Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity

Biol Blood Marrow Transplant. 1997 Apr;3(1):34-44.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Adjuvants, Immunologic / pharmacology
  • Adjuvants, Immunologic / therapeutic use*
  • Adult
  • Bone Marrow Transplantation / immunology*
  • Breast Neoplasms / immunology
  • Breast Neoplasms / therapy
  • Cells, Cultured
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic / drug effects
  • Female
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Injections, Subcutaneous
  • Interleukin-2 / administration & dosage
  • Interleukin-2 / pharmacology
  • Interleukin-2 / therapeutic use*
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Lymphocyte Activation / drug effects
  • Lymphoma / immunology
  • Lymphoma / therapy
  • Male
  • Middle Aged
  • Self Administration
  • Transplantation, Autologous / immunology*
  • Treatment Outcome
  • Tumor Cells, Cultured


  • Adjuvants, Immunologic
  • Cytokines
  • Interleukin-2