Evidence for involvement of clonally expanded CD8+ T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation

Abstract

We have analyzed the clonotype composition of CD8 þ T cells following nonmyeloablative (NMA) conditioning and hematopoietic cell transplantation (HCT), of patients with chronic lymphocytic leukemia (CLL). Consecutive analyses of blood samples taken up to 2 years following HCT, demonstrated that CD8 þ T-cell clonality was highly dynamic in the early phases after HCT, but became more stable after 4-5 months. Moreover, donor lymphocyte infusion (DLI) given for disease progression in one of the patients led to establishment of recurrent as well as new T-cell clonotypes. This coincided with disease remission, strongly suggesting that these T cells were engaged with anti-CLL cytotoxicity. To examine the functional capacity of stable clonally expanded T cells after HCT, CD8 þ T cells isolated post-transplant from the recipients were stimulated ex vivo with CLL cells and subsequently analyzed by FACS for surface expression of the marker for cytotoxic activity, CD107a. Stimulation with CLL cells indeed led to surface expression of CD107a, and clonotype analyses of sorted cells demonstrated that CD107a positive T cells were stably expanded following HCT. Our data suggest that clonally expanded CD8 þ T-cell clones participate in the ongoing T-cell response against CLL cells following HCT with NMA conditioning.

Graft-versus-leukemia in chronic lymphocytic leukemia

“…These cells killed recipient CLL cells in vitro. Kollgaard et al 49 analyzed the clonotype of CD8-T-cells following RIC allotransplants. They showed that an early dynamic phase is followed by the appearance of stable T-cell clonotypes several months after transplant coinciding with clinical anti-leukemia response.…”

“…There are several reports of eradication of persistent and/or recurrent CLL after transplant. 18,[20][21][22]28,30,[41][42][43][44][45][46][47][48][49][50][51][52] Most report small numbers of subjects; only two had more than 10. 21,28 Overall, 43 of 92 subjects responded; 35 achieved complete remission and eight partial remission.…”

Generation of a Dendritic Cell‐based Vaccine in Chronic Lymphocytic Leukaemia Using CliniMACS Platform for Large‐scale Production

“…Naturally occurring T cells recognizing leukemic cells have been previously described in CLL and play a role in controlling CLL [3,4]. Allogeneic T-cells in haematopoietic stem cells transplants or administered as donor lymphocyte infusions are known to mediate 'graft-versusleukaemia' effect which can effectively eradicate leukaemic cells [5][6][7][8].…”

Natural T-cell responses against minor histocompatibility antigen (mHag) HY following HLA-matched hematopoietic cell transplantation: what are the requirements for a ‘good’ mHag?

“…However, at least concerning patient 766, absence of HY-A2 reactivity was concurrent with significant overall reactivity. 11 Reactivity, in the context of HLA-B7 could potentially be relevant; 16 however, none of the patients expressed this HLA molecule (Table 1).…”

“…The dextramer analyses of peripheral blood mononuclear cells from UPN 766 showed that only 0.2% of CD8 þ T cells (compared to approximately 10% being CD107a CD8 þ T cells upon CLL stimulation), were specific for HY in HLA-A2 context. 11 We, therefore, analyzed male patients that received HLAidentical NMA-HCT from their female sibling. To facilitate comparative studies, patient/donor pairs should be HLA-A2 positive and be characterized by parity for HA-1, HA-2 and HA8Fall of which give rise to HLA-A2 restricted peptides that might be dominant over HY.…”