Cellular immunotherapy and autologous transplantation for hematologic malignancy

Abstract

The success of allogeneic transplantation is in part due to the immunotherapeutic effect mediated by the graft. Autologous transplantation is hampered by the absence of this effect, leading to a higher relapse rate. We have conducted a series of studies designed to augment the immunologic activity of the graft after autologous transplant with a view towards introducing an autologous graft-versus-tumor effect that could decrease the rate of relapse after autologous transplant. These studies have included IL-2 activation of marrow followed by post-transplant infusional IL-2, the development of a novel protocol for the generation of highly efficient cytotoxic effector cells, termed cytokine-induced killer (CIK) cells, with broad and potent antitumor activity. In order to determine the potential for generating peptide-specific cytolytic T cells, studies have been conducted upon transducing antigen-presenting cells (APC) with AAV vector-mediated gene transfer, a vector capable of transducing non-proliferating target cells. Transduction of human monocytes and macrophages resulted in high expression of the transduced gene. This latter study forms the basis for determining whether genetic modification of APC can potentiate specific immune responses to tumor-specific gene products. Taken together, these strategies will hopefully increase the therapeutic efficacy of autologous transplantation.

Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

“…15,24 We have investigated development of DCs from primitive (M0/M1), maturing (M2), and myelomonocytic (M4/M5) leukemias. However, in 16 of 40 samples there was no evidence of generation of leukemic DCs; either the blasts did not survive in culture, 5 there was no morphological or immunophenotypic evidence of maturation, 6 or allostimulatory capacity was poor 3 or not investigated because of an insufficient number of cells after culture. 2 The wide variations in our ability to generate leukemic DCs from different samples persisted across FAB types.…”

“…2 As cure rates in AML approach plateau, studies of in vivo and ex vivo immune modulation are also being extended to the setting of autologous BMT and to patients not eligible for high-dose therapies. 3 Immune manipulations in the treatment of leukemia are not new. In the 1970s, pooled, irradiated allogeneic leukemic cells were given to patients with AML in first remission or after relapse and led to increased duration of remission in one study.…”

“…4 Interleukin (IL) 2, which can augment immune activity through release of secondary cytokines such as interferon-␥, has also been used as an immune modulator in patients with AML after conventional treatment. 2,3 Donor lymphocyte infusions (DLIs) following allogeneic BMT are now the mainstay of treatment for early relapse of chronic myeloid leukemia, 5,6 but are considerably less successful in the treatment of relapse of AML. This may be because the exponential increase in malignant cells in relapsing AML outstrips any clinical response to DLI, or because AML blasts are poor antigen-presenting cells (APCs) and fail to induce a sustained antileukemic response.…”

Role of cytokines in the treatment of acute leukemias: a review

“…The known ability of IL-2 to recruit T-cells and in particular natural killer (NK) cells, as well as the efficacy of the immune system to eradicate minimal residual leukemia provided the rational for a number of studies of IL-2 in acute leukemias. [63][64][65][66][67][68] Clinical responses have been reported, but generally these were only observed in patients with limited disease. 66,67 Toxicity in the form of fever, hypotension, vascular leak, thrombocytopenia, rash, and sepsis has generally been acceptable, in particular for lower dose regimens.…”

CD4+T Cells in CIKs (CD4+CIKs) Reversed Resistance to Fas-Mediated Apoptosis Through CD40/CD40L Ligation Rather Than IFN-γStimulation

“…[1][2][3] CIKs are known as potent antitumor effectors with several advantages over the lymphokine activated killer cells (LAKs), and tumor infiltrating lymphocytes (TILs), which are expandable both from healthy donors and tumor patients with similar cell expansion efficiency, and well tolerated both in animal models and human patients. As known, CD3 ϩ CD56 ϩ cells that coexpress CD8 rather than CD4 are the main cytotoxic population in CIKs.…”