Targeting the colorectal cancer-associated GUCY2C antigen, Flickinger Jr et al. found that heterologous prime-boost vaccination with an adenoviral (Ad5) followed by bacterial (Listeria monocytogenes, Lm) vector improved GUCY2C-specific CD8+ T cell responses and CT26 metastatic burden compared to either alone or to homologous prime-boosts. CD8+ T cells of mice receiving the Lm boost had greater avidity and polyfunctionality (IFNγ, TNFα, MIP1α), without signs of toxicity, compared to the prime alone. The efficacy of the Ad5 + Lm regimen was retained with low, but reduced with high, pre-existing Ad5-neutralizing antibody titers.
Contributed by Alex Najibi
ABSTRACT: Strategies to augment immunity to self/neoantigens expressed by cancers are urgently needed to expand the proportion of patients benefiting from immunotherapy, particularly for GI cancers where only a fraction of patients respond to immunotherapies. However, current vaccine strategies are limited by poor immunogenicity, pre-existing vector-specific immunity, and vaccine-induced vector-specific immunity. Here, we examined a prime-boost strategy using a chimeric adenoviral vector (Ad5.F35) that resists pre-existing immunity followed by recombinant Listeria monocytogenes (Lm) to amplify immunity to the GI cancer antigen GUCY2C. This previously unexplored combination enhanced the quantity, avidity, polyfunctionality, and antitumor efficacy of GUCY2C-specific effector CD8(+) T cells, without toxicity in any tissue, including GUCY2C-expressing intestines and brain. Importantly, this combination was partially resistant to pre-existing immunity to Ad5 which is endemic in human populations and vector-specific immunity did not limit the ability of multiple Lm administrations to repeatedly enhance GUCY2C-specific responses. Broadly, these findings suggest that cancer patient immunizations targeting self/neoantigens, as well as immunizations for difficult infectious diseases (HIV, malaria, etc), may be most successful using a combination of Ad5.F35-based priming, followed by Lm-based boosting. More specifically, Lm-GUCY2C may be utilized to amplify GUCY2C-specific immunity in patients receiving adenovirus-based GUCY2C vaccines currently in clinical trials to prevent or treat recurrent GI cancer.
Author Info: (1) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (2) Department of Pharmacolo
Author Info: (1) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (2) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (3) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (4) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (5) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (6) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (7) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (8) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Department of Surgery, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (9) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. (10) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. Sidney Kimmel Cancer Center, Jefferson Health, Philadelphia, PA, 19107, USA. (11) Department of Pharmacology, Physiology, & Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA. adam.snook@jefferson.edu. Sidney Kimmel Cancer Center, Jefferson Health, Philadelphia, PA, 19107, USA. adam.snook@jefferson.edu.
