Immunization of High-Risk Breast Cancer Patients with Clustered sTn-KLH Conjugate plus the Immunologic Adjuvant QS-21

Gilewski, Teresa; Ragupathi, Govind; Dickler, Maura N.; Powell, Shemeeakah; Bhuta, Sonal; Panageas, K.; Koganty, R. Rao; Chin-Eng, Jeannette; Hudis, Clifford A.; Norton, Larry; Houghton, Alan N.; Livingston, Philip O.

doi:10.1158/1078-0432.ccr-06-2189

Cited by 86 publications

(48 citation statements)

References 36 publications

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“…In fact, several cutting-edge therapeutic vaccines for cancer, including melanomas, neuroblastoma, sarcomas, and cancers of the breast, prostate, ovary, and lung tissues, utilize hemocyanins as carrier-adjuvants to generate Abs against different tumor-associated antigens (TAAs). Such TAAs include gangliosides and mucin-like epitopes, which are used to eliminate cancer recurrence by circulating tumor cells and micrometastases [54][55][56]. Surprisingly, our results demonstrate that periodate treatment of CCH enhanced its carrier protein capacity.…”

Section: Discussionmentioning

confidence: 67%

Enhanced structural stability of Concholepas hemocyanin increases its immunogenicity and maintains its non‐specific immunostimulatory effects

et al. 2012

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Hemocyanins, which boost the immune system of mammals, have been used as carrieradjuvants to promote Ab production against haptens and peptides, as immunostimulants during therapy for bladder carcinoma and as a component in therapeutic vaccines for cancer. These biomedical applications have led to growing interest in obtaining hemocyanins with high immunogenicity. Here, we study the immunological properties of a modified oxidized Concholepas concholepas hemocyanin (Ox-CCH) obtained by the oxidation of its carbohydrates using sodium periodate. We assessed the internalization of Ox-CCH into DCs and its immunogenicity and antitumor effects. Transmission electron microscopy showed no changes in Ox-CCH quaternary structure with respect to native CCH, although proteolytic treatment followed by SDS-PAGE analysis demonstrated that Schiff bases were formed. Interestingly, DCs internalized Ox-CCH faster than CCH, mainly through macropinocytosis. During this process, Ox-CCH remained inside endosome-like structures for a longer period. Mouse immunization experiments demonstrated that Ox-CCH is more immunogenic and a better carrier than CCH. Moreover, Ox-CCH showed a significant antitumor effect in the B16F10 melanoma model similar to that produced by CCH, inducing IFN-γ secretion. Together, these data demonstrate that the aldehydes formed by the periodate oxidation of sugar moieties stabilizes the CCH structure, increasing its adjuvant/immunostimulatory carrier effects.

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Section: Discussionmentioning

confidence: 67%

Enhanced structural stability of Concholepas hemocyanin increases its immunogenicity and maintains its non‐specific immunostimulatory effects

et al. 2012

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“…Ongoing vaccination studies of QS21 adjuvant involve breast cancer, HIV, prostate cancer, colorectal cancer and small cell lung cancer responsive to initial therapy. 33 Available data show that QS21 adjuvanted vaccine is immunogenic in high-risk breast cancer patients, 40 elicits high antibody titers in small cell lung cancer patients, 41 and induces specific T-cell responses against P. falciparum malaria. 42 …”

Section: Discussionmentioning

confidence: 99%

Improving vaccine delivery using novel adjuvant systems

Pichichero¹

2008

Human Vaccines

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ASO4, a novel adjuvant, contains aluminum hydroxide and monophosphoryl lipid (MPL) (500 mg aluminum hydroxide and 50 mg 3-O-desacyl-4' MPL A). Aluminum hydroxide is an adjuvant known to facilitate vaccine antigen delivery and transport to the draining lymph nodes by creating a 'depot' at the injection site. 2 Like all aluminum adjuvants, aluminum hydroxide helps improve immunogenicity of low molecular weight antigens, which could otherwise clear rapidly from the injection site or draining lymph nodes. 2 MPL, a non-toxic derivative of lipopolysaccharide, improves specific antibody and cell-mediated immune responses to vaccination. 4 With only minimal toxicity, 5 MPL enhances macrophage and B-and Tcell responses, as well as T-helper cell generation. 5,6 AS04 adjuvant has been shown to improve vaccine-induced immune responses in hepatitis B (HBV) and cervical cancer vaccines.In 2004, Boland et al. 7 described a randomized study where healthy subjects received two doses of HBV vaccine with ASO4 adjuvant or three doses of HBV vaccine with aluminum adjuvant. 7 After the first and second dose of ASO4, substantially more subjects were seropositive for anti-HBV antibodies than after the first and third dose of aluminum adjuvanted vaccine (Table 1). Thus, the ASO4 adjuvant provided the potential for an effective two dose HBV vaccine schedule. In addition, after two doses of ASO4 adjuvanted vaccine, geometric mean titers (GMT) were two times higher than those observed with the aluminum adjuvanted vaccine (7,832 mlU/ml vs 3,725 mlU/ml). No serious adverse events (SAEs) related to the vaccinations occurred, and the overall incidence of vaccine-related adverse events (AEs) (e.g., pain, redness and swelling around the injection site) was comparable between groups. 7 For patients undergoing haemodialysis, the Centers for Disease Control recommends stronger or increased doses of HBV vaccine to assure protective immunity. 8 A clinical trial comparing the immune responses of pre-haemodialysis and haemodialysis patients showed four doses of HBV vaccine was more effective with ASO4 adjuvant than with aluminum adjuvant (Table 1). 9 More patients achieved seroprotection at three months (p = 0.005) and remained seroprotected at 36 months with ASO4 adjuvanted vaccine than with aluminum adjuvanted vaccine (p = 0.03, Table 1). 9 At three and seven months post final dose, signficiantly more patients in the HBV-ASO4 adjuvant group had anti-HB concentrations >100 mlU/mL (p < 0.001 and p < 0.04, respectively), and a higher percentage retained these high anti-HB levels at 36 months

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“…Abnormal glycosylation is a hallmark of malignancy (12,13), and changes in carbohydrate expression can serve as focal points of immune responses. For example, a number of cancer vaccines in clinical trials have been designed specifically to target tumor-associated carbohydrate antigens (14)(15)(16). Other cancer vaccines in clinical development, such as glycoprotein-targeted vaccines and whole-cell vaccines, display a diverse set of glycans to the immune system that potentially induce antiglycan responses.…”

Section: Significancementioning

confidence: 99%

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

Campbell

Gulley

Oyelaran

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Because individual cancer patients differ considerably in their clinical benefits from immunotherapies, early indicators of response could help physicians personalize treatments. Unfortunately, conventional clinical response criteria can be misleading for cancer vaccines. Herein, we show that early humoral responses to xenogenic Forssman disaccharide displayed on PROSTVAC-VF’s viral vectors correlate with long-term survival of vaccinated prostate cancer patients. The survival correlation for anti-Forssman responses was observed consistently when PROSTVAC-VF was used either as monotherapy or combined with the radiopharmaceutical Quadramet. Monitoring postvaccination anti-Forssman humoral responses could offer a simple indicator of response many months before conventional clinical response criteria become reliable. Finally, this study suggests that modifying glycans may improve poxvirus-based vaccines even when not specifically designed to target glycans.

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Immunization of High-Risk Breast Cancer Patients with Clustered sTn-KLH Conjugate plus the Immunologic Adjuvant QS-21

Abstract: Purpose: To determine the clinical toxicities and antibody response against sTn and tumor cells expressing sTn following immunization of high-risk breast cancer patients with clustered sTn-KLH

Cited by 86 publications

References 36 publications

Enhanced structural stability of Concholepas hemocyanin increases its immunogenicity and maintains its non‐specific immunostimulatory effects

Enhanced structural stability of Concholepas hemocyanin increases its immunogenicity and maintains its non‐specific immunostimulatory effects

Improving vaccine delivery using novel adjuvant systems

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

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