Detection of T-Cells Specific for Leukemia-Associated Antigens in Pediatric Patients with Acute Lymphoblastic Leukemia in First Complete Remission.

Abstract The ability of allogeneic hematopoietic stem cell transplantation to cure leukemia provides compelling evidence that the human immune system is able to mediate an effective anti-tumor effect and, as such, provides a rationale for the development of immune-mediated therapies for this disease. To design such therapies, it is necessary to identify both suitable target antigens and also the disease stages at which immune mechanisms are effective. One promising candidate antigen is the Wilms’ tumor 1 (WT1) protein which is over-expressed, relative to normal hematopoietic progenitors, by most adult and pediatric leukemias. In this study, we investigated whether T-cells specific for a dominant WT1 epitope could be detected in pediatric patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) following treatment with conventional chemotherapy alone. After informed consent, peripheral blood was obtained from 20 HLA-A*0201 positive children with ALL and from 3 HLA-A*0201 positive children with chemotherapy-treated, non-hematologic malignancies. All patients had completed therapy and were in CR. Blood was also obtained from 11 HLA-A*0201 positive healthy volunteers. Interferon-g (IFN-g) production by peripheral blood T-cells specific for the WT1-derived HLA-A*0201 binding peptide RMFPNAPYL was detected using the enzyme-linked immunospot (ELISPOT) assay. A mixture of HLA-A*0201 restricted immunodominant influenza, cytomegalovirus, and Epstein-Barr virus epitopes was used as a positive control. Absence of peptide was used as a negative control. IFN-g production in response to the WT1 peptide antigen was observed in 7/20 (35%) ALL patients, of which 4/7 had spots detected in wells containing 1 x 106 PBMC’s and 3/7 had spots detected in wells containing 0.25 x 106 PBMC’s. All samples secreted IFN-g in response to the positive control peptide mix. No IFN-g production was detected in the absence of peptide. All ALL patients in whom a WT1 response was detected were 2.5 – 5 years following therapy completion. Of the 13 ALL patients with no WT1 response, 6/13 were less than 2 years and 5/13 greater than 5.5 years following therapy completion. All other clinical and biologic features were evenly distributed between those with and without a WT1 response. No response to WT1 was observed in any of the three patients with non-hematologic malignancies, all of whom were 1.9–5.2 years following therapy completion, or in any of the healthy volunteers. T-cell responses to the WT1 leukemia-associated antigen can develop in pediatric patients with ALL. The generation of this specific T-cell population requires the presence of WT1 protein over-expressing leukemic cells, as indicated by the results from our control groups and in agreement with previous reports. This is the first study to report the development of T-cells specific for leukemia-associated antigens in pediatric patients with ALL treated with conventional chemotherapy alone. The findings suggest that tumor antigen specific T-cells may play a role in the maintenance of CR and that WT1 is an appropriate target for the development of immune-mediated therapies for pediatric ALL.

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