Ex Vivo Characterization of Multiepitopic Tumor-Specific CD8 T Cells in Patients with Chronic Myeloid Leukemia: Implications for Vaccine Development and Adoptive Cellular Immunotherapy

Abstract

Identification of tumor-associated Ags is a prerequisite for vaccine-based and adoptive immune therapies. Some tumor-associated Ags elicit specific CD8 T cells in patients with chronic myeloid leukemia (CML). Here, we characterized ex vivo responses of CD8 T cells from CML patients to extrajunction bcr-abl peptides and telomerase 540–548 hTert, PR1, and WT1 peptides. CML-specific CD8 T cells were present in most treated patients and were usually multiepitopic: WT1, hTert, PR1, and bcr74 tetramer+ cells were detected in 85, 82, 67, and 61% of patients, respectively. The breadth and magnitude of these responses did not differ significantly according to treatment or disease status. CML-specific tetramer+ CD8 T cells had a predominantly memory phenotype, an intermediate perforin content, and low intracellular IFN-γ accumulation in the presence of the relevant peptide. However, in short-term culture with HLA-matched leukemia cells, the patients’ memory T cells were specifically reactivated to become IFN-γ-producing effector cells, suggesting that CD8 T cell precursors with lytic potential are present in vivo and can be activated by appropriate stimulation. In conclusion, this study shows that multiepitopic tumor-specific CD8 T cell responses occur naturally in most CML patients, opening the way to new strategies for enhancing anti-CML immunity, in particular in patients with minimal residual disease.

Clinical evaluation of BCR-ABL peptide immunisation in chronic myeloid leukaemia: results of the EPIC study

“…4 CD8 þ T cells directed against KQSSKALQR and GFKQSSKAL may circulate in HLA-A3 þ and HLA-B8 þ CML patients respectively, 5 in line with similar studies after allogeneic stem cell transplantation (SCT) 6 and for other antigens. 7 Taken together, these data suggest that vaccination with e14a2 BCR-ABL junctional peptides could benefit e14a2 CML patients.…”

Improved human T-cell responses against synthetic HLA-0201 analog peptides derived from the WT1 oncoprotein

“…38,39 WT1-specific HLA-A0201 tetramers were found in a high percentage of patients with CML and from a small group of healthy subjects. 40 However, only low-avidity CD8 þ T-cell responses were seen likely secondary to tolerance mechanisms. Furthermore, there is no evidence that the specific T cells detected were able to lyse leukemic blasts or normal cell in vivo.…”

BCR-ABL fusion regions as a source of multiple leukemia-specific CD8+ T-cell epitopes

“…[14][15][16][17]20 Motif-based peptide-binding predictions, which are needed to limit the amount of peptides to be tested, are adequately pré-selecting peptides with binding capacity. 3,43 Despite that, binding affinities have to be determined experimentally because the ranking of prediction scores mostly differs substantially from the ranking of measured values as we have shown previously. 43 Predicted absence of binding is only occasionaly contradicted by actual positive binding measurements.…”

“…1 Proposed antigens involved in this graft-versus-leukemia effect include minor histocompatibility antigens, 2 BCR-ABL fusion proteins, proteinase 3, 3,4 Wilm's tumor protein 1 3 and the telomerase catalytic subunit (hTERT). 3 Treatment of CML with defined vaccines or T cells would enable bypassing SCT, which is often accompanied with serious graft-versus-host reactions. In the search for leukemia-specific antigens particularly the BCR-ABL fusion proteins have attracted much attention.…”