PANVAC is a cancer vaccine therapy delivered through two viral vectors--recombinant vaccinia and recombinant fowlpox--which are given sequentially. Both vectors contain transgenes for the tumor-associated antigens epithelial mucin 1 and carcinoembryonic antigen, which are altered or overexpressed in most carcinomas. The vectors also contain transgenes for three human T cell costimulatory molecules required to enhance immune response: B7.1, intracellular adhesion molecule-1 and leukocyte function-associated antigen-3. PANVAC is injected subcutaneously and processed by the body's antigen-presenting cells. Preclinical studies have demonstrated the efficacy of PANVAC in inducing both carcinoembryonic antigen- and mucin 1-specific cytotoxic T lymphocyte responses in vitro and in murine models. Other strategies that enhance the immune response include the use of granulocyte-macrophage colony-stimulating factor and a prime-boost administration sequence. Clinical trials have demonstrated PANVAC's safety and its ability to induce antigen-specific T cell responses. Early clinical trials are evaluating PANVAC alone and in combination with conventional chemotherapy and/or radiation. Studies to date hold promise for the use of PANVAC as a means to stimulate the immune system against malignancies and to provide clinical benefit.
"The current platform designed to express a tumor antigen such as prostate-specific antigen (PSA) or CEA on a poxviral vector expressing multiple human T-cell co-stimulatory molecules (B7.1, LFA-3, and intracellular adhesion molecule-1), named TRICOM, demonstrated promising prospect in both pre-clinical and clinical studies. Such incorporation of tumor antigen transgenes into the TRICOM platform led to the development of rV/F-PSA-TRICOM (PROSTVAC-V/F) and rV/F-MUC1-CEA-TRICOM (PANVAC-V/F) which are currently being evaluated in a phase III clinical trial in metastatic castration-resistant prostate cancer and in advanced pancreatic cancer, respectively [44,54]. "
[Show abstract][Hide abstract] ABSTRACT: Traditional approach of inactivated or live-attenuated vaccine immunization has resulted in impressive success in the reduction and control of infectious disease outbreaks. However, many pathogens remain less amenable to deal with the traditional vaccine strategies, and more appropriate vaccine strategy is in need. Recent discoveries that led to increased understanding of viral molecular biology and genetics has rendered the used of viruses as vaccine platforms and as potential anti-cancer agents. Due to their ability to effectively induce both humoral and cell-mediated immune responses, viral vectors are deemed as an attractive alternative to the traditional platforms to deliver vaccine antigens as well as to specifically target and kill tumor cells. With potential targets ranging from cancers to a vast number of infectious diseases, the benefits resulting from successful application of viral vectors to prevent and treat human diseases can be immense.
"The induction of CD8+ T cells was only observed in few patients or after several rounds of re-stimulation in vitro
–, however, several of the vaccines have demonstrated efficacy, albeit limited –, –. Two viral vaccines expressing MUC1, either in combination with IL-2 (TG4010) , – or in combination with carcinoembryonic antigen (PANVAC) , have demonstrated clinical effect in patients with non small-cell lung and pancreatic cancer –, –. In addition, clinical effect has also been demonstrated with the liposomal vaccine (BLP25) consisting of a 25 mer non-glycosylated peptide from the MUC1 tandem repeat region –. "
[Show abstract][Hide abstract] ABSTRACT: Aberrant glycosylation of mucins and other extracellular proteins is an important event in carcinogenesis and the resulting cancer associated glycans have been suggested as targets in cancer immunotherapy. We assessed the role of O-linked GalNAc glycosylation on antigen uptake, processing, and presentation on MHC class I and II molecules. The effect of GalNAc O-glycosylation was monitored with a model system based on ovalbumin (OVA)-MUC1 fusion peptides (+/- glycosylation) loaded onto dendritic cells co-cultured with IL-2 secreting OVA peptide-specific T cell hybridomas. To evaluate the in vivo response to a cancer related tumor antigen, Balb/c or B6.Cg(CB)-Tg(HLA-A/H2-D)2Enge/J (HLA-A2 transgenic) mice were immunized with a non-glycosylated or GalNAc-glycosylated MUC1 derived peptide followed by comparison of T cell proliferation, IFN-γ release, and antibody induction. GalNAc-glycosylation promoted presentation of OVA-MUC1 fusion peptides by MHC class II molecules and the MUC1 antigen elicited specific Ab production and T cell proliferation in both Balb/c and HLA-A2 transgenic mice. In contrast, GalNAc-glycosylation inhibited the presentation of OVA-MUC1 fusion peptides by MHC class I and abolished MUC1 specific CD8+ T cell responses in HLA-A2 transgenic mice. GalNAc glycosylation of MUC1 antigen therefore facilitates uptake, MHC class II presentation, and antibody response but might block the antigen presentation to CD8+ T cells.
PLoS ONE 11/2012; 7(11):e50139. DOI:10.1371/journal.pone.0050139 · 3.23 Impact Factor
"A limited number of MUC1-based vaccines are now being used and evaluated in advanced clinical trials. PANVAC-VF and MVA-MUC1-IL2 are virus-based vaccines expressing MUC1 and T cell co-stimulatory molecules (B7.1, intracellular adhesion molecule-1 and leukocyte function-associated antigen-3)  or interleukin-2 , respectively. Stimuvax is a liposome-based vaccine composed of a synthetic MUC1 peptide, coupled with the adjuvant monophosphoryl lipid A, evaluated in NSCLC . "
[Show abstract][Hide abstract] ABSTRACT: Sialyl-Tn antigen (STn) is a short O-glycan containing a sialic acid residue a2,6-linked to GalNAca-O-Ser/Thr. The biosynthesis of STn is mediated by a specific sialyltransferase termed ST6GalNAc I, which competes with O-glycans elongating glycosyltransferases and prevents cancer cells from exhibiting longer O-glycans. While weakly expressed by fetal and normal adult tissues, STn is expressed by more than 80% of human carcinomas and in all cases, STn detection is associated with adverse outcome and decreased overall survival for the patients. Because of its pan-carcinoma expression associated with an adverse outcome, an anti-cancer vaccine, named Theratope, has been designed towards the STn epitope. In spite of the great enthusiasm around this immunotherapy, Theratope failed on Phase III clinical trial. However, in lieu of missing this target, one should consider to revise the Theratope design and the actual facts. In this review, we highlight the many lessons that can be learned from this failure from the immunological standpoint, as well as from the drug design and formulation and patient selection. Moreover, an irrefutable knowledge is arising from novel immunotherapies targeting other carbohydrate antigens and STn carrier proteins, such as MUC1, that will warrantee the future development of more successful anti-STn immunotherapy strategies.
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