA-A0201, A3, A11, and B8.53 55-58 Recent mass spectrom-etry studies have further demonstrated the presence of cell-surface HLA-associated BCR/ABL peptides previously described as binders of HLA-A0301 in primary CML cells from HLA-A3-positive patients.59 This is the first direct evidence of naturally processed and expressed endogenous BCR/ABL peptides on the surface of CML cells. Support for the immunogenicity of synthetic BCR/ABL fusion peptides capable of interacting with class II MHC molecules has been accumulating as well. Peptides corresponding to the b3a2 fusion sequences have been shown to bind DR3 (DRB1*0301), DR4 (DRB1*0402), and DR11 (DRB1*1101), and b3a2 peptides have been shown to induce HLA-DR1 (DRB1*0101), DR2 (DRB1*1501), DR4 (DRB1*0401), DR9 (DRB1*0901), and DR11 (DRB1*1101) restricted proliferative responses of CD4-positive T lymphocytes and cytotoxic cell responses associated with DRB1 *0901.55' 60-64 Indirect evidence for processing and recognition of p210-b3a2 class II has been described.606465 Evidence for immunogenicity on class I and class II b2a2 and e1a2 peptides-derived breakpoint translocations have also been reported.

Based on the immunogenic evidence of b3a2 peptides-derived translocation, the Memorial Sloan-Kettering Cancer Center (MSKCC) Group initiated studies to evaluate the safety and immunogenicity of a multidose, multivalent BCR/ABL breakpoint peptide vaccine in CML patients, with a b3a2 breakpoint.

Based on these results, a phase II trial in adult CML patients with any HLA type and a b3a2 breakpoint was undertaken. Patients were vaccinated five times over a 10-week period using a preparation of six peptides (100 ^g each) and the immunologic adjuvant QS-21 (100 ^g). Immunologically responding patients received three additional monthly vaccinations, and those with continued response received another three bimonthly vaccinations. Immune and clinical responses were measured. All 14 patients developed delayed-type hypersensitivity (DTH) and/or CD4 pro-liferative responses, and 11 of 14 patients showed IFN-7 release by CD4 ELISPOT. A peptide-specific CD8-positive IFN-7 ELISPOT was found in four patients; two of them had received an allogeneic stem cell transplantation prior to relapse. Four patients in hematologic remission had a decrease in Ph percentage (three concurrently receiving IFN-a and one on imatinib), and three patients in molecular relapse after allogeneic transplant became transiently PCR negative after vaccination. Two of these patients received DLI after the first vaccination in an attempt to vaccinate the naive donor leukocytes within the recipient (vaccination by proxy). All five patients on IFN ultimately reached a complete cytogenetic remission. These results suggested that a tumor-specific BCR/ABL breakpoint peptide-derived vaccine could be safely administered to patients and that such a vaccine could elicit measurable peptide-specific CD4 immune responses in all treated patients, including patients post stem cell transplantation, on interferon, or on imatinib. A causal relationship between clinical response and vaccination, however, remains unclear and requires further study in the context of well-designed clinical trials.

Recently, an Italian group has reported results using the same BCR/ABL vaccine. In this study, 16 evaluable patients with CML in chronic phase with at least one of a group of designated specific HLA subtypes (HLA A3, A11, B8, DR11, DR1, or DR4) were treated. Patients with a b3a2, BCR/ABL breakpoint were vaccinated sub-cutaneously six times over a 12-week period (every 2 weeks) using a preparation of five peptides mixed with QS-21 and granulocyte-macrophage colony-stimulating factor (GM-CSF) the day before and the day of vaccination. Patients who responded immunologically received two booster vaccinations at 4- and 8-month interval from the date of the last vaccination. As in the prior study, no significant toxic effects were observed. Thirteen of 16 patients developed CD4 proliferative responses and 9 of 16 DTH. In 10 patients treated with imatinib, 5 of 9 patients became CCR after three to six vaccinations.66 Three of the five CCR patients were also able to achieve a molecular response. In six patients treated with IFN-a, two had a CCR. These results supported the findings from the MSKCC Group regarding the safety and measurable peptide-specific CD4 immune responses in all treated patients, and provide a rationale for future clinical trials in the context of minimal residual disease induced by imatinib.66

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