Immune mobilization of autologous blood progenitor cells: direct influence on the cellular subsets collected

Abstract

Background aims A phase I trial examined the ability of immunotherapy to mobilize progenitor and activated T cells. Methods Interleukin (IL)-2 was administered subcutaneously for 11 days, with granulocyte (G)-colony-stimulating factor (CSF) (5 mcg/kg/day) and granulocyte–macrophage (GM)-CSF (7.5 mcg/kg/day) added for the last 5 days. Leukapheresis was initiated on day 11. Thirteen patients were treated (myeloma n = 11, non-Hodgkin’s lymphoma n = 2). Results Toxicities were minimal. IL-2 was stopped in two patients because of capillary leak (n = 1) and diarrhea (n = 1). Each patient required 2.5 leukaphereses (median; range 1–3) to collect 3.2 × 106 CD34+ cells/kg (median; range 1.9–6.6 × 106/kg). Immune mobilization increased the number of CD3+ CD8+ T cells (P = 0.002), CD56+ natural killer (NK) cells (P = 0.0001), CD8+ CD56+ T cells (P = 0.002) and CD4+ CD25+ cells (P = 0.0001) compared with cancer patients mobilized with G-CSF alone. There was increased lysis of myeloma cells after 7 days (P = 0.03) or 11 days (P = 0.02). The maximum tolerated dose of IL-2 was 1 × 106 IU/m2/day. Conclusions Immune mobilization is well tolerated with normal subsequent marrow engraftment. As cells within the graft influence lymphocyte recovery, an increased number of functional lymphocytes may result in more rapid immune reconstitution.

Novel mobilization strategies to enhance autologous immune effector cells in multiple myeloma

“…Our data demonstrate that CD8 + T lymphocytes upregulate surface expression of NKG2D in vivo during immune mobilization, rendering highly effective lymphocytes, especially, NKG2D + CD8 + T cells that recognize NKG2D ligands on target cells and aggressively lyse myeloma cells. The clinical results from this phase I clinical trial have been described previously, (11) and indicate that immune mobilization significantly increased the number of NKG2D + CD8 + T cells (P< 0.004), CD56 + T cells (p< 0.002), and CD3 + CD8 + T cells, within the mobilized product, when compared to a control group. There was significant increase in the lysis of myeloma cells by patients’ cytotoxic T cells after mobilization.…”

“…These clinical results were previously published. (11) Ten patients completed the full course of treatment. The median number of CD34 + cells/kg collected was 3.6 × 10 6 cells/kg (range of 1.9 – 6.6 × 10 6 CD34 + cells/kg).…”

“…(14) (11) (Figure 1) Briefly, eligible patients between the ages of 17–70 years, with a Karnofsky status ≥ 80 %, were required to have confirmed multiple myeloma with therapy-sensitive disease. The endpoints of this trial were to determine if immune mobilization would increase the number of lymphocytes and improve cytotoxic function of the lymphocytes within the mobilized cells, and yield sufficient number of CD34 + progenitor cells.…”

“…(11) This specialized subset of CD8 + T cells, labeled NKG2D + CD8 + T cells, recognized and killed myeloma cells in a non-MHC restricted manner that was independent of the T cell receptor (TCR). (11) While many tumor cells down regulate the MHC expression, thereby escaping MHC-restricted and TCR-dependent tumor cell killing, malignant cells up regulate NKG2D ligand expression.…”

“…(11) This specialized subset of CD8 + T cells, labeled NKG2D + CD8 + T cells, recognized and killed myeloma cells in a non-MHC restricted manner that was independent of the T cell receptor (TCR). (11) While many tumor cells down regulate the MHC expression, thereby escaping MHC-restricted and TCR-dependent tumor cell killing, malignant cells up regulate NKG2D ligand expression. (12), (13) The selective expression of NKG2D ligands on malignant cells makes this specialized NKG2D + CD8 + T cell population a potential candidate for adoptive cellular therapy for patients with multiple myeloma.…”