Defective lymphokine-activated killer cell generation and activity in acute leukemia patients with active disease

Abstract

In 26 myeloid and lymphoid acute leukemia patients at presentation the capacity to generate interleukin-2 (IL-2)-induced lymphokine-activated killer (LAK) cells effective against the natural killer (NK)-resistant Raji cell line, as well as the susceptibility of the blasts to normal peripheral blood (PB) LAK cells and to autologous LAK effectors was analyzed. The overall PB LAK activity against Raji cells was significantly lower in acute leukemia patients compared with normal controls (mean, 1,473 +/- 971 SD LU/10(8) LAK effectors v 3,340 +/- 1,862; P less than .001). The sensitivity of the blasts to autologous LAK cells was also significantly lower than to normal LAK effectors (517 +/- 593 LU/10(8) LAK effectors v 1,304 +/- 1,066; P less than .01). When the data were analyzed independently, four patterns of behavior could be recognized. The relatively largest group (9 of 26) included patients in whom effective LAK cells could be generated against the Raji line, but in whom the blasts were resistant to autologous PB-LAK effectors while being susceptible to normal LAK cells (defective specific LAK activity). In 5 of 26 cases, an incapacity to generate LAK activity against both allogeneic and autologous target cells was observed (defective LAK generation). In six further cases, the blasts were resistant to both allogeneic and autologous LAK populations, though the latter were effective against the Raji line (resistant blasts). The same defects could also be shown with bone marrow-derived LAK cells. Only in six cases did the leukemic blasts appear susceptible to autologous and allogeneic LAK cells. In four patients the analysis could be repeated at remission, and in three a restoration of the LAK function against the primary blasts was recorded. In the 10 cases studied at relapse, the blasts were resistant to autologous LAK effectors in nine and to normal LAK in seven. These data demonstrate that in most acute leukemia patients with active disease, a defect of the LAK machinery, either a deficient generation of LAK cells or the resistance of the blasts to LAK effectors, may be documented, pointing therefore to a possible contributory role of the LAK system in the control of leukemic cell growth. In view of the frequent normalization of the autologous LAK activity at the time of remission, immunotherapy with IL-2/LAK cells should be primarily aimed to patients with minimal residual disease.

NKp46 and NKG2D receptor expression in NK cells with CD56dim and CD56bright phenotype: regulation by histamine and reactive oxygen species

“…While the integrity of cytotoxic lymphocytes is pivotally important for patients with AML – in particular in protecting patients in complete remission against leukaemic relapses – these lymphocytes are frequently incapable of eliminating arising or residual leukaemic cells. Thus, several investigators have reported a reduction of the anti‐leukaemic activity of lymphocytes recovered from AML patients (Hersh et al , 1971; Foa et al , 1991; Tajima et al , 1996; Orleans‐Lindsay et al , 2001; Costello et al , 2002). A plethora of mechanisms have been proposed to account for the dysfunctional anti‐leukaemic lymphocytes in AML, including the production of T‐ and NK cell‐inhibitory factors by AML blasts (Buggins et al , 2001), a deficient expression of NK cell receptors on AML blasts (Nowbakht et al , 2005), deficient expression of the CD3 ζ transduction molecule (Buggins et al , 1998), inhibition of anti‐leukaemic lymphocytes by MPs (Pizzolo et al , 1988), an impaired stimulatory interaction between the CD28 antigen expressed by T cells and contact antigens on AML blasts (Notter et al , 2001), and a propensity of dormant AML blasts to resist cytotoxic T‐lymphocyte‐mediated killing (Saudemont & Quesnel, 2004).…”

A pilot study of interleukin-2 for adult patients with acute myelogenous leukemia in first complete remission

“…First CR would be an appropriate setting for IL‐2 therapy if a status of minimal residual disease is required, and blast cells at this stage probably are most likely to be sensitive to immune‐mediated cytotoxicity 9. Only a few patients have been reported in the literature receiving IL‐2 maintenance in first remission outside of a BMT setting (Table 3).…”

“…Natural killer (NK) cell activity is deficient in patients with acute leukemia, but this deficiency frequently is corrected upon achievement of CR 9. Interleukin‐2 (IL‐2) stimulates NK cell activity 10.…”

“…Most studies have used IL‐2 in patients with relapsed or refractory AML, or as maintenance for patients in second or later remission,15–19 or after autologous or allogeneic BMT 20–22. However, use of IL‐2 in first CR might be relatively more beneficial, because residual disease might be less, and LAK activity and sensitivity of leukemic cells to LAK‐mediated cytotoxicity might be better 9. However, only a few patients in first CR treated with IL‐2 maintenance have been reported 19, 23…”

Post‐consolidation Immunotherapy with Histamine Dihydrochloride and Interleukin‐2 in AML

“…The fact that as many as 70–80% of AML patients in CR will eventually relapse implies that the host’s immune system is frequently incapable of eliminating arising or residual leukaemic cells. Several investigators have demonstrated that lymphocytes recovered from AML patients are commonly dysfunctional [36–40]. A plethora of mechanisms have been proposed to account for the dysfunction of anti‐leukaemic lymphocytes in AML, including but not limited to the production of T‐ and NK cell‐inhibitory factors by AML blasts [41], a deficient expression of NK cell receptors [40], inhibition of anti‐leukaemic lymphocytes by mononuclear myeloid cells [16], an impaired stimulatory interaction between the CD28 antigen expressed by T cells and contact antigens on AML blasts [42], and Fas ligand‐induced apoptosis of T cells [43].…”