ABSTRACT
Functional tumor-specific cytotoxic T cells elicited by therapeutic cancer vaccination in combination with oncolytic viruses offer opportunities to address resistance to checkpoint blockade therapy. Two cancer vaccines, the self-adjuvanting protein vaccine KISIMA, and the recombinant oncolytic vesicular stomatitis virus pseudotyped with LCMV-GP expressing tumor-associated antigens, termed VSV-GP-TAA, both show promise as a single agent. Here we find that, when given in a heterologous prime-boost regimen with an optimized schedule and route of administration, combining KISIMA and VSV-GP-TAA vaccinations induces better cancer immunity than individually. Using several mouse tumor models with varying degrees of susceptibility for viral replication, we find that priming with KISIMA-TAA followed by VSV-GP-TAA boost causes profound changes in the tumor microenvironment, and induces a large pool of poly-functional and persistent antigen-specific cytotoxic T cells in the periphery. Combining this heterologous vaccination with checkpoint blockade further improves therapeutic efficacy with long-term survival in the spectrum. Overall, heterologous vaccination with KISIMA and VSV-GP-TAA could sensitize non-inflamed tumors to checkpoint blockade therapy.
Subject(s)
Cancer Vaccines/immunology , Neoplasms/immunology , Neoplasms/therapy , Oncolytic Viruses/immunology , Vesicular stomatitis Indiana virus/immunology , Animals , Antigens, Neoplasm/administration & dosage , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Cancer Vaccines/administration & dosage , Combined Modality Therapy , Female , Humans , Mice , Mice, Inbred C57BL , Oncolytic Virotherapy , Oncolytic Viruses/genetics , Oncolytic Viruses/physiology , T-Lymphocytes, Cytotoxic/immunology , Tumor Microenvironment , Vaccination , Vesicular stomatitis Indiana virus/genetics , Vesicular stomatitis Indiana virus/physiology , Virus ReplicationABSTRACT
BACKGROUND: Evaluating beneficial effects of potential protective therapies following cardiac arrest in rodent models could be enhanced by exploring behavior and cognitive functions. The Morris Water Maze is a well-known cognitive paradigm to test spatial learning and memory. RESULTS: Behavioral testing with the Morris Water Maze in Sprague-Dawley rats (300 ± 25 g) resuscitated after 8 min of ventricular fibrillation cardiac arrest was carried out 5 and 12 weeks after cardiac arrest (CA) and compared to results of naïve rats (CONTROL). At 5 weeks, within each group latency time to reach the hidden platform (reflecting spatial learning) decreased equally from day 1 to 4 (CA: 105.6 ± 8.2 vs. 8.9 ± 1.2 s, p < 0.001; CONTROL: 75.5 ± 13.2 vs. 17.1 ± 4.5, p < 0.001) with no differences between groups (p = 0.138). In the probe trial 24 h after the last trial, time spent in the target sector (reflecting memory recall) within each group was significantly longer (CA: 25 ± 1.3; CONTROL: 24.7 ± 2.5 s) than in each of the three other sectors (CA: 7.7 ± 0.7, 14.3 ± 2.5, 8.4 ± 0.8 and CONTROL: 7.8 ± 1.2, 11.7 ± 1.5, 10.3 ± 1.6 s) but with no significantly differences between groups. Seven days later (reflecting memory retention), control group animals remained significantly longer in the target sector compared to every other sector, whereas the cardiac arrest group animals did not. Even 12 weeks after cardiac arrest, the single p values showed that the control animals displayed a trend to perform better than the resuscitated animals. CONCLUSIONS: Memory recall was impaired early after 8 min of ventricular fibrillation cardiac arrest and might be a more valuable tool for cognitive testing than learning recall after global ischemia due to cardiac arrest.
