Cytotoxic chemotherapy preceding apheresis of peripheral blood progenitor cells can affect the early reconstitution phase of naive T cells after autologous transplantation

Abstract

Summary:Transient T cell immunodeficiency is a common complication following hematopoietic stem cell transplantation. In breast cancer patients transplanted with autologous peripheral blood progenitor cells (PBPC) harvested after cytotoxic treatment with either cyclophosphamide or epirubicin plus paclitaxel, we evaluated T cells infused in grafts and in peripheral blood during the early reconstitution phase. We found that PBPC grafts harvested after treatment with epirubicin plus paclitaxel contained substantially larger numbers of T cells with less altered composition than after cyclophosphamide. Three months after high-dose cytotoxic chemotherapy, the numbers and the kinetics of circulating naive T cells, but not of memory and CD28À T cells, correlated positively with the number of naive T cells infused PBPC grafts. Finally, retrospective analysis of two cohorts of patients transplanted in different clinical settings with PBPC grafts harvested following cyclophosphamide or epirubicin plus paclitaxel showed apparently different susceptibilities to develop endogenous varicella zoster virus reactivation in the first year after high-dose cytotoxic chemotherapy. On the whole, these data indicate that number and composition of T cells in PBPC grafts vary according to the former cytotoxic therapy, and suggest that autologous transfer of T cells may accelerate the early T cell reconstitution phase and possibly ameliorate immune competence in patients rendered lymphopenic by high-dose chemotherapy. Bone Marrow Transplantation (2003) 31, 31-38. doi:10.1038/sj.bmt.1703782 Keywords: T lymphocytes; immunodeficiency; autologous hematopoietic cell transplantation; cell therapy; cytotoxic chemotherapy; immunotherapy Acute T cell depletion is a common complication occurring after high-dose chemotherapy (HD-ChT) with autologous hematopoietic stem cell transplantation. 1 In spite of the rapid recovery of myelopoiesis allowed by infusion of peripheral blood progenitor cells (PBPC) and myelopoietic growth factors, recovery of total T cell numbers to baseline values is more gradual since it usually takes at least 3 months. 2 However, peripheral T cells in the early reconstitution phase invariably show an abnormal inversion of the CD4/CD8 ratio lasting several months or even longer, which is mainly because of an increase in atypical CD8+ T cells. 3 In this regard, we have recently documented that CD8+ T cells exceeding CD4+ T cells and accounting for such inversion, are constituted by a compensatory expansion of CD8+CD28À T cells 4 whose TcR diversity and potential for immune competence are reportedly limited. 5,6 Consistently, notwithstanding normal WBC values, in the early phase of recovery from HD-ChT, patients are susceptible to opportunistic infections such as Pneumocysti carinii, to endogenous reactivation of varicella zoster virus (VZV), and are not readily eligible for vaccination protocols. 7 Thus, specific approaches to enhance early recovery of CD28+ T cells after HD-ChT are necessary in order to abbreviate T cell immunod...

Combination of Transient Lymphodepletion With Busulfan and Fludarabine and Peptide Vaccination in a Phase I Clinical Trial for Patients With Advanced Melanoma

“…Interestingly, the analysis of the immune reconstitution period revealed that a single cycle of Busulfan and Fludarabine particularly depleted CD8 + T-cells, resulting in increased CD4/CD8 ratios followed by a slow recovery compared with the CD4 + subset. This is in contrast with previous reports of marked depletion CD4 + T-cells for several months with decreased CD4/ CD8 ratios <1 and clinical immunosuppression, 15,[25][26][27][28][29] although lymphodepletion in these studies was usually induced by the use of cyclophosphamide (CTX) in a transplant setting. Data from preclinical, in vitro analyses indicate that the treatment of PBMCs with Fludarabine leads to a higher level of apoptosis in CD8 + T-cells compared with CD4 + T-cells.…”

Immune phase transition under steroid treatment

“…Thus, the dynamics of T-cell are very sensitive to the dose of GC [4,37,42,63,64]. Hence, an optimal level of GC administration is essential for the proper functioning of the human body.…”

Lasting remission following multimodal treatment in a patient with metastatic breast cancer

“…Since transient T cell immunodeficiency is a common complication following hematopoietic stem cell transplantation, rescue of T cell function by autologous T cells was expected to be beneficial for immunotherapeutic approaches [5]. In our own pilot study for MBC, this immunotherapeutic approach was included into the HDCT protocol (Fig.…”