Novel Vaccine Cures Prostate Cancer in Mice

Janis C. Kelly

June 20, 2011

June 20, 2011 — Animal studies of a new human prostate cancer vaccine show that repeated intravenous injections can destroy well-established prostate tumors in mice, without adjuvant chemotherapy or radiation and with no apparent adverse effects. The proof-of-concept study by American and British researchers was published online June 19 in Nature Medicine.

The authors write that "virus-expressed cDNA [complementary DNA] libraries represent a novel paradigm by which the ability of highly mutable tumor cells to escape selective pressures in vivo can be exploited to therapeutic advantage."

The vaccine was developed by inserting a cDNA library from healthy human prostate tissue into mutated vesicular stomatitis viruses, which were then cultured and given to test mice with established prostate tumors. The results showed that 9 intravenous injections cured more than 80% of the established tumors in the mice, without triggering autoimmunity.

"Nobody knows how many antigens the immune system can really see on tumor cells," senior author Richard Vile, PhD, said in a press statement. "By expressing all of these proteins in highly immunogenic viruses, we increased their visibility to the immune system. The immune system now thinks it is being invaded by the viruses, which are expressing cancer-related antigens that should be eliminated." Dr. Vile is the Richard M. Schulze Family Foundation Professor of Immunology at the Mayo Clinic in Rochester, Minnesota.

James L. Gulley, MD, PhD, who reviewed the study for Medscape Medical News, said that the vesicular stomatitis viruses vector approach is almost like a vaccine carrying along its own adjuvant.

"Danger signals are part of the response to the viral vector, and may augment the immune response, with a shift toward more of a cytotoxic T-cell response," said Dr. Gulley, who is director of the Clinical Trials Group, and deputy chief of the laboratory of tumor immunology and biology at the National Cancer Institute's Center for Cancer Research in Bethesda, Maryland.

"Tumor models are good for proof of concept, but don't necessarily reflect what is going on in humans," Dr. Gulley said. "It would be useful to have this study replicated in several tumor models so we know that it is not model-dependent. Probably 2 to 3 more years of work are needed before this vaccine can be moved into the clinic. Since the vector has not be used in humans, the US Food and Drug Administration might ask for safety and toxicity studies in nonhuman primates."

New Approach Targets Tumor From Many Routes

Previous attempts to vaccinate against prostate and other types of cancerous tumors have been hampered, largely by the inability of researchers to isolate a sufficiently diverse and robust collection of antigens in tumor cells. Because of this, tumors often mutate and reestablish themselves in spite of the body's immune system. The use of viruses as vectors for cDNA libraries overcomes the difficulty of isolating antigens in tumor cells by giving the immune system a more complete picture of the cancerous invader.

This approach used doses of a vaccine that contained a library of DNA with multiple fragments of genes and, therefore, many possible antigens. This approach did not send the immune system into overdrive, which had been a concern. Instead, the range of DNA meant that the vaccine was able to target the tumor through many routes.

Importantly, the DNA library was harvested from the same organ as the tumor. This meant that the immune system self-selected the cancer antigens it respond to, and did not react against healthy parts of the body. The fact that the process of self-selection was triggered when the vaccine was injected intravenously means that the vaccine can be given systemically, obviating the need for tumor targeting.

The authors write that "with this approach, a broad repertoire of individually weak T-cell responses is raised against multiple [tumor-associated antigens], imposing a cumulatively strong selective pressure against immune escape, and no tumors have to be accessed by targeted vector delivery."

We were surprised by how specific it was.

Study coinvestigator Alan A. Melcher, PhD, told Medscape Medical News that"we were surprised by how specific it was, in that it didn't cause prostate inflammation on intravenous injection. In fact, it does cause some inflammation if directly injected into the prostate, but doesn't do that when given intravenously. This is helpful, because intravenous injection is much more practical for use in the clinic." Dr. Melcher is senior clinical research fellow at Cancer Research UK, and professor of clinical oncology and biotherapy at the Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom.

"Because the vaccine is derived from normal tissue, it can be a generalized approach, rather than having to be individualized to each patient. Also, we don't have to grow cells from patients to make the vaccine," Dr. Melcher said.

An off-the-shelf vaccine suitable for use by many patients might be possible.

Dr. Gulley said that scaling up for clinical use is likely to be simpler and less expensive with the new vaccine than with targeted tumor vaccines, which often have to be specially created for each patient. "An off-the-shelf vaccine suitable for use by many patients might be possible," he said.

The researchers write that "with suboptimal vaccination, immune escape was possible, but only when tumor cells were forced to acquire a radically new phenotype, readily treated by second-line therapy."

Dr. Melcher said that issues to be resolved include the use of the vaccine in combination with chemotherapy and its use for other cancers. "It is early days for clinical application; we are a few years away, but that is where we are heading," he said.

Dr. Gulley noted that "this is a great proof-of-concept study that also makes intuitive sense. You don't know in advance what the essential target is for a tumor in an individual patient, so it would be good to have a vaccine that could hit a variety of targets — a shotgun rather than a rifle approach."

According to Dr. Gulley, the most important steps in developing an effective cancer vaccine are initial training of the immune system to recognize and kill the tumor in an immunologically relevant fashion, leading to epitope spreading and an antigen cascade.

"In mice, we have seen that T-cells killing tumors are often not T-cells against antigens in the vaccine. The epitope spreading and antigen cascade are important," Dr. Gulley said.

The vesicular stomatitis virus vector does raise some safety concerns because it has never been tested in humans. However, Dr. Gulley said, "there is no reason not to think it would be possible to use the same cDNA library technology with virus vectors that have already been used in clinical trials."

The study was funded by the National Institutes of Health, Cancer Research UK, the Richard M. Schulze Family Foundation, the Mayo Clinic, and a private grant. Dr. Vile, Dr. Melcher, and Dr. Gulley have disclosed no relevant financial relationships.

Nat Med. Published online June 19, 2011. Abstract

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