J. V. Teichmann

Incidence and Prognostic Significance of Immunophenotypic Subgroups in Childhood Acute Lymphoblastic Leukemia: Experience of the BFM Study 86

Due to the increasing availability of monoclonal antibodies (MAbs) recognizing lymphoid-, myeloid-, and progenitor-cell-associated antigens, immunophenotyping has greatly influenced studies on the biologic features of normal and leukemic hematopoietic progenitor cells (Greaves 1986). It has become possible to demonstrate the practical value of these data for the precise diagnosis and definition of clinically relevant immunophenotypic subsets of acute lymphoblastic leukemia (ALL) (Janossy et al. 1989). More recently, immunophenotyping has been supplemented by cytogenetic and molecular-genetic analyses in order to better characterize the biologic heterogeneity of ALL and to elucidate the mechanisms of lymphoid cell transformation and aberrant regulation of leukemic cell growth (Look 1988; Bain and Catovsky 1990; Pui et al. 1990c; van Dongen and Wolvers-Tettero 1991).

Chronic myelocytic leukemia as a second neoplasia in the course of chronic lymphocytic leukemia—Case report and review of the literature☆

A patient with chronic lymphocytic leukemia developed Ph1-positive chronic myelocytic leukemia after a 6-yr course of CLL. Chemotherapy for CLL consisted of chlorambucil and steroids, later vincristine and bleomycin; after resistance to these agents, cyclophosphamide, vincristine and prednisolone were applied. When CML was diagnosed, we found two morphologically distinct populations of malignant cells in the bone marrow; the Ph1-chromosome was identified, and immunological surface marker studies also demonstrated two distinct malignant cell populations. Up to now, only five cases of CML have been reported following CLL and one case accompanying it. Three patients were treated with cytostatic drugs, one patient by total body irradiation and two patients received no therapy. At present, it is not clear whether the development of CML during CLL represents a therapy-induced complication or an increased susceptibility to second malignancies due to the leukemic process itself or possibly to immunological deficiencies in CLL. Since two patients received no treatment for CLL, previous therapy does not seem to be a prerequisite for the development of CML.

Cytotoxicity of interleukin 2-induced lymphokine-activated killer (LAK) cells against human leukemia and augmentation of killing by interferons and tumor necrosis factor☆

Adoptive immunotherapy with interleukin 2-induced lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) and the induction of anti-tumor responses by IL-2 alone having proven to be promising approaches in cancer therapy. The present study investigated the cytotoxicity of LAK cells towards human leukemia cells. LAK cells were generated by culturing peripheral blood mononuclear cells from normal donors for six days in the presence of recombinant interleukin 2 (IL-2). Cytotoxicity was evaluated using a standard 4-h chromium-release assay. A significant lysis of fresh uncultured leukemia cells by IL-2-activated killer cells could be detected in 77 of 150 leukemias examined. The mean Cr-release was 35.7 +/- 12.9% in the LAK cell-sensitive vs 9.9 +/- 5.9% in the resistant leukemias. With a view to the therapeutic utilization of the LAK-cell system, we attempted to improve the efficiency of its cytotoxic mechanisms. Combined application of IL-2 and interferon-alpha, interferon-gamma, or tumor necrosis factor-alpha in cultures for generation of activated killer cells significantly improved the effectiveness of cytotoxic mechanisms. Our results suggest that the performance of adoptive immunotherapy with ex vivo-activated LAK cells and the in vivo induction of cytotoxic immune responses by IL-2 alone or combined with different lymphokines or cytokines may be of value in treating human leukemia, especially when the tumor burden is low, e.g. during maintenance therapy or after bone marrow transplantation to eliminate minimal residual disease or in early relapse.

Immunosuppressive effects of recombinant interferon‐α during long‐term treatment of cancer patients

Interferons (IFN) are known to modulate immune responses in an either stimulatory or inhibitory manner. Most of the knowledge about immunomodulatory activities of IFN comes from investigations of IFN effects on cells in vitro. This study examines the influence which long‐term treatment with recombinant interferon‐α2 exerts on immune functions in cancer patients. Serial in vitro immune function studies of peripheral blood mononuclear cells were done to determine parameters of B‐cell and T‐cell functions as well as natural killer (NK)‐cells activity. The authors detected profound suppression of in vitro immunoglobulin synthesis and lymphocyte proliferation as well as depression of NK‐cell activity during IFN treatment. All suppressed immune functions normalized on discontinuation of IFN therapy. The authors conclude from these observations that, apart from their beneficial effects, IFN produce substantial immunosuppression.

Induction of lymphokine-activated killer cells against human leukemia cells in vitro

SummaryThe induction of lymphokine-activated killer (LAK) cells against fresh human leukemia cells was investigated. Two thirds of the 62 leukemias examined were susceptible to the lytic effect of allogeneic IL-2 induced LAK cells in vitro. No substantial differences could be detected between myeloid or lymphoid leukemias or with regard to the FAB subtype or the immunophenotype. Culturing mononuclear cells from peripheral blood or bonemarrow of leukemia patients with IL-2 resulted in an expansion of residual large granular lymphocytes and development of cytotoxic activity. The combination of IL-2 with IFN-gamma or the presence of tumor cells during the activation process led to an enhancement of LAK cell cytotoxicity. These results suggest that LAK cells may be useful in the treatment of leukemia.

Incidence and Clinical Implications of Acute Hybrid Leukemia in Childhood

Acute leukemias are thought to arise from a single abnormal progenitor cell in which expression of differentiation is restricted to either myeloid or lymphoid pathways [1]. Recently, however, this concept has been challenged by the fact that the availability of monoclonal antibodies (moAbs) to lineage-associated surface antigens and their use to characterize immature leukemic cells demonstrate an increasing amount of multilineage differentiation and phenotypic ambiguity (reviewed in [2]). Furthermore, application of molecular biological techniques has revealed that clonal rearrangements of the Ig heavy-chain (IgH) or T-cell receptor (TCR) genes occur in leukemic cells of the “inappropriate” lineage (reviewed in [3]).

Augmentation of the Susceptibility of Human Leukemia to Lymphokine-Activated Killer (LAK) Cells by Exposure of the Leukemic Target Cells to Cytotoxic Drugs in Vitro and in Vivo

Experimental studies have shown that interleukin-2-induced lymphokine-activated killer (LAK) cells are able to lyse fresh noncultured leukemia cells and that human leukemia cells have a distinct susceptibility to LAK-cell-mediated cytolysis. Cytolysis is considerably lower with fresh noncultured leukemia cells than with the leukemia cell lines K562 and Daudi. For therapeutic considerations it would be desirable to achieve as much cytolysis as possible. The current study revealed that incubating leukemia cells with cytotoxic drugs in vitro significantly augments their susceptibility to the lytic effect of LAK cells and, more importantly that exposing leukemia cells to anticancer agents in vivo during induction chemotherapy also increases their sensitivity to LAK-cell-mediated cytolysis. These results support a possible benefit from combining chemotherapy with immunotherapeutic approaches in leukemia treatment.

Susceptibility of human leukemia cells to allogeneic and autologous lymphokine-activated killer cells and its augmentation by exposure of leukemia target cells to cytotoxic drugs in vitro and in vivo

Interleukin-2- (IL-2-)activated cytotoxic effector cells, known as lymphokine- activated killer (LAK) cells, lyse a wide variety of fresh solid tumor cells (Grimm et al. 1982; Itoh et al. 1986) as well as fresh noncultured leukemia cells (Oshimi et al. 1986; Lotzova et al. 1987; Fierro et al. 1988; Teichmann et al. 1989) in a fashion not restricted by the major histocompatibility complex (MHC). LAK cell cytotoxicity is predominantly mediated by CD3-/CD56+ activated natural killer (NK) cells and only to a small degree by MHC-unrestricted CD3+/CD56+ T cells (Phillips and Lanier 1986; Herberman et al. 1987; Tilden et al. 1987; Saito et al. 1988). Human leukemia cells possess a distinct LAK cell susceptibility which varies considerably in different subtypes of leukemia (Teichmann et al. 1992). Maximal cytolysis by activated effector cells is desirable for therapy. The current study therefore aimed at investigating whether in vitro exposure of leukemic cells to cytotoxic agents, relevant for leukemia treatment, can augment the susceptibility of fresh noncultured leukemia cells to LAK cell lysis. In addition, we also studied the susceptibility of leukemia cells both before and after exposure to cytotoxic drugs given in vivo during induction chemotherapy.

Lymphokine-Activated Killer (LAK) Cells Against Human Leukemia:Augmentation of LAK-Cell Cytotoxicity by Combinations of Lymphokines or Cytokines

Adoptive immunotherapy with lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2) or induction of cytotoxic mechanisms by IL-2 alone was shown to be a promising approach in cancer therapy [1–11]. Most of the available data come from experimental and clinical studies of solid tumors, while only little is known about the effect of LAK cells against human leukemia [12–14]. Leukemia patients have been reported to have a deficiency in natural killer (NK) cell functions which may contribute to leukemogenesis. Experimental data on correcting this deficiency by IL-2 make it possible that adoptive immunotherapy of leukemia patients may be of great value in the treatment of human leukemia [15, 16]. In the present study we investigated the ability of LAK cells to lyse fresh human leukemia cells in vitro and evaluated the augmentation of cytotoxic mechanisms by combined application of IL-2 and other lymphokines or cytokines and by inhibition of prostaglandin synthesis during the activation process.

Induction of Lymphokine-Activated Killer (LAK) Cells Against Human Leukemia Cells*

Lymphokine-activated killer (LAK) cells are known to lyse fresh solid tumor cells in vitro [1], and clinical studies suggest that adoptive immunotherapy with LAK cells and interleukin-2 (IL-2) may be a promising approach in the treatment of solid tumors [2, 3]. As only few data are available on the LAK cell system in connection with human leukemia [4, 5], we investigated the induction of LAK cells against human leukemia cells in vitro and studied the augmentation of cytotoxic mechanisms which may be achieved by the combined application of different lymphokines or the coculturing of effector cells with tumor cells.