Peptide vaccine research: problems and accomplishments

On October 5, 2011, Apple’s Steve Jobs died in California at age 56, seven years after being diagnosed with pancreatic cancer. Pancreatic cancer, a malignant neoplasm of the pancreas, is the fourth most common cause of cancer death worldwide. Jobs’s death is a great loss for the technology industry, and it highlights the need for effective treatments for pancreatic and other cancers.

Immune-based cancer treatments are one emerging type of therapy, and they show great potential. Synthetic-peptide-based vaccines, which are designed to elicit T cell immunity, are also a promising approach to the prevention and treatment of both infectious diseases and malignant disorders, such as cancer. A number of peptide vaccines have been successfully used to produce antigen-specific responses in pancreatic cancer patients by targeting the differences between healthy and cancerous cells.

Mucin 1 (MUC1) is a type I transmembrane glycoprotein found on cancer cells. MUC1’s extracellular domain, which is composed of a polypeptide core with multiple tandem repeats of a 20 amino acid sequence with numerous carbohydrate chains. Peptide vaccines allow the body’s own HLA-unrestricted cytotoxic T lymphocytes (CTLs) to recognize cancerous cells. In one early study, a humoral immune response against MUC1 was also shown, and circulating antibodies against its tandem repeat peptides were detected in various cancers. These findings led researchers to recognize the potential applications of MUC1 in cancer immunotherapy. MUC1 peptide vaccines are currently in clinical trials.

Cancer cells also differ from healthy ones in their telomere-building enzymes and vascular endothelial growth factors (VEGF). A telomerase-based vaccine, known as GV1001 peptide, was found to induce a telomerase-specific immune response in 63% of evaluable patients, as measured by DTH in nonresectable pancreatic cancer. Another peptide epitope vaccine, VEGF receptor (VEGFR)2–169, has been administered alongside gemcitabine to patients with advanced pancreatic cancer. A total of 83% of patients showed a median overall survival time of 8.7 months. Phase II and III studies of this VEGFR2–169 peptide vaccine therapy are currently under way in patients with recurrent pancreatic cancer.

Peptide vaccines can even be tailored to specific patients. In one pilot study, pancreatic and colorectal cancer patients were vaccinated with K-Ras peptides containing patient-specific mutations. Of the patients who received the vaccine, 20% were still alive. Memory T-cell responses were observed in 75% of the survivors. In addition, some effort has been made to generate peptide vaccines based on the specific tumor-antigen epitopes that are most immunogenic in a given patient.

Unfortunately, the advantages that peptide vaccines offer are somewhat diminished by their lack of inherent immunogenicity, as can be seen in their clinical results, which, while encouraging, do not equal those of other types of vaccines. However, there are several ways in which the immunogenicity of peptide vaccines can be increased. Key anchor residues within the peptides, such those that bind to MHC-I molecules, can be mutated. Target peptides can be linked to more highly immunogenic peptides or to antibodies. For example, the TAT protein from HIV, which facilitates entry into cells, has been fused to antigens in order to enhance uptake by cells.

Successful clinical application of peptide vaccines requires a strong understanding of how pancreatic cancers evade immune recognition and target immune suppressor mechanisms. Although peptide vaccines constitute an attractive path for immunotherapy, there are various issues that must be addressed in order to increase the likelihood that these vaccines will preferentially stimulate high-quality CTL responses. Close examination of peptide dosage and vaccine formulation and identification of potential cryptic T cell epitopes will be key parts of any future clinical study.

Will Killer Peptide Offer New Therapy Against Swine Flu H1N1 Virus?

The 2009 swine flu outbreak in humans was caused by a new strain of influenza A virus subtype H1N1. The origin of this new strain is unknown, and the World Organization for Animal Health (OIE) reports that this strain has not been isolated in pigs.

This is a version of the swine flu hemagglutinin amino acid sequence:

MKAILVVMLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLCK
LRGVAPLHLGKCNIAGWILGNPECESLSTASSWSYIVETSSSDNGTCYPGDFIDYEELRE
QLSSVSSFERFEIFPKTSSWPNHDSNKGVTAACPHAGAKSFYKNLIWLVKKGNSYPKLSK
SYINDKGKEVLVLWGIHHPSTSADQQSLYQNADAYVFVGSSRYSKKFKPEIAIRPKVRDQ
EGRMNYYWTLVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCQTPK
GAINTSLPFQNIHPITIGKCPKYVKSTKLRLATGLRNVPSIQSRGLFGAIAGFIEGGWTG
MVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQFTAVGKEFNHLEKR
IENLNKKVDDGFLDIWTYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNG
CFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQILAIYSTVASS
LVLVVSLGAISFWMCSNGSLQCRICI

The H1N1 swine flu can be transmitted from human to human and causes normal influenza symptoms, such as fever, coughing, and headache. The emergence of swine flu has raised concerns of a pandemic outbreak. Although vaccination can be an effective strategy for preventing infection, it takes at least a few months to develop antiviral drugs.

Researchers have described a killer decapeptide (KP) with killer action against influenza A virus. This killer decapeptide represents the functional internal image of a yeast (Pichia anomala) killer toxin with antimicrobial and anti-human-immunodeficiency-virus-type-1 (HIV-1) activity. After treatment with a KP concentration of 4ug/ml, the scientists observed the complete inhibition of virus particle production and a marked reduction of the synthesis of viral proteins (membrane protein and hemagglutinin, in particular). Moreover, mice infected with influenza A/NWS/33 (H1N1) virus were inoculated with KP (100ug/mouse) once a day for ten days resulting in an improved survival rate of 40% and significantly decreased viral levels in their lungs.

It has been suggested that this peptide could be used to treat swine flu, but the matter needs further study. The KP is an anti-idiotypic antibody-derived (KT-scFv) peptide. Killer decapeptide exerted a strong fungicidal activity against Candida albicans, which was attributed to peptide interactions with beta-glucan. The fact that this polysaccharide is also a critical component of the cryptococcal cell wall, may explain KP's inhibitory activity. All of this suggests that KP may have therapeutic effects against pathogenic microorganisms, HIV-1, and influenza A virus, all by different mechanisms of action.

Synthetic peptides have been widely used in the search for therapeutic peptides. A synthetic peptide antigen corresponding to a region of the glycoprotein gp41 encoded by the env gene of HIV-2 was found to be immunologically reactive with HIV-2-specific antibodies. This is useful in assays for the detection of HIV-2 infection or exposure and in compositions meant to elicit the production of antibodies against HIV-2 in animals, including humans.

The specificity of peptides has tremendous clinical value and makes them very attractive therapeutics. More than 40 therapeutic peptides are in use and about 270 peptides are in clinical trials. In addition, more than 400 peptides are in advanced preclinical phases. These trends suggest that the therapeutic peptide represents a novel therapeutic strategy in clinical settings. We may hope that scientists will son have an answer to the headlining question, "Will killer peptide offer new therapy against swine flu H1N1 virus?"

References:

G. Conti, W. Magliani, S. Conti, L. Nencioni, R. Sgarbanti, A.T. Palamara, L. Polonelli. Therapeutic activity of an anti-idiotypic antibody-derived killer peptide against influenza A virus experimental infection. Antimicrobial Agents and Chemotherapy, 52. 12: 4331-4337

Peptides and Obesity Control!

No single agent has been proven to reduce body weight by more than 10%. However, researchers have found that single molecules can be tailored to simultaneously activate more than one of the body's mechanisms for the safe normalization of body weight.

Glucagon and GLP-1 are peptide hormones best known for their insulin and glucose counter-regulatory actions. Scientists have generated a set of high-potency glucagon-based co-agonist peptides. After weekly administration of PEGylated peptides, it was found that these peptides were highly effective in lowering adiposity and improving glucose tolerance of diet-induced obese mice. Peptides with balanced co-agonism proved especially efficacious, and within only a few weeks of therapy, there was an apparent normalization of body weight and blood glucose.

Reference:

Day JW, etc. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009 Oct;5(10):749-57. Epub 2009 Jul 13.