Identification of a Novel P190-Derived Breakpoint Peptide Suitable for Peptide Vaccine Therapeutic Approach in Ph+ Acute Lymphoblastic Leukemia Patients

Ph+ acute lymphoblastic leukemia (Ph+ ALL) is a high-risk acute leukemia with poor prognosis, in which the specific t(9;22)(q34;q11) translocation results in a chimeric bcr-abl (e1a2 breakpoint) and in a 190？KD protein (p190) with constitutive tyrosine kinase activity. The advent of first- and second-generation tyrosine kinase inhibitors (TKIs) improved the short-term outcome of Ph+ ALL patients not eligible for allo-SCT; yet disease recurrence is almost inevitable. Peptides derived from p190-breakpoint area are leukemia-specific antigens that may mediate an antitumor response toward p190+ leukemia cells. We identified one peptide named p190-13 able to induce in vitro peptide-specific CD4+ T cell proliferation in Ph+ ALL patients in complete remission during TKIs. Thus this peptide appears a good candidate for developing an immune target vaccine strategy possibly synergizing with TKIs for remission maintenance. 1. Introduction Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) is a high-risk, aggressive form of acute leukemia, affecting primarily adults and the elderly. The hallmark of this disease is the presence in all leukemia cells of a reciprocal translocation termed t(9; 22)(q34; q11) resulting in a chimeric bcr-abl (e1a2 breakpoint) fusion gene that encodes a 190？KD protein (p190) with constitutively active tyrosine kinase activity that can alter multiple signaling pathways, contributing to tumor growth and proliferation. Before the advent of tyrosine kinase inhibitors (TKIs), the outcome of Ph+ ALL patients not eligible for allogeneic stem cell transplant (allo-SCT) was characterized by an extremely poor prognosis, a weak response to most chemotherapy combinations, short remission durations, and poor survival rates. The introduction of imatinib, a selective inhibitor of the ABL tyrosine kinase, has revolutionized the treatment and the outcome of this subset of patients [1]. However, a substantial proportion of imatinib-treated Ph+ ALL patients develop resistance to imatinib. Second-generation TKIs have demonstrated promising efficacy in the treatment of imatinib-resistant Ph+ ALL patients, but despite these results, the relapse rate of Ph+ ALL patients remains very high with an overall survival still unsatisfactory [2]. The persistence of a measurable residual disease at molecular level appears to be the key issue for treatment failure [3–5]. The development of alternative strategies that could selectively target Ph+ ALL cells and synergistically work in combination with TKI may have a crucial impact on disease control and ultimately