title: Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity.
abstract: Autologous transplantation can induce extended remission in some patients with advanced breast cancer and lymphoma yet nearly 80% and 50%, respectively, will ultimately relapse. In vitro studies suggest that activated natural killer cells (NK) mediate lytic activity against breast cancer and lymphoma cell lines. Therefore, immunotherapy with interleukin-2 (IL-2, Amgen) to activate NK may improve long-term disease-free survival when administered in a post-transplant minimal residual disease setting. To determine the feasibility of administering IL-2 and activation of NK post-transplant, twelve patients (6 breast cancer, 6 lymphoma) were enrolled on a phase I dose escalation study after autologous transplantation (median day + 94, range 50-166). IL-2 was self administered at 0.25 x 10(6) (n = 6) or 0.5 x 10(6) (n = 6) U/m2/day subcutaneously for 84 consecutive days. The best tolerated dose was 0.25 x 10(6) U/m2/day (75% of planned doses given vs. 48% at the higher dose). Dose limiting toxicity occurred in 6 patients (n = 2 at 0.25 x 10(6) U/m2/day, n = 4 at 0.5 x 10(6) U/m2/day) consisting of decreased performance status (n = 2), thrombocytopenia (n = 3, 1 at the lower dose), and mild neutropenia (n = 1 at the lower dose). However, all symptoms resolved within a week following discontinuation of IL-2 and no patient required hospitalization. Circulating soluble IL-2 receptor levels were significantly increased in all patients receiving IL-2. Patients receiving at least 28 days of IL-2 exhibited a greater than 10-fold increment in circulating CD56+bright/CD3- NK. Furthermore, lytic function was increased against NK resistant targets, MCF-7 (breast cancer), and Raji (lymphoma). In vivo IL-2 primed NK cells obtained by lymphapheresis were activated in large-scale ex vivo incubation in high dose IL-2 (1,000 U/mL) at high cell density (10 x 10(6)/mL), in gas permeable bags, and using serum-free media. NK lytic function against MCF-7 and Raji targets was further enhanced. We conclude that low dose subcutaneous IL-2 based immunotherapy is feasible, relatively safe, can be administered in an outpatient setting and hypothesize that additional ex vivo incubation in IL-2 may be used to generate NK cells with potent antitumor effects in vivo.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Miller
authors.forename: J
authors.initials: J
authors.lastname: Tessmer-Tuck
authors.forename: B A
authors.initials: BA
authors.lastname: Pierson
authors.forename: D
authors.initials: D
authors.lastname: Weisdorf
authors.forename: P
authors.initials: P
authors.lastname: McGlave
authors.forename: B R
authors.initials: BR
authors.lastname: Blazar
authors.forename: E
authors.initials: E
authors.lastname: Katsanis
authors.forename: C
authors.initials: C
authors.lastname: Verfaillie
authors.forename: J
authors.initials: J
authors.lastname: Lebkowski
authors.forename: J
authors.initials: J
authors.lastname: Radford
authors.forename: L J
authors.initials: LJ
authors.lastname: Burns
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D016026:Bone Marrow Transplantation / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008223:Lymphoma / Q000276:immunology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D012646:Self Administration; D014182:Transplantation, Autologous / Q000276:immunology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D007376:Interleukin-2