Acute myelogenous leukemia (AML) is caused by the clonal expansion of myeloid blasts with multiple recurrent oncogenic translocations and point mutations [Citation1]. While chemotherapy and targeted therapy are successful in inducing the remission of AML, drug resistance of leukemic cells is frequently responsible for disease relapse and death of the majority of patients [Citation2]. There is therefore an urgent need for alternative approaches to eradicate minimal residual disease. The advent of stem cell transplant has produced some success for curative therapy of leukemia by replacing the hematopoietic system of the patient with healthy allogeneic bone marrow. The success of this approach depends largely on immune mediated eradication of the residual tumor cells in bone marrow transplanted patients [Citation3,Citation4]. Pre-existing immune responses to AML provide the option of antigen specific immune therapy through vaccination [Citation5]. However, a major drawback of antigen specific immunization is the natural selection for aggressive tumor cells that lack expression of the antigen [Citation6]. A promising approach is to target molecules that are etiologically connected to the process of carcinogenesis by combined chemo-immunotherapy. The article by Schneider et al. in this issue of Leukemia and Lymphoma [Citation7] reports the discovery and characterization of pre-existing cytotoxic T-cell responses to Aurora kinase A and B in patients with AML. Aurora kinases are serine/threonine kinases with potentially non-redundant roles in the process of mitosis and cell cycle regulation of leukemic cells. Aurora kinase inhibitors are described to sensitize malignant cells to cytosine arabinoside and specific antibodies by mediating apoptosis. As such this is potentially an effective target for combined chemo-immunotherapy of AML. The investigators used established techniques to identify immunogenic epitopes of Aurora A and B and pre-existing T-cell responses in patients with AML. First they used available algorithms and software programs to identify epitopes with the highest scores for human HLA-A*0201 binding. Having synthesized these peptides they validated them as targets for pre-existing T-cell responses using enzyme-linked immunosorbent spot (ELISpot) assays employing fresh peptide pulsed antigen presenting cells and T-cells from patients with AML. The immune responses were then ranked according to the frequencies of responding patients. Also, comparisons were made with immune responses of T-cells from healthy donors to the same peptides. Surprisingly, a number of the identified epitopes elicited strong responses by T-cells from healthy donors. Immune responses that were specifically elevated in patients with cancer were then selected. The authors propose a sequential treatment starting with Aurora kinase inhibitor to induce apoptosis in leukemic cells and enhance presentation of tumor antigens followed by in vivo peptide vaccination to activate specific cytotoxic T-lymphocytes (CTLs).
Immunotherapy is becoming an effective means of treating human cancers, and the application of such approaches in combination with other targeted therapies is expected to lead to a significant benefit in survival and quality of life for patients with cancer. Discovery of the Aurora kinase tumor-associated antigens will provide fresh opportunities for testing targeted chemo-immunotherapy in a disease that has resisted the most recent advances in cancer treatment. It remains to be seen whether vaccination with only CTL epitopes without harnessing the T-helper response will be sufficiently effective. Other potential obstacles that need to be overcome are mechanisms of immune tolerance that block tumor-specific CTLs. In this respect, the identification of immunogenic targets that can elicit high-affinity cytotoxic and helper T-cell responses and not immune suppressive regulatory T cell (Treg) responses is critical [Citation8]. The concept of targeted chemo-immunotherapy is still in its early days, and the synergistic action of the two modalities has not been sufficiently exploited. The report by Schneider et al. is a step forward.
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