A combination of a Listeria-E7 vaccine and an agonist anti-GITR antibody yielded a synergistic anti-tumor effect (60% complete tumor regression) and long-term systemic immunity in HPV-E6/E7 TC-1 tumor-bearing mice. The effect is likely due to an increase in infiltrating and peripheral antigen-specific CD8+ T cells, a dilution of T regulatory cells via expansion of FoxP3- CD4+ cells, and the stabilization of myeloid-derived suppressor cells.
BACKGROUND: We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. METHODS: Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. RESULTS: We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4+ and CD8+ T cells along with a decrease of inhibitory cells. CONCLUSION: To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy.
Author Info: (1) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (2) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 309
Author Info: (1) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (2) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (3) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (4) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (5) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (6) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (7) Advaxis Immunotherapies, Princeton, NJ 08540 USA. (8) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (9) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA. (10) Augusta University, Georgia Cancer Center, 1410 Laney Walker Blvd, Augusta, GA 30912 USA.
