Gene-based cancer vaccines require persistence

Zürich - Faced with a lack of clinical breakthroughs and shifting priorities among investors, researchers targeting cancer through genetic immunization face an uphill climb even as they gain important insights into tumor immunology.

To date, strategies including cytokine gene transfer, tumor antigen transfer via recombinant bacteria/virus mechanisms, and direct gene transfer have yielded no clinically significant results.

"Not one of these approaches has reached clinical phase 3 studies," says Dirk Schadendorf, M.D., head of the Skin Cancer Unit of the German Cancer Research Center in Mannheim. "There are various reasons for that."

As such, he says, "The kinds of vectors that they used were not optimal for clinical application. Viruses like adenovirus and retrovirus were used for immunization purposes and for targeting specific cells. Over the last 10 years, virologists and gene therapists have been able to modify the specificity of viruses to attack specific molecules. All that had not been available when these studies were designed and started in the early to mid-1990s."

Additionally, he says, "Most of the trials which have been performed were performed in very advanced tumor stages because at that time, gene therapy was absolutely new. But we know that tumor immunology, if it has an impact on the clinical course of the disease, probably works best in early clinical stages. Because we haven't seen any clinical benefit in (treating) advanced tumor stages does not mean there is no benefit. However, it's more difficult to prove efficacy in low- or minimal-tumor disease because you need many more patients to demonstrate efficacy."

Likewise, most early gene-based immunization trials used cytokine gene transfer in hopes that merely changing the inflammatory environment around the tumor might have a clinical impact.

"We know from large interferon trials in solid tumors that only a small percentage of patients in the adjuvant clinical stage benefit from such an approach," Dr. Schadendorf tells Dermatology Times. "Indirect, unspecific immunological methods are probably not strong enough to have a clear anti-tumor effect. I would argue one should pursue either more specific tumor immunological vaccination strategies or techniques moving away from immunotherapy like gene replacement or other techniques to have an impact on a specific disease."

Practical considerations Practical considerations also hampered early researchers' efforts: "In order to treat patients," Dr. Schadendorf says, "you must overcome a number of hurdles including GMP and regulatory problems. At that time, it took quite a long time to get these vectors and gene therapeutics through regulatory authorities."

Nevertheless, researchers have learned much over the past decade.

"We have improved vector technology, so there's a better chance that vectors used are doing their job in terms of improved immunogenicity and better targeting of cells either in the immune system, like antigen-presenting cells, or targeting of tumor cells, for example by introducing additional molecules which would allow better adhesion or trafficking to these cells. And we have an increased understanding of some of the pathways we are targeting, like angiogenesis, apoptosis and tumor immunology," he says.

Thanks to a deeper knowledge of some signal transduction pathways, he adds, "It appears that nowadays, more specific targeting using these improved vector technologies might be more promising."

However, such technologies will have to overcome the backlash generated by the hype that initially surrounded gene therapy in the early 1990s, when investment capital for small, high-risk biotechnology ventures was more plentiful.

Dr. Schadendorf says, "Attention has shifted somewhat away from gene therapy because a number of investors did not see their money pay off very quickly in the first phases."

No way around impasse Unfortunately, Dr. Schadendorf sees no way around this impasse in the short term.

"People in the field need to be persistent. They'll probably have to do the first phase 1 and 2 studies more or less on their own with research money" in hopes that these results will attract an investor's attention, he says.

Disclosure: Dr. Schadendorf reports no financial interests pertaining to this article.