Autologous leukemia-specific T-cell-mediated lymphocytotoxicity in patients with acute myelogenous leukemia.

Abstract

It is more than 80 years since the first attempts were made to immunize human cancer patients against their own tumors (for review see reference 1). As yet, there are no immunological manipulations of proven value in terms of ensuring long-term cure, though there are randomized control studies demonstrating short-term prolongation of survival in patients with acute myelogenous leukemia receiving bacille Calmette-Guerin (BCG) 1 with or without aUogeneic leukemic blasts (for review see reference 2). In experimental animals, particularly inbred mice, it has been considerably easier to demonstrate tumor-specific antigens, both by serological and cell-mediated techniques and to prolong survival by immunizing against these antigens (3). Despite a welter of publications, there are few studies in human tumor systems where the concept of tumorspecific antigens has been clearly established and universally confirmed. In particular, though many authors have demonstrated lymphocyte-mediated cytotoxicity against tumor lines in both normal individuals and patients with tumors (4, 5), evidence for Tlymphocyte-mediated autologous tumor cytotoxicity has been very difficult to establish.In vitro assays of transplantation rejection using the mixed lymphocyte culture and cell-mediated lympholysis tests, have provided clear insight into the nature of antigenic determinants necessary for generation of cytotoxic T cells. The pioneering studies of Eijsvoogel et al. (6) on HLA recombinant families demonstrated the need for two types of antigens, the first type coded for by genes closely associated with those of the HLA D locus cause lymphocyte activation, whereas the second class of determinants, closely associated with the serologically defined HLA A, B, and C locus antigens, acts as the target for the cytotoxic T lymphocytes. Eijsvoogel et al. (7) also showed that production of cytotoxic T lymphocytes was possible even if the lymphocyte-activating determinant and serologically defined antigens were present on different cells. Zarling et al. (8) applied this principal to study leukemia patients and then reported one patient where stimulation of remission lymphocytes by mitomycin C inactivated autologous myeloblasts and a third party inactivated allogeneic lymphocytes in short-term culture led to the production of cytotoxic cells against autologous blasts but not the remission lymphocytes.We report and confirm this observation in a series of 14 patients with acute myelogenous leukemia and investigate the nature of the effector cell, the helper * Present address:

In vitro generation of lymphocytotoxicity to autochthonous leukaemic cells in chronic myeloid leukaemia

“…Zarling et al (1976) have shown that when leukaemic blasts are used as stimulators, cytotoxicity was not always demonstrable. Lee & Oliver (1978) have shown that myeloid blasts are poor stimulators even in allogeneic stimulation. The CML leukaemic cell population consists of cells in different stages of maturation, and may express antigens which can be recognized by sensitized lymphocytes.…”

“…We have not included stimulator allogeneic normal cells as targets in this study . Zarling et al (1976 and Lee & Oliver (1978) have shown the lysis of allogeneic stimulator targets by the responders sensitized in vitro in a 3-cell assay.…”

“…Zarling et al (1976) also showed that addition of helper stimulus enhances anti-leukaemic cell-mediated cytotoxicity in acute-leukaemic patients. Lee & Oliver (1978) extended this work further to demonstrate in vitro generation of cytotoxicity with third-party allogeneic stimulus in 11/14 AML patients. Their experiments confirmed that the cytotoxicity was mediated by T lymphocytes.…”

“…It is, however, difficult to ascertain that the in vitro demonstration of target-cell lysis is a function of sensitized T cells. Human leukaemic blasts are possibly unable to induce cytotoxic responses in autologous remission lymphocytes (Zarling et al, 1976;Lee & Oliver, 1978). It was felt that if the stimulator cells did not differ from the responders with respect to LD antigens, proliferative and cytotoxic responses would not be easily generated (Zarling et al, 1976;Zarling & Bach, 1979).…”

Intensity of class I antigen expression on human tumour cell lines and its relevance to the efficiency of non-MHC-restricted killing

“…Though these can be demonstrated in a minority of melanomas with apparently normal class I expression but over expression of non-functioning class II (Alexander et al, 1989) and the occasional other tumour under certain conditions (Lee et al, 1978;Belldegrun et al, 1988), most adult solid tumour patients only show lymphokine activated killer (LAK) and natural killer (NK) cytotoxicity (Itoh et al, 1988;Nouri et al, 1991) possibly a reflection of their degree of aberrant class I expression. NK activity was first described by Kiessling et al (1975).…”