ABSTRACT
Humans integrate visual information about their surrounding environment to properly adapt their locomotion to step over or around obstacles in their path. We know that cognition aids in the execution of locomotion and in complex maneuvers such as obstacle avoidance. However, the role of the cognitive system in performing online adjustments to an obstacle avoidance strategy during locomotion has not yet been elucidated. Nineteen young adults instrumented with kinematic markers were asked to step over or circumvent an obstacle to the left or right. In half of these trials, participants were required to adjust this strategy when cued by LED lights two steps prior to obstacle crossing. In 75% of trials, a cognitive task was simultaneously presented (incongruent or congruent auditory Stroop cue, or neutral cue). Center of mass position and velocity was estimated and gait metrics (eg. step length) were calculated to quantify how individuals performed this last-minute direction change and determine how these responses changed when simultaneously performing a cognitive task. Results showed statistically shorter crossing steps, where the trailing limb was placed further from the leading edge and the lead limb was placed closer to the trailing edge when responding to the auditory Stroop task. Performing these avoidance strategy changes also decreased cognitive task performance. Our findings suggest that visually integrating a new stepping pattern to cross an obstacle is a complex locomotor maneuver, and requires the aid of the cognitive system to be performed effectively in a young adult population.
Subject(s)
Cognition , Biomechanical Phenomena , Gait , Humans , Locomotion , Psychomotor Performance , Walking , Young AdultABSTRACT
Prime-boost vaccination employing heterologous viral vectors encoding an antigen is an effective strategy to maximize the antigen-specific immune response. Replication-deficient adenovirus serotype 5 (Ad5) is currently being evaluated clinically in North America as a prime in conjunction with oncolytic rhabdovirus Maraba virus (MG1) as a boost. The use of an oncolytic rhabdovirus encoding a tumor antigen elicits a robust anti-cancer immune response and extends survival in murine models of cancer. Given the prevalence of pre-existing immunity to Ad5 globally, we explored the potential use of DEC205-targeted antibodies as an alternative agent to prime antigen-specific responses ahead of boosting with an oncolytic rhabdovirus expressing the same antigen. We found that a prime-boost vaccination strategy, consisting of an anti-DEC205 antibody fused to the model antigen ovalbumin (OVA) as a prime and oncolytic rhabdovirus-OVA as a boost, led to the formation of a robust antigen-specific immune response and improved survival in a B16-OVA tumor model. Overall, our study shows that anti-DEC205 antibodies fused to cancer antigens are effective to prime oncolytic rhabdovirus-boosted cancer antigen responses and may provide an alternative for patients with pre-existing immunity to Ad5 in humans.
ABSTRACT
We have demonstrated that microtubule destabilizing agents (MDAs) can sensitize tumors to oncolytic vesicular stomatitis virus (VSVΔ51) in various preclinical models of cancer. The clinically approved T-DM1 (Kadcyla®) is an antibody-drug conjugate consisting of HER2-targeting trastuzumab linked to the potent MDA and maytansine derivative DM1. We reveal that combining T-DM1 with VSVΔ51 leads to increased viral spread and tumor killing in trastuzumab-binding, VSVΔ51-resistant cancer cells. In vivo, co-treatment of VSVΔ51 and T-DM1 increased overall survival in HER2-overexpressing, but trastuzumab-refractory, JIMT1 human breast cancer xenografts compared to monotherapies. Furthermore, viral spread in cultured HER2+ human ovarian cancer patient-derived ascites samples was enhanced by the combination of VSVΔ51 and T-DM1. Our data using the clinically approved Kadcyla® in combination with VSVΔ51 demonstrates proof of concept that targeted delivery of a viral-sensitizing molecule using an antibody-drug conjugate can enhance oncolytic virus activity and provides rationale for translation of this approach.
