Injury to Autologous Normal Tissues and Tumors Mediated by Lymphokine-Activated Killer (LAK) Cells Generated In Vitro from Peripheral Blood Mononuclear Cells of Glioblastoma Patients

Abstract

Activation of peripheral blood mononuclear cells (PBMC) with IL-2 generates lymphokine-activated killer (LAK) cells that show a broad target cell range. In adoptive immunotherapy using in vitro-generated LAK cells, the intensity and specificity of their cytotoxic activity affect the prognosis of cancer patients. The present study was designed to examine the tumor-specific spectrum of T lymphocytes generated from the PBMC of patients with recurrent glioblastoma by in vitro propagation with IL-2 plus either soluble or solid-phase anti-CD3 monoclonal antibody (MAb) in short-term or long-term cultures. Both short-term and long-term culturing with solid-phase anti-CD3 MAb plus IL-2 yielded broad-reactivity CD8+ alphabetaT and gammadeltaT lymphocytes, both of which were non-MHC restricted, as shown by the fact that they were able to lyse autologous glioblastoma cells, MHC class I+II- allogeneic glioblastoma cells, and MHC class I-II-NK-sensitive K562 target cells. More importantly, these cells from patients failed to lyse fresh autologous PBMC. These results demonstrate that cells generated using this approach are non-MHC-restricted LAK cells and exhibit marked tumor specificity. In contrast, incubation with soluble anti-CD3 MAb generated T lymphocytes that after long-term culture, were either CD4+ or CD8+. These caused significant lysis of both allogeneic and autologous glioblastoma target cells, the extent of lysis being greater than that using cells produced by culturing with the solid-phase MAb. However, both the CD4+ and CD8+ cells also caused greater lysis of autologous normal PBMC, indicating that cells generated using this approach may cause significant adverse reactions in cancer patients if used for immunotherapy.

Retargeting of natural killer–cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction

“…6 These HLA alleles are able to inhibit NK cell function upon ligation with certain killer cell immunoglobulinlike receptors (KIRs) on the NK cell surface. 7 Numerous studies have been conducted with the aim to improve the antitumoral activity of NK cells by activation of endogenous NK cells through systemic application of cytokines [8][9][10] or through adoptive transfer of ex vivo-expanded autologous or donor-derived lymphokine-activated killer cells, [11][12][13][14][15] or a combination thereof. 11,12,16 The efficacy of such approaches can be limited by impaired function of patient-derived NK cells, which is usually not fully reconstituted through ex vivo expansion and lymphokine activation.…”

Intracardiac echocardiography off piste? Closure of the left atrial appendage using ICE and local anesthesia

“…This approach is based on observations of an impaired proliferation and cytotoxicity of NK cells in patients with malignant tumors as well as enhanced carcinogenesis and malignant cell proliferation in patients with NK cell dysfunction (30, 31). Approaches to inhibit tumor proliferation by improving NK cell defense comprise activation of endogenous NK cell reserves by stimulation via cytokines (32) or by ex vivo expansion (33). Unfortunately, while these therapeutic approaches are well tolerated by patients (34), only few have reaped significant anticancer benefit (31).…”

Genetic and Immunology of Brain Tumors

“…An adaptive immune response implies antigen recognition (Prasad et al, 2004). A variety of immunologically based strategies, including passive immunization and adoptive cellular immunotherapy (Fujimiya et al, 1999;Inoue et al, 1996;Kruse et al, 1990;Merchant et al, 1997;Plautz et al, 1997;Plautz et al, 1998) local and systemic delivery of biological response modifiers (Dranoff et al, 1993;Färkkilä et al, 1994;Jean et al, 1998;Jean et al, 2004;Lichtor et al, 1995;Ohno et al, 2009;Thompson et al, 1996;Yu et al; and vaccination with parental and genetically modified tumor cells (Dranoff et al, 1993;Jean et al, 1998;Lichtor et al, 1995;Thompson et al, 1996;Ohno et al, 2009;Yu et al; have been attempted.…”