ABSTRACT
Leukemic blasts overexpress immunogenic antigens, so-called leukemia-associated antigens like the receptor for hyaluronan acid-mediated motility (RHAMM). Persistent RHAMM expression and decreasing CD8+ T-cell responses to RHAMM in the framework of allogeneic stem cell transplantation or chemotherapy alone might indicate the immune escape of leukemia cells. In the present study, we analyzed the expression of RHAMM in 48 patients suffering from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Furthermore, we correlated transcripts with the clinical course of the disease before and after treatment. Real-time quantitative reverse transcriptase polymerase chain reaction was performed from RNA of peripheral blood mononuclear cells. T cell responses against RHAMM were assessed by tetramer staining (flow cytometry) and enzyme-linked immunospot (ELISPOT) assays. Results were correlated with the clinical outcome of patients. The results of the present study showed that almost 60% of the patients were RHAMM positive; specific T-cells recognizing RHAMM could be detected, but they were nonfunctional in terms of interferon gamma or granzyme B release as demonstrated by ELISPOT assays. Immunotherapies like peptide vaccination or adoptive transfer of RHAMM-specific T cells might improve the immune response and the outcome of AML/MDS patients.
Subject(s)
Extracellular Matrix Proteins/immunology , Hyaluronan Receptors/immunology , Leukemia, Myeloid, Acute/immunology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Extracellular Matrix Proteins/genetics , Female , Gene Expression , Hematopoietic Stem Cell Transplantation , Humans , Hyaluronan Receptors/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Male , T-Lymphocytes, Cytotoxic/immunology , Transcription, GeneticABSTRACT
The favorable graft-versus-leukemia (GVL) effect that occurs after stem cell transplantation suggests that T cells can eradicate leukemia blasts. T cells specifically recognize peptides and exert an antileukemia effect. Several leukemia-associated antigens (LAAs) have been found to be overexpressed in malignant cells from patients with acute or chronic leukemia leading to the generation of peptide-based leukemia immunotherapy. Peptide vaccination with LAAs, whose expression is low in normal tissue, such as the receptor for hyaluronic acid-mediated motility (RHAMM), Wilms tumor 1 (WT1), proteinase-3 (PR-3) and the breakpoint cluster region-Abelson (bcr-abl) has been reported to induce leukemia-specific T-cell responses in patients with a variety of hematological malignancies. Moreover, the immune responses achieved after vaccination positively correlated with good clinical outcomes, that is complete remission. Large efforts have been made to optimize the dose and format of vaccines, as well as their adjuvants, in small pilot trials. In this article we summarize clinical Phase I and II peptide vaccination trials with RHAMM, WT1, PR-3 and bcr-abl for leukemia patients.
Subject(s)
Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Leukemia/immunology , Leukemia/therapy , Vaccines, Subunit/administration & dosage , Vaccines, Subunit/immunology , Adjuvants, Immunologic/administration & dosage , Antigens, Neoplasm/administration & dosage , Antigens, Neoplasm/immunology , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Humans , T-Lymphocytes/immunology , Treatment OutcomeABSTRACT
Wilms' tumor 1 (WT1) is a leukemia associated antigen (LAA) differentially expressed by leukemic blasts. Thus, WT1 may constitute a target for therapies such as those mediated by adoptive-specific T lymphocytes. Serological and cellular immune responses have been elicited by WT1 in patients with leukemia. Specific CD8+ T cells able to recognize this antigen can be selected by streptamers and then infused into leukemia patients. Potentially, these T cells could lyse leukemic blasts expressing WT1. The only good manufacturing practice-certified technology is streptamers, which are available for antigen-specific T-cell sorting. Immunocompromised patients may have their antigen-specific immune responses restored through the transfer of adoptive T cells specific for this LAA.
