Lenalidomide is an effective therapeutic agent with direct inhibitory effects on malignant B- and plasma cells and immunomodulatory effects on the tumor microenvironment. The dual functions of Lenalidomide make it an appealing candidate for combination with other novel agents for lymphoma and myeloma therapy. In this study, we investigated the immune stimulatory effects of Lenalidomide on the potency of a model lymphoma vaccine (MCP3-sFv). Therapeutic vaccines based on the idiotype of the clonal Ig receptor on malignant B cells have been shown previously to elicit specific immunity in human patients, and a recent controlled Phase III trial of an idiotype protein vaccine demonstrated prolongation of disease free survival in follicular lymphoma patients (J Clin Oncol. 10;29(20):2787–94 2011). In prophylactic experiments, the groups of 10 BALB/c mice immunized with a novel fusion DNA idiotype vaccine (MCP3-sFv, Science. 1;298(5595):1025–9 2002) were then treated with Lenalidomide at various doses (5–50 mg/kg) or saline as control i.p. for 35 consecutive days. This combination strategy protected mice from a lethal syngeneic A20 murine lymphoma, resulting in significantly improved survival comparing with vaccine or Lenalidomide alone or saline. Furthermore, more than 70% of surviving mice treated with the combination were resistant to tumor re-challenge suggesting memory antitumor immunity. Mechanistically, protection required effector cellular immunity, as tumor protection was abrogated by treatment of depleting antibody against CD8+ T cells, either alone or together with CD4 depleting antibody in vivo. Lenalidomide showed little impact on humoral immunity, with serum anti-idiotype antibody levels in the combination group similar to the vaccine alone group. In addition to adaptive immune system, we also examined the effect of Lenalidomide on other immune cells including NK cells, myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). Interestingly, Lenalidomide treatment did not affect the number of these immune cell populations in non-tumor bearing mice; but in tumor-bearing mice, Lenalidomide-induced tumor regression was associated with reduced numbers of immune suppressive cells (MDSC/Treg) and rescue of circulating NK cells. This finding suggests a role of Lenalidomide in ameliorating tumor-induced immune suppression. This hypothesis was supported by the demonstration that the combination of Lenalidomide and vaccine (vaccine given starting on day 8) produced significantly improve survival, compared with controls receiving vaccine or Lenalidomide alone (log rank p<0.05). In conclusion, the opposing effects of Lenalidomide on enhancing cellular immunity and ameliorating immune suppression make it ideal for combination with active specific immunotherapy for treatment of hematological malignancies.
Kwak:Biovest International, Antigenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biovest International: ; Antigenics, Xeme Biopharma: Equity Ownership.
Asterisk with author names denotes non-ASH members.