Abstract
Vaccination with lymphoma cells secreting gp96-Ig together with directed IL-2 rapidly elicit effective tumor immunity after syngeneic HSCT.
IL-2 cytokine-antibody complex expands CD8
+
T lymphocytes and NK cells and enhances pathogen immunity early after HSCT.
Tumor relapse is the primary cause of mortality in patients with hematologic cancers following autologous hematopoietic stem cell transplantation (HSCT). Vaccination early after HSCT can exploit both the state of lymphopenia and minimal residual disease for generating antitumor immunity. Here, multiple vaccinations using lymphoma cells engineered to secrete heat shock protein fusion gp96-Ig within 2 weeks of T cell-replete syngeneic HSCT led to cross-presentation and increased survival of lymphoma-bearing mice. To enhance vaccine efficacy, interleukin (IL)-2 was directed to predominantly memory phenotype CD8
+
T lymphocytes and natural killer (NK) cells via administration bound to anti-IL-2 monoclonal antibody clone S4B6 (IL-2
S4B6
). Combination therapy with gp96-Ig vaccination and coordinated infusions of IL-2
S4B6
resulted in marked prolongation of survival, which directly correlated with ∼500% increase in effector CD8
+
T-cell numbers. Notably, this dual regimen elicited large increases in both donor CD8
+
T and NK cells, but not CD4
+
T lymphocytes; the former 2 populations are essential for both vaccine efficacy and protection against opportunistic infections after HSCT. Indeed, IL-2
S4B6
-treated HSCT recipients infected with
Listeria monocytogenes
exhibited decreased bacterial levels. These preclinical studies validate a new strategy particularly well suited to the post-HSCT environment, which may augment adaptive and innate immune function in patients with malignant disease receiving autologous HSCT.
