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Jan 20, 2014

Exploiting Glycans for Potential Cancer Vaccines

Researchers are tackling TACAs in the search for better immunotherapies.

Exploiting Glycans for Potential Cancer Vaccines

In the tumor environment, changes in glycosylation allow neoplastic cells to hijack many of the events that occur during normal development. [© Alex - Fotolia.com]

  • According to scientists, the “booming” development of glycobiology and glycochemistry has enabled identification and analysis of many structures of tumor-associated carbohydrate antigens (TACAs), potentially leading to novel immunotherapeutic targets and cancer biomarkers.

    Tumors aberrantly express various glycoproteins, defined as proteins that contain oligosaccharide chains (glycans) covalently attached to polypeptide side chains. Glycoproteins may be important integral membrane proteins, where they play a role in cell–cell interactions.

    Glycoproteins regulate many different aspects of tumor progression including proliferation, invasion, angiogenesis, and metastasis. In the tumor environment, changes in glycosylation allow neoplastic cells to hijack many of the events that occur during normal development such as receptor activation, cell adhesion, and cell motility, allowing tumor cells to invade and spread throughout the body.

    Tumors expressing a high level of certain types of TACAs exhibit greater metastasis and progression than those expressing low levels of TACAs, as reflected in decreased patient survival rate.

    Documented examples of such TACAs include H/Le(y)/Le(a) in primary non-small-cell lung carcinoma, sialyl-Le(x) (SLe(x)) and sialyl-Le(a) (SLe(a)) in various types of cancer, Tn and sialyl-Tn in colorectal, lung, breast, and many other cancers; GM2, GD2, and GD3 gangliosides in neuroectodermal tumors (melanoma and neuroblastoma), globo-H in breast, ovarian, and prostate cancer, and disialylgalactosylgloboside in renal cell carcinoma.

    But because of their characteristic variable immunogenicity and/or immunotolerance, most TACAs fail to induce the T-cell-mediated immunity that is critical for cancer therapy. Approaches to overcome this limitation or improve their immunogenicity include coupling covalently TACAs to proper carrier molecules to form clustered or multi-epitopic conjugate vaccines, pairing TACAs with a T-cell peptide epitope and/or an immunostimulant epitope to form fully synthetic multicomponent glycoconjugate vaccines.

  • Rolling in the MUC1

    Writing in the journal Vaccines last year, Behjatolah Monzavi-Karbassi, Ph.D., and colleagues reviewed some of the challenges associated with development of glycoprotein-based vaccines. Citing the favorite target of glycan-based vaccine developers, MUC1, cancer vaccines targeting this antigen had been based on carrier-conjugated unglycosylated MUC1 tandem repeat peptides or carrier-conjugated glycosylated epitopes. These efforts proved largely unsuccessful. MUC1 is a high-molecular-weight glycoprotein having few isoforms encoding both a transmembrane and cleavage-truncated secreted (soluble) product. Both forms are expressed by more than 90% of solid epithelial tumor cancers as well as most common nonsolid tumors including multiple myeloma.

    Obstacles, the authors said, partially relate to the conformational differences between nonglycosylated vaccine sequences and tumor-expressed, aberrantly glycosylated MUC1. Moreover, densely glycosylated MUC1 glycopeptide might be inefficiently processed by antigen-presenting cells, which ultimately means T helper cells and CTLS aren’t highly activated.

    In 2012, Vani Lakshminarayanan, Ph.D., and colleagues working in the laboratory of Sandra Gendler, Ph.D., at the department of biochemistry and molecular biology, Mayo Clinic, AZ, and the Complex Carbohydrate Research Center University of Georgia in Athens, GA, thought that better immunogenicity of MUC1 would be obtained using glycopeptides more representative of the novel forms of MUC1. The rationale was that individuals would be less tolerant to these novel cancer-associated glycopeptide forms and that direct linking of the vaccine components would result in superior cytotoxic CD8+ T cells, eliciting robust titers of IgG antibodies that lyse relevant tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC).

    They note that MUC1 is aberrantly glycosylated by epithelial cancer cells, as shown by truncated O-linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and can be recognized by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate ADCC.

    The vaccine is composed of the immunoadjuvant Pam(3)CysSK(4), a peptide T(helper) epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three vaccine components, they said, was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs, which recognized only nonglycosylated peptides. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control.

    Results of vaccine testing in a humanized mouse model of mammary cancer demonstrated that the tripartite vaccine could elicit IgG antibodies that can lyse MUC1-expressing cancer cells, stimulate cytotoxicity of T lymphocytes, and activate innate immune responses, thereby reversing tolerance and generating a therapeutic response.

    The authors say that besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.

    “This vaccine elicits a very strong immune response,” said study co-senior author Geert-Jan Boons, Ph.D., Franklin Professor of Chemistry and a researcher in the UGA Cancer Center and its Complex Carbohydrate Research Center. “It activates all three components of the immune response.”

  • Cancer-Targeting mABs and Fungal Carbohydrates

    And in a completely novel approach to using carbohydrate targets to treat cancer, Lexington, MA-based ImmuneXcite chemically conjugates a fungal carbohydrate to cancer-targeting monoclonal antibodies.

    The company’s scientific co-founder, Yaniv Rubin-Bejerano, discovered a fungal carbohydrate responsible for attracting neutrophils to fungal infections. By chemically conjugating this carbohydrate to cancer-targeting monoclonal antibodies, neutrophils traffic to the site of tumors and initiate tumor destruction.

    ImmuneXcite was founded based on research originating from the Whitehead Institute at the Massachusetts Institute of Technology, where a unique carbohydrate was shown to activate neutrophils.

    The Lexington-based biopharmaceutical company said earlier this month that it has secured $3.58 million in second-round financing from new and existing private investors.

    That amount is in addition to the $2.42 million that the company raised in 2011 in its first round of financing, and an accelerator loan for about $1 million from the Massachusetts Life Sciences Center, the agency that invests state money in local life sciences companies.

  • ImMucin

    Finally, Vaxil BioTherapeutics in Ness Ziona, Israel, is developing its ImMucin, an anti-MUC1 therapeutic cancer vaccine currently in Phase I/II clinical trials on multiple myeloma patients and which is being carried out at Hadassah Medical Center in Jerusalem.

    In April 2013, Vaxil reported that the vaccine had met all the endpoints of the clinical trial VAXIL-001 on 15 patients with multiple myeloma. All the patients enrolled in this study were experiencing a gradual re-emergence of the disease after a period of remission that had been attained through autologous stem cell transplantation. Patients in the VAXIL-001 study received either six or 12 ImMucin injections at a dose of 100 or 250 micrograms, along with GM-CSF (Leukine) at a dose of 250 micrograms.

    The results, the company said, demonstrated a high safety profile for ImMucin and all of the patients demonstrated a strong immunological response to ImMucin, with nine of the 15 patients demonstrating a clinical response. Of these, five patients ended the study in a state of complete response and a further four ended the study with stable disease, which required no further treatment.

    Earlier this month, Vaxil said 100% of patients enrolled in their VAXIL-002 study testing the vaccine in multiple myeloma patients demonstrated a strong immune response of both CD4+ and CD8+ T cells to ImMucin. In addition, a strong antibody response to ImMucin was observed in 65% of patients.

    Four out of the five patients enrolled in the study are still in remission from their illness and have been so for a period of between 12 and 26 months following completion of their treatment with the vaccine. The fifth patient was in a period of remission of 13 months following completion of his treatment with ImMucin until the disease returned and he was taken out of the study. Monitoring of these patients is being carried out at Hadassah Medical Center, and the patients are not receiving any other treatments.

    Lior Carmon, Ph.D., Vaxil’s CEO and founder, noted the significance of the antibody response, pointing out that, to the best of the company’s knowledge, this combination of T cells and antibodies does not exist in other MUC1 vaccines.

    “Moreover,” he noted, the “trial results in patients with a wide range of different immune repertoires support the company’s hypothesis of the ability of ImMucin to be universal—that it can activate the patient’s immune system with no need for personalization or prior selection based on the patient’s immune system type.”

    And as researchers further define the minimum requirements to consistently induce CTLs and ADCC-mediating antibodies specific for the tumor form of tumor cell TACAs including MUC1, other vaccines will move toward the clinic.



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