In the Oct 22, 2007, Journal of Experimental Medicine, researchers from Emory University, along with colleagues from the National Institutes of Health and 3M Pharmaceuticals, reported on boosting DNA vaccine efficacy by adding TLR ligands, a method that is known to boost protein vaccine efficacy, and ligands of the tyrosine kinase flt3.

The researchers treated five experimental groups of rhesus monkeys with varying combinations of flt3 kinase ligands, DNA encoding proteins of the simian immunodeficiency virus (which is the monkey version of HIV) and agonists of either TLR9 or TLR 7/8 ligands, and found that a combination of TLR9 and flt3 kinase ligands strongly enhanced the immune response to a DNA vaccine for SIV.

The paper is another attempt to harness T cells for the clinic. Though no one doubts their enormous promise, right now T cells are definitely still on the bumpy part of the ride to therapeutic significance.

The drug development problem with T cells to date has by and large been an immune response that's too weak. Dendreon's Provenge is in limbo, and a number of biotech companies (and former companies) can attest to the difficulty of getting T cells to perform on demand.

Most clinical trials aimed at activating T cells have had a favorable toxicity profile, though a notable exception was the trial of TGN1412, which sent six previously healthy volunteers into the intensive care unit within hours of receiving the drug in March of 2006. (See BioWorld Today, March 16, 2006, and May 26, 2006.)

Still, it's currently the more pressing problem to get enough of a T-cell response, not to suppress an overactive one.

Besides the work now published in the Journal of Experimental Medicine, academic and industrial researchers are working on upping the T-cell response in a number of ways. Argos Therapeutics, for example, lets the immune system decide for itself which tumor antigens to attack.

"We're not smart enough, at this point, to identify the antigens that will give the best success" in tumor-fighting vaccines, Argos Chief Science Officer Charles Nicolette told BioWorld Today.

So Argos dispenses with the educated guessing altogether. The company isolates total mRNA from tumor cells and transfers them wholesale to a patient's own dendritic cells, leading to dendritic cells that "transiently express exactly what the tumor is expressing."

Using that approach, Argos is developing vaccines for cancer and HIV, and is in the clinic for three indications. The company's trial in renal-cell cancer showed an increase in median survival from 11 to 25 months - a result that Nicolette termed "competitive with the latest drugs that are out there, but without the toxicity."

The company uses a technology known as electroporation to load the RNA into the dendritic cells. In Argos' case, the dendritic cells are removed from the patient's body, electroporated and returned. But electroporation also can be used to deliver vaccines directly. San Diego-based biotech Inovio Inc. is specialized on electroporation. Inovio CEO Avtar Dhillon told BioWorld Today that when electroporation is used to deliver DNA to muscle cells, the method augments the immune response by also stimulating the release of cytokines; with electroporation "you get your own adjuvant."

Inovio and its partners, who include academic, biotech and big pharma firms, by and large try to find a happy medium between using one antigen and using them all; Dhillon said that "the chances of failure are much greater with just one protein," but lots of proteins make an autoimmune reaction more likely. Argos' Nicolette noted that the company has not seen undue problems with autoimmunity in its trials, probably because of natural mechanisms that delete autoreactive T cells during development.

Dhillon said that the company's vaccines typically consist of two to three proteins. But, he said, "we can make these plasmids as large as we want."