Custom designing therapeutic cancer vaccines: delivery of immunostimulatory molecule adjuvants by protein transfer.

Attempts to create vaccines for humans against invading pathogens such as viruses and bacteria have met with tremendous success. The process of developing vaccines against these pathogens is greatly aided by the fact that they contain antigens that are entirely foreign to humans. Although the knowledge and strategies developed for designing vaccines against these microbes may be of use in developing cancer vaccines, the poor antigenicity and immunosuppressive ability of cancers pose major hurdles to vaccine development. Established tumors have not only withstood immune screening and selection pressure, making them poor stimulators of an immune response, but have also adapted mechanisms to continue evading immune surveillance by creating an immunosuppressive environment. Also, genetic differences in immune responses to an antigen among individuals result in an antigenic profile that varies from patient to patient. Cancers bear such great similarities to normal cells in the body that, on a molecular level, the differences between cancerous and non-cancerous cells are minor. Therefore, developing vaccines which use the host's own tumor tissues carries the risk of breaking tolerance to self-antigens that are present in the tumor tissue. Vaccination strategies that will optimally stimulate the immune system against tumor specific antigens under immunosuppressive conditions need to be developed. In practical terms, this calls for a method by which therapeutic vaccines may be custom-designed to treat cancers case by case. Ex vivo manipulation of dendritic cells and gene transfer of immunostimulatory molecules in ex vivo expanded tumors are being tested in both experimental models and also in human clinical trials. Some of them have met with limited success. Emerging technologies such as protein transfer, which make it possible to express immunostimulatory molecules on tumor cell membranes, offer the means to develop efficient tumor vaccines that are simple and fast, while being easy to store and administer in human patients. Progress in these techniques will move the cancer vaccine field a step closer towards realizing custom designed cancer vaccines in human clinical settings.

Comparison of mental-status scales for predicting mortality on the general wards.

BACKGROUND: Altered mental status is a significant predictor of mortality in inpatients. Several scales exist to characterize mental status, including the AVPU (Alert, responds to Voice, responds to Pain, Unresponsive) scale, which is used in many early-warning scores in the general-ward setting. The use of the Glasgow Coma Scale (GCS) and Richmond Agitation Sedation Scale (RASS) is not well established in this population. OBJECTIVE: To compare the accuracies of AVPU, GCS, and RASS for predicting inpatient mortality. DESIGN: Retrospective cohort study. SETTING: Single, urban, academic medical center. PARTICIPANTS: Adult inpatients on the general wards. MEASUREMENTS: Nurses recorded GCS and RASS on consecutive adult hospitalizations. AVPU was extracted from the eye subscale of the GCS. We compared the accuracies of each scale for predicting in-hospital mortality within 24 hours of a mental-status observation using area under the receiver operating characteristic curves (AUC). RESULTS: There were 295,974 paired observations of GCS and RASS obtained from 26,873 admissions; 417 (1.6%) resulted in in-hospital death. GCS and RASS more accurately predicted mortality than AVPU (AUC 0.80 and 0.82, respectively, vs 0.73; P < 0.001 for both comparisons). Simultaneous use of GCS and RASS produced an AUC of 0.85 (95% confidence interval: 0.82-0.87, P < 0.001 when compared to all 3 scales). CONCLUSIONS: In ward patients, both GCS and RASS were significantly more accurate predictors of mortality than AVPU. In addition, combining GCS and RASS was more accurate than any scale alone. Routine tracking of GCS and/or RASS on general wards may improve the accuracy of detecting clinical deterioration.

Expression of membrane anchored cytokines and B7-1 alters tumor microenvironment and induces protective antitumor immunity in a murine breast cancer model.

Many studies have shown that the systemic administration of cytokines or vaccination with cytokine-secreting tumors augments an antitumor immune response that can result in eradication of tumors. However, these approaches are hampered by the risk of systemic toxicity induced by soluble cytokines. In this study, we have evaluated the efficacy of 4TO7, a highly tumorigenic murine mammary tumor cell line, expressing glycosyl phosphatidylinositol (GPI)-anchored form of cytokine molecules alone or in combination with the costimulatory molecule B7-1 as a model for potential cell or membrane-based breast cancer vaccines. We observed that the GPI-anchored cytokines expressed on the surface of tumor cells greatly reduced the overall tumorigenicity of the 4TO7 tumor cells following direct live cell challenge as evidenced by transient tumor growth and complete regression within 30 days post challenge. Tumors co-expressing B7-1 and GPI-IL-12 grew the least and for the shortest duration, suggesting that this combination of immunostimulatory molecules is most potent. Protective immune responses were also observed following secondary tumor challenge. Further, the 4TO7-B7-1/GPI-IL-2 and 4TO7-B7-1/GPI-IL-12 transfectants were capable of inducing regression of a wild-type tumor growing at a distant site in a concomitant tumor challenge model, suggesting the tumor immunity elicited by the transfectants can act systemically and inhibit the tumor growth at a distant site. Additionally, when used as irradiated whole cell vaccines, 4TO7-B7-1/GPI-IL-12 led to a significant inhibition in tumor growth of day 7 established tumors. Lastly, we observed a significant decrease in the prevalence of myeloid-derived suppressor cells and regulatory T-cells in the tumor microenvironment on day 7 post challenge with 4TO7-B7-1/GPI-IL-12 cells, which provides mechanistic insight into antitumor efficacy of the tumor-cell membrane expressed IL-12. These studies have implications in designing membrane-based therapeutic vaccines with GPI-anchored cytokines for breast cancer.