Addition of interleukin-2in vitro augments detection of lymphokine-activated killer activity generatedin vivo

Abstract

The in vivo administration of repetitive weekly cycles of interleukin-2 (IL-2) to patients with cancer enhances the ability of freshly obtained peripheral blood lymphocytes (PBL) to lyse both the natural-killer(NK)-susceptible K562 and the NK-resistant Daudi targets. Lysis of both targets is significantly augmented by inclusion of IL-2 in the medium during the cytotoxicity assay. This boost is much greater for cells obtained following the in vivo IL-2 therapy than for cells obtained prior to the initiation of therapy or for cells from healthy control donors. In addition to direct lytic activity, the PBL obtained following in vivo IL-2 show a rapid increase in lymphokine-activated killer (LAK) activity with more prolonged in vitro IL-2 exposure, indicating that LAK effectors primed in vivo respond with "secondary-like" kinetics to subsequent IL-2 in vitro. Lymphocytes from healthy control individuals, cultured in IL-2 under conditions attempting to simulate the in vivo IL-2 exposure, function similarly to PBL obtained from patients following IL-2, in that low-level LAK activity was significantly boosted by inclusion of IL-2 during the cytotoxic assay and the cells also responded with secondary-like kinetics to subsequent IL-2 in vitro. The augmentation of the LAK effect was also dependent on the dose of IL-2 added during the 4-h 51Cr-release cytotoxicity assay, with higher doses of IL-2 having a more pronounced effect. While continuous infusion of IL-2 induces a greater cytotoxic potential per milliliter of blood obtained from patients, the peak serum IL-2 levels attained are greater with bolus IL-2 infusions. These pharmacokinetic results, together with the IL-2 dose dependence of LAK activity generated in vivo shown in this report, suggest that a combination of treatment with bolus IL-2 infusions superimposed on continuous IL-2 infusion may transiently expose IL-2 dependent LAK cells, activated in vivo, to higher concentrations of IL-2, facilitating their in vivo cytotoxic potential.

Interleukin-2 dose, blood monocyte and CD25+ lymphocyte counts as predictors of clinical response to interleukin-2 therapy in patients with renal cell carcinoma

“…Despite this finding, only the CD25 marker was related to the clinical response, which may be because of the expression of these markers on different P B M C cell subsets. The L A K cytotoxicity determined in this study varied as described in other studies using IL-2 alone, and was not related to the clinical response [2,10]. Only two previous reports have indicated a correlation between L A K cytotoxicity and the clinical response.…”

High-Dose Continuous Infusion Plus Pulse Interleukin-2 and Famotidine in Melanoma

“…[7][8][9] Hank et al found that LAK generated by continuous infusion, then exposed to additional IL-2, were significantly more cytotoxic against the Daudi cell line than LAK generated by continuous infusion alone. 14 In our study, we sought to translate the in vitro observation of Hank to melanoma patients by administering continuous infusion followed 24 hours laser by pulse dose IL-2. The single pulse IL-2 dose is based on prior outpatient data.…”

“…[10][11][12][13] Hank et al showed in vitro that LAK generated by continuous infusion IL-2 had significantly increased lytic activity against tumor cells when the LAK were subsequently pulsed with IL-2. 14 Horton et al showed that the LAK cytolytic activity of lymphocytes generated by infusional IL-2 then pulsed with IL-2 were equal to the LAK activity of lymphocytes that were cultured up to 7 days in vitro with IL-2. 15 These studies suggest that a combination of first continuous infusion IL-2 to generate higher amounts of LAK cells followed by the superimposition of a pulse dose of IL-2 to further augment tumor-cell killing may offer some theoretical advantage.…”

Activity of Continuous Infusion Plus Pulse Interleukin-2 with Famotidine in Patients with Metastatic Kidney Cancer or Melanoma Previously Treated with Interleukin-2

“…[21][22][23][24] Furthermore, Hank et al showed in vitro that LAK produced by constant infusion IL-2, then subsequently pulsed with additional IL-2 displayed significantly greater cytotoxicity against tumor cell lines. 25 Increased lymphocytic infiltration of tumors may be seen in patients receiving famotidine. 26 Famotidine, in vitro, has been shown to increase lymphocyte cytotoxicity against tumor cell lines, possibly by increasing internalization of IL-2 by the IL-2 receptors on natural killer (NK) cells.…”