Immunologic Effects of Intermediate-Dose IL-2 i.v. After Autologous Hematopoietic Cell Transplantation in Pediatric Solid Tumors

Abstract

Adoptive immunotherapy with interleukin-2 (IL-2) may control minimal residual disease (MRD) and prevent relapse after autologous hematopoietic cell transplantation (AHCT). The objective of this study was to determine the immunologic effects of intermediate doses of intravenous (i.v.) IL-2 after AHCT in children with poor-prognosis solid tumors. Eleven patients received a median five cycles consisting of escalating doses of IL-2 i.v. for 5 days after a median time interval of 94 days post-AHCT. The phenotype of lymphocyte subsets was investigated before and after each cycle, and parallel determination of natural killer (NK) cell activity was performed. Immunotherapy induced a significant increase in total lymphocyte count (TLC), T, NK, and, to some extent, B cells. Among NK cells, CD56+ bright cells expanded more than CD56+ dim cells. High expansion of CD56+ cells with CD94 inhibitory receptor was observed, whereas no difference was recorded in the number of CD3+ CD56+ and CD8+ CD57+ cells. NK activity stabilized after the first cycle of IL-2 and remained elevated during the study period. Cycles of IL-2 immunotherapy induced repeated significant expansion of T cells and NK cells, mostly of the immature CD56+ bright phenotype. Despite enhanced NK activity, relapses occurred frequently, which might have been due to increased CD94 activation and a poor response from the cytotoxic NK T cells and CD8+ CD57+ T cells.

Clinical-grade, large-scale, feeder-free expansion of highly active human natural killer cells for adoptive immunotherapy using an automated bioreactor

“…Treatment of patients with breast cancer and lymphoma using IL-2 was shown to significantly increase numberofcirculatingNKcellsandtheircytotoxicityagainstNKresistantbreastcancer and lymphoma cell lines 183 . Many other similar studies on immunostimulation in cancer patients have made similar observations where IL-2 infusions induce an increaseinwhitebloodcellcounts,increaseincirculatingTcellsandmostlyCD56 bright NKcells,elevatedcytotoxicactivityofNKcells [184][185][186] .Yet,suchstudieshaveprimarily shown only temporary responses leading to eventual tumor relapse and no survival improvement.…”

Pediatric Cancer Immunotherapy: Opportunities and Challenges

“…In the pediatric population, IL-2 is most noted for its success in high-risk neuroblastoma when combined with an anti-GD2 monoclonal antibody and granulocyte-macrophage colony-stimulating factor (GM-CSF). Unfortunately, many other studies utilizing IL-2 have shown no antitumor effects [ 31 , 32 ]. Schwinger et al investigated high-dose IL-2 in patients with heavily pre-treated solid tumors after resection of primary and/or metastatic lesions in an attempt to maintain remission.…”

Omenn syndrome due to ARTEMIS mutations

“…25,26 In brief, fluorescent DiOC 18 3 -stained K562 cells were gated and propidium iodide-stained cells emitting red fluorescence were evaluated for percentage of lysis.…”