Immunotherapy with low-dose interleukin-2: rationale for prevention of immune-deficiency-associated cancer

Congenital, acquired, and some iatrogenically induced immune deficiencies are characterized by an increased incidence of viral-associated cancers. Preclinical and clinical studies were conducted to understand the pathogenesis of immune-deficiency-associated cancer and its response to low-dose recombinant interleukin-2 (rIL-2) therapy, with the ultimate goal of applying this or other immune therapy in the treatment or prevention of immune-deficiency-associated lymphoma.

We have used the severe combined immune-deficient (SCID) mouse engrafted with human peripheral blood lymphocytes (PBL) from healthy Epstein-Barr virus seropositive donors to study the pathogenesis of malignant B-cell lymphoproliferative disease that commonly occurs in some immune-deficient patients. In this chimeric human (hu)-PBL-SCID mouse model, administration of daily low-dose rIL-2 interacts with murine natural killer cells and human CD8+ T cells to prevent the outgrowth of human Epstein-Barr virus lymphoproliferative disease. We have utilized the information gained from this chimeric mouse model to perform a phase I study of daily, subcutaneous, low-dose rIL-2 therapy in patients with both acquired immune deficiency syndrome (AIDS) and cancer.

Plasma concentrations of rIL-2 were achieved in vivo comparable to those seen in our hu-PBL-SCID model, in the absence of significant (grade 3) clinical toxicity or an increase in the plasma human immune deficiency virus (HIV) RNA level. Significant expansion in human cells, particularly the CD3-CD56bright natural killer cell subset, resulted after 6 weeks of therapy. Results of the hu-PBL-SCID mouse model and the phase I study have led to a national trial of low-dose rIL-2 therapy in AIDS-associated lymphoma.

Daily low-dose rIL-2 therapy may be effective in treating or preventing AIDS-associated lymphoma without amplifying HIV replication.