Humoral response to a viral glycan correlates with survival on PROSTVAC-VF

Campbell, Christopher T.; Gulley, James L.; Oyelaran, Oyindasola; Hodge, James W.; Schlom, Jeffrey; Gildersleeve, Jeffrey C.

doi:10.1073/pnas.1314722111

Cited by 44 publications

(40 citation statements)

References 64 publications

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“…The epitope profiles were analyzed at a molecular level using a glycan microarray, 37 which contains a panel of 328 glycoconjugates derived from glycoproteins or glycolipids with 39 Tn peptides and 44 other GalNAc terminal glycans (for a full list of array components, see Table S1). Sera from mice immunized with Q β –Tn 1 or Q β –Tn 6 were incubated on the microarray and then detected by a fluorescently labeled secondary antibody (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

Significant Impact of Immunogen Design on the Diversity of Antibodies Generated by Carbohydrate-Based Anticancer Vaccine

et al. 2015

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Development of an effective vaccine targeting tumor associated carbohydrate antigens (TACAs) is an appealing approach toward tumor immunotherapy. While much emphasis has been typically placed on generating high antibody titers against the immunizing antigen, the impact of immunogen design on the diversity of TACA-specific antibodies elicited has been overlooked. Herein, we report that the immunogen structure can significantly impact the breadth and the magnitude of humoral responses. Vaccine constructs that induced diverse TACA-binding antibodies provided much stronger recognition of a variety of Tn positive tumor cells. Optimization of the breadth of the antibody response led to a vaccine construct that demonstrated long lasting effcacy in a mouse tumor model. After challenged with the highly aggressive TA3Ha cells, mice immunized with the new construct exhibited a statistically significant improvement in survival relative to controls (0% vs 50% survival; p < 0.0001). Furthermore, the surviving mice developed long-term immunity against TA3Ha. Thus, both the magnitude and the breadth of antibody reactivity should be considered when designing TACA-based antitumor vaccines.

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Section: Resultsmentioning

confidence: 99%

Significant Impact of Immunogen Design on the Diversity of Antibodies Generated by Carbohydrate-Based Anticancer Vaccine

et al. 2015

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“…Most have used mixing the whole cell vaccine with nonspecific adjuvants, such as BCG, but difficulties in overcoming immune suppression within the tumor microenvironment have limited results (34). Nonetheless, clinical trials have consistently shown that survival is significantly better in those patients that are able to mount an immune response to the whole cell vaccine, suggesting that when an immune response is generated, prognosis is improved (35). Cytokines, such as IL12, have also been used to direct an antitumor immune response but the short half-life of these cytokines, when administered as proteins, and the doselimiting toxicities encountered following systemic administration have diminished their potential effectiveness (36).…”

Section: Discussionmentioning

confidence: 99%

NK-Cell Recruitment Is Necessary for Eradication of Peritoneal Carcinomatosis with an IL12-Expressing Maraba Virus Cellular Vaccine

Alkayyal

Tai

Kennedy

et al. 2017

Cancer Immunology Research

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Despite improvements in chemotherapy and radical surgical debulking, peritoneal carcinomatosis (PC) remains among the most common causes of death from abdominal cancers. Immunotherapies have been effective for selected solid malignancies, but their potential in PC has been little explored. Here, we report that intraperitoneal injection of an infected cell vaccine (ICV), consisting of autologous tumor cells infected ex vivo with an oncolytic Maraba MG1 virus expressing IL12, promotes the migration of activated natural killer (NK) cells to the peritoneal cavity in response to the secretion of IFNγ-induced protein-10 (IP-10) from dendritic cells. The recruitment of cytotoxic, IFNγ-secreting NK cells was associated with reduced tumor burden and improved survival in a colon cancer model of PC. Even in mice with bulky PC (tumors > 8 mm), a complete radiologic response was demonstrated within 8 to14 weeks, associated with 100% long-term survival. The impact of MG1-IL12-ICV upon NK-cell recruitment and function observed in the murine system was recapitulated in human lymphocytes exposed to human tumor cell lines infected with MG1-IL12. These findings suggest that an MG1-IL12-ICV is a promising therapy that could provide benefit to the thousands of patients diagnosed with PC each year. Cancer Immunol Res; 5(3); 211–21. ©2017 AACR.

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“…Indeed, B cell-based predictive biomarkers may aid patient stratification and design of adaptive clinical trials. The clinical benefit of such strategies is supported by evidence that pre-existing serum antibodies for a blood group determinant and a viral glycan correlated with overall survival in patients immunized with a candidate prostate cancer vaccine (41; 42). Analysis of the vaccine-specific B and T cell repertoire may be combined with high-throughput immune repertoire sequencing (43) to accelerate development of vaccines against chronic non-communicable diseases.…”

Section: Discussionmentioning

confidence: 99%

The Frequency of Naive and Early-Activated Hapten-Specific B Cell Subsets Dictates the Efficacy of a Therapeutic Vaccine against Prescription Opioid Abuse

Laudenbach

Baruffaldi

Vervacke

et al. 2015

The Journal of Immunology

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Translation of therapeutic vaccines for addiction, cancer or other chronic non-communicable diseases has been slow because only a small subset of immunized subjects achieved effective antibody levels. We hypothesize that individual variability in the number of naïve and early-activated hapten-specific B cells determines post-vaccination serum antibody levels and vaccine efficacy. Using a model vaccine against the highly abused prescription opioid oxycodone, the polyclonal B cell population specific for an oxycodone-based hapten (6OXY) was analyzed by flow cytometry paired with antigen-based magnetic enrichment. A higher frequency of 6OXY-specific B cells in either spleen biopsies or blood, before and after immunization, correlated to subsequent greater oxycodone-specific serum antibody titers and their efficacy in blocking oxycodone distribution to the brain and oxycodone-induced behavior in mice. The magnitude of 6OXY-specific B cell activation and vaccine efficacy was tightly correlated to the size of the CD4+ T cell population. The frequency of enriched 6OXY-specific B cells was consistent across various mouse tissues. These data provide novel evidence that variations in the frequency of naïve or early-activated vaccine-specific B and T cells can account for individual responses to vaccines and may predict the clinical efficacy of a therapeutic vaccine.

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Humoral response to a viral glycan correlates with survival on PROSTVAC-VF

Cited by 44 publications

References 64 publications

Significant Impact of Immunogen Design on the Diversity of Antibodies Generated by Carbohydrate-Based Anticancer Vaccine

Significant Impact of Immunogen Design on the Diversity of Antibodies Generated by Carbohydrate-Based Anticancer Vaccine

NK-Cell Recruitment Is Necessary for Eradication of Peritoneal Carcinomatosis with an IL12-Expressing Maraba Virus Cellular Vaccine

The Frequency of Naive and Early-Activated Hapten-Specific B Cell Subsets Dictates the Efficacy of a Therapeutic Vaccine against Prescription Opioid Abuse

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