Phase I study of a novel therapeutic vaccine as perioperative treatment for patients with surgically resectable hepatocellular carcinoma: The YCP02 trial.

AIM: Developing effective adjuvant therapies is essential for improving the surgical outcomes in patients with hepatocellular carcinoma (HCC). Immunotherapy against HCC has become a promising strategy; however, only approximately 30% of all HCC patients respond to immunotherapy. Previously, we generated the novel therapeutic vaccine comprising multi-human leukocyte antigen-binding heat shock protein 70/glypican-3 peptides with a novel adjuvant combination of hLAG-3Ig and poly-ICLC. We also confirmed the safety of this vaccination therapy, as well as its capacity for the effective induction of immune responses in a previous clinical trial. METHODS: In this phase I study, we administered this vaccine intradermally six times before surgery, and 10 times after surgery to patients with untreated, surgically resectable HCC (stage II to IVa). The primary end-points of this study were the safety and feasibility of this treatment. We also analyzed the resected tumor specimens pathologically using hematoxylin-eosin staining and immunohistochemistry for heat shock protein 70, glypican 3, CD8 and programmed death-1. RESULTS: A total of 20 human leukocyte antigen-matched patients received this vaccination therapy with an acceptable side-effect profile. All patients underwent planned surgery without vaccination-related delay. Immunohistochemical analyses revealed that potent infiltration of CD8+ T cells into tumors with target antigen expression was observed in 12 of 20 (60%) patients. CONCLUSIONS: This novel therapeutic vaccine was safe as perioperative immunotherapy for patients with HCC, and has the potential to strongly induce CD8+ T cells infiltration into tumors.

A phase I study of multi-HLA-binding peptides derived from heat shock protein 70/glypican-3 and a novel combination adjuvant of hLAG-3Ig and Poly-ICLC for patients with metastatic gastrointestinal cancers: YNP01 trial.

BACKGROUND: This phase I study aimed to evaluate the safety, peptide-specific immune responses, and anti-tumor effects of a novel vaccination therapy comprising multi-HLA-binding heat shock protein (HSP) 70/glypican-3 (GPC3) peptides and a novel adjuvant combination of hLAG-3Ig and Poly-ICLC against metastatic gastrointestinal cancers. METHODS: HSP70/GPC3 peptides with high binding affinities for three HLA types (A*24:02, A*02:01, and A*02:06) were identified with our peptide prediction system. The peptides were intradermally administered with combined adjuvants on a weekly basis. This study was a phase I dose escalation clinical trial, which was carried out in a three patients' cohort; in total, 11 patients were enrolled for the recommended dose. RESULTS: Seventeen patients received this vaccination therapy without dose-limiting toxicity. All treatment-related adverse events were of grades 1 to 2. Peptide-specific CTL induction by HSP70 and GPC3 proteins was observed in 11 (64.7%) and 13 (76.5%) cases, respectively, regardless of the HLA type. Serum tumor marker levels were decreased in 10 cases (58.8%). Immunological analysis using PBMCs indicated that patients receiving dose level 3 presented with significantly reduced T cell immunoglobulin and mucin-domain containing-3 (TIM3)-expressing CD4 + T cells after one course of treatment. PD-1 or TIM3-expressing CD4 + T cells and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)-expressing CD8 + T cells in PBMCs before vaccination were negative predictive factors for survival. CONCLUSIONS: This novel peptide vaccination therapy was safe for patients with metastatic gastrointestinal cancers.

Identification of a Promiscuous Epitope Peptide Derived From HSP70.

We previously found that heat-shock protein 70 (HSP70) is expressed on hepatocellular carcinoma cells and developed an HSP70 mRNA-transfected dendritic cell therapy for treating unresectable or recurrent hepatocellular carcinoma. The phase I trial was completed successfully. The purpose of this study is to identify a promiscuous epitope peptide derived from HSP70 for the purpose of developing a novel cancer peptide vaccine. Using a computational algorithm to analyze the specificity of previously reported major histocompatibility complex class I-binding peptides, we selected candidates that bound to >2 of the 3 HLA types. Twenty-nine HSP70-derived peptides (9-mers) that bound to HLA-class I was selected. The peptides were prioritized based on the results of peptide binding experiments. Using dendritic cells stimulated with the candidate peptide described previously as stimulators and CD8 T cells as effectors, an ELISPOT assay was performed. Cytotoxicity of CD8 lymphocytes stimulated with the candidate peptides toward HSP70-expressing cancer cells was analyzed using an xCELLigence System. Peptides were administered to HLA-A 24 transgenic mice as vaccines, and peptide-specific T-cell induction was measured in vivo. We identified a multi-HLA-class I-binding epitope peptide that bound to HLA-A*02:01, *02:06, and *24:02 in vitro using an interferon-γ ELISPOT immune response induction assay. Cytotoxicity was confirmed in vitro, and safety and immune response induction were confirmed in vivo using HLA-A 24 transgenic mice. Our study demonstrated that the promiscuous HSP70-derived peptide is applicable to cancer immunotherapy in patients with HLA-A*24:02-positive, *02:01-positive, and *02:06-positive HSP70-expressing cancers.

Combined adjuvants of poly(I:C) plus LAG-3-Ig improve antitumor effects of tumor-specific T cells, preventing their exhaustion.

Therapeutic cancer vaccines are designed to treat cancer by boosting the endogenous immune system to fight against the cancer. In the development of clinically effective cancer vaccines, one of the most practical objectives is to identify adjuvants that are capable of optimizing the vaccine effects. In this study, we explored the potential of polyinosinic-polycytidylic acid (poly(I:C)) and LAG-3-Ig (soluble recombinant protein of lymphocyte activation gene-3 [LAG-3] extracellular domain fused with human IgG Fc region) as adjuvants for P1A tumor antigen peptide vaccine in a pre-established P815 mouse tumor model with a transfer of tumor-specific T cells. Whereas the use of poly(I:C) or LAG-3-Ig as a signal adjuvant induced a slight enhancement of P1A vaccine effects compared to incomplete Freund's adjuvant, combined treatment with poly(I:C) plus LAG-3-Ig remarkably potentiated antitumor effects, leading to complete rejection of pre-established tumor and long-term survival of mice. The potent adjuvant effects of poly(I:C) plus LAG-3-Ig were associated with an enhanced infiltration of T cells in the tumor tissues, and an increased proliferation and Th1-type cytokine production of tumor-reactive T cells. Importantly, the combined adjuvant of poly(I:C) plus LAG-3-Ig downregulated expressions of PD-1, LAG-3, and TIGIT on P1A-specific T cells, indicating prevention of T cell exhaustion. Taken together, the results of the current study show that the combined adjuvants of poly(I:C) plus LAG-3-Ig with tumor peptide vaccine induce profound antitumor effects by activating tumor-specific T cells.

Is the useful field of view a good predictor of at-fault crash risk in elderly Japanese drivers?

AIM: Although age-related decline in the useful field of view (UFOV) is well recognized as a risk factor for at-fault crash involvement in elderly drivers, there is still room to study its applicability to elderly Japanese drivers. In the current study, we thus examined the relationship between UFOV and at-fault crash history in an elderly Japanese population. We also explored whether potential factors that create awareness of reduced driving fitness could be a trigger for the self-regulation of driving in elderly drivers. METHODS: We measured UFOV and at-fault crash history from 151 community-dwelling Japanese aged 60 years or older, and compared UFOV of at-fault crash-free and crash-involved drivers. We also measured self-evaluated driving style using a questionnaire. RESULTS: UFOV in crash-involved drivers was significantly lower than that in crash-free drivers. No significant difference was found in self-evaluated driving style between crash-free and crash-involved drivers. In addition, there was no significant association between UFOV and self-evaluated driving style. CONCLUSIONS: The present study showed that UFOV is a good predictor of at-fault crash risk in elderly Japanese drivers. Furthermore, our data imply that it might be difficult for elderly drivers to adopt appropriate driving strategies commensurate with their current driving competence.

Regional frontal gray matter volume associated with executive function capacity as a risk factor for vehicle crashes in normal aging adults.

Although low executive functioning is a risk factor for vehicle crashes among elderly drivers, the neural basis of individual differences in this cognitive ability remains largely unknown. Here we aimed to examine regional frontal gray matter volume associated with executive functioning in normal aging individuals, using voxel-based morphometry (VBM). To this end, 39 community-dwelling elderly volunteers who drove a car on a daily basis participated in structural magnetic resonance imaging, and completed two questionnaires concerning executive functioning and risky driving tendencies in daily living. Consequently, we found that participants with low executive function capacity were prone to risky driving. Furthermore, VBM analysis revealed that lower executive function capacity was associated with smaller gray matter volume in the supplementary motor area (SMA). Thus, the current data suggest that SMA volume is a reliable predictor of individual differences in executive function capacity as a risk factor for vehicle crashes among elderly persons. The implication of our results is that regional frontal gray matter volume might underlie the variation in driving tendencies among elderly drivers. Therefore, detailed driving behavior assessments might be able to detect early neurodegenerative changes in the frontal lobe in normal aging adults.

Can passengers' active head tilt decrease the severity of carsickness? Effect of head tilt on severity of motion sickness in a lateral acceleration environment.

OBJECTIVE: We investigated the effect of the passenger head-tilt strategy on the severity of carsickness in lateral acceleration situations in automobiles. BACKGROUND: It is well known that the driver is generally less susceptible to carsickness than are the passengers. However, it is also known that the driver tilts his or her head toward the curve center when negotiating a curve, whereas the passenger's head moves in the opposite direction. Therefore, we hypothesized that the head-tilt strategy has the effect of reducing the severity of carsickness. METHOD: A passenger car was driven on a quasi-oval track with a pylon slalom while the participant sat in the navigator seat. The experiment was terminated when either the participant felt the initial symptoms of motion sickness or the car finished 20 laps. In the natural head-tilt condition, the participants were instructed to sit naturally, to relax, and not to oppose the lateral acceleration intentionally. In the active head-tilt condition, the participants were asked to tilt their heads against the centrifugal acceleration, thus imitating the driver's head tilt. RESULTS: The number of laps achieved in the active condition was significantly greater than that in the natural condition. In addition, the subjective ratings of motion sickness and symptoms in the active condition were significantly lower than those in the natural condition. CONCLUSION: We suggest that an active head tilt against centrifugal acceleration reduces the severity of motion sickness. APPLICATION: Potential applications of this study include development of a methodology to reduce carsickness.

Effects of self-motion on attention in real 3D space.

Human behavioral space is three-dimensional (3D), and when moving through 3D space individuals selectively allocate their attention to acquire necessary information. This study aimed to examine the characteristics of attention in real 3D space when observers were moving forward. In static and self-motion situations, relative and absolute cues were used. Results indicated that internal representation for allocation of attention in 3D space is in depth-aware mode whether in static or moving condition. Moreover, near superior asymmetrical switching of attention is more strongly manifested under moving than under static conditions. Our findings indicate that focusing of attention by relative and absolute cues is maintained in self-motion, and that allocation of attention during movement is more viewer-centered than when observers are static.

Attentional processing of location and color cues during driving.

Studies have shown that prior information concerning the spatial location of a subsequent target facilitates the selection of that target for further visual processing in three-dimensional (3-D) space. Using Posner's cuing paradigm, our work examined the reaction time of drivers when cue duration and peripheral environment luminance was changed, and explored the effect color and location on reaction time. Experiment 1 showed that reaction time was not affected by cue duration, and that shifts of attention operated more efficiently for cue location validity. Experiment 2 showed that there was no main effect of background luminance on reaction time. Experiment 3 showed that location produces a greater effect than color.