Emergence of CD52 ⁻, glycosyiphosphatidylinositol-anchor deficient lymphocytes in rheumatoid arthritis patients following Campath-1H treatment

Abstract

CD52 is a glycosylphosphatidyl-inositol (GPI)-linked glycoprotein expressed at high levels on normal T and B lymphocytes and at lower levels on monocytes, while being absent on granulocytes and bone marrow stem cell precursors. The emergence of CD52- lymphocytes of both T and B cell lineages was observed in three out of 25 rheumatoid arthritis patients treated with teh humanized antibody Campath-1H in phase II clinical trial. Whereas the majority of CD52- B cells had disappeared from the peripheral blood by 3 months post-treatment, both CD52- CD4+ and CD8+ T cells persisted in the circulation for at least 20 months. In the two patients that were tested, the GPI-anchored surface molecules CD55 and CD59 were also absent on the CD52- cells, although expression of other cell surface transmembrane, proteins (CD3, CD4 and CD2) was unaffected. The CD52- cells maintained a stable phenotype in vitro despite repeated re-stimulation in culture. Both CD52- and C52+ clones, established from one of the patients, responded to a similar extent to several T cell mitogens, as assessed by proliferation, suggesting that a general defect in expression of GPI-linked molecules does not impair T cell activation. These data show that an immune attack against a GPI-anchored surface molecule can result in the selection of a GPI-anchor-deficient cell population. Despite the persistence of CD52- T cells in the peripheral blood, no adverse reactions associated with the presence of these cells were noted in any of the patients; in fact they responded with longer remission times after Campath-1H treatment than the other patients in the trial.

New approaches in the immunotherapy of haematological malignancies

“…NK cells and monocytes return to pre-treatment level within 1-2 months, and B cells within 5 months, while CD4 + and CD8 + T lymphocytes can remain at less than half of initial levels for more than 1 yr, with a poor proliferative response to polyclonal stimuli (62). The emergence of glycosylphosphatidylinositol-anchor-deficient lymphocytes [paroxysmal nocturnal hemoglobinuria (PHN)-like phenotype] in patients following alemtuzumab treatment has been observed, although the clinical significance of such an observation has to be defined (63). The anti-CD52 mAb therapy has been proposed in various settings in CLL, but the approval for use corresponds to a third line therapy, in patients already treated with alkylating agents and with no response or short response (<6 months) to fludarabine phosphate.…”

Phenotypic transformation of CD52pos to CD52neg leukemic T cells as a mechanism for resistance to CAMPATH-1H

“…After the CD52-positive cells are cleared, a population of persistent CD52-negative B and T cells sometimes emerges. 18,19,22 Emergent cells exhibit a severe defect in the synthesis of a glycosylphosphatidylinositol (GPI) precursor resulting in defective surface expression of other GPI-anchored proteins. 19 The defect induced by CAM-PATH-1H may be different in B and T cells.…”

“…18,19,22 Emergent cells exhibit a severe defect in the synthesis of a glycosylphosphatidylinositol (GPI) precursor resulting in defective surface expression of other GPI-anchored proteins. 19 The defect induced by CAM-PATH-1H may be different in B and T cells. In B cells, the defect in CD52 expression appears to be reversible in vitro.…”

“…Use of CAMPATH-1H has resulted in CD52-negative populations emerging in rheumatoid arthritis and non-Hodgkin's lymphoma patients. 18,19 This is the first reported case of phenotypic conversion of leukemic cells from CD52-positive to CD52-negative during CAMPATH-1H therapy in T-PLL. Aspects of this case provide insight into mechanisms of treatment failure.…”

A mechanistic rationale for combining alemtuzumab and rituximab in the treatment of ALL

“…Because small numbers of GPI-defective lymphocytes exist in virtually all healthy persons, loss of GPI-anchored proteins appears to be a relatively common event in lymphoid cells. 19 In patients treated with ALM for CLL or rheumatoid arthritis, the frequencies of GPI-defective lymphocytes increased, [20][21][22] and emergence of GPI-defective lymphocytes was observed in patients receiving ALM as part of a stem cell transplantation regimen. 23 It can be hypothesized that, if GPI-defective subclones exist in ALL, this would lead to antigenic escape.…”