2014 PCRP Investigator Vignette

Title: Developing Antigen-specific DNA Vaccines as a Treatment for Prostate Cancer

Investigator: Doug McNeel, MD, PhD; University of Wisconsin, Madison

We have, for the last 15 years, been interested in the use of the immune system as a treatment for prostate cancer. And we've been interested in doing this by means of vaccines-vaccines to treat existing cancer. So, things that we've been working on are: What are potential targets for vaccines? How do we deliver these targets? And we've been most focused on a means called DNA immunization, or plasma DNA immunization. We've been studying in animals, how do we immunize and generate a response that will destroy prostate cancer tissue? And we've been moving these into human trials to ask how do we best immunize people, and can we get these same kinds of immune responses that we believe are associated with the beneficial response?

My first grant with the DoD Prostate Cancer Research Program was a Post-Doctoral Fellowship Grant and that was in 1999, I believe, when I was doing my post-doctoral training in Seattle at the Fred Hutchinson Cancer Research Center and the University of Washington. And that was to begin to look at DNA vaccines compared with other vaccines targeting a particular protein called prostatic acid phosphatase. And then how do we target this in preclinical models?

It was a couple of years after that that I moved to the University of Wisconsin, Madison, and then had a second grant, which was a New Investigator Grant at that time, to really extend those studies even further, and shortly after that was awarded a Clinical Trial Award to help a Phase 1 clinical trial. So we had actually taken that work from the laboratory studies into an early phase clinical trial. In all of these, I was supported by the Department of Defense.

Our long-term plan has been, first, what are appropriate targets for prostate cancer vaccines? How do we target these in animal models? And then, can we apply these to humans? Will they actually work in human patients? And then ultimately, if we have a simple vaccine strategy, can we identify in patients using the same kind of a vaccine approach-is one target better than another? So, that's been kind of our long-term goal and mission.

We had another Trial Award, which was a Laboratory Clinic Transition Award, was really to identify what may be good targets as a second-line target that we might bring towards clinical trials. And that's been successful, because we're actually planning this year to open another trial targeting ligand binding domain of the androgen receptor, and that work is progressing, and we expect to open a clinical trial targeting that later this year.

So, a DNA vaccine is in some ways similar to a viral vaccine. Viruses are taken up by cells and then the proteins are made within the cells, and then there are what are called professional antigen presenting cells-dendritic cells usually-that then display these to T-cells, and the T-cells can then circulate in the body and destroy cells expressing the protein for which they're specific.

The downside is that plasma DNA is not very efficiently taken up, and so we've been interested in can we make the DNA vaccines better, and one approach that we took to doing that was making specific changes to make the vaccines generate better killing T-cells.

So, we've demonstrated in two pilot clinical trials that if we repetitively immunize people with plasma DNA, we can get the kinds of T-cell responses that we're interested in. This is looking at T-cells taken from individuals before immunization, after three months, or after a year. What we found is that they generate a response that we call TH1; that they make a particular kind of cytokines that are more associated with cells that have killing ability-same with the CD8 T-cells-and this just highlights that a number of these cells make a number of these different cytokines, and the pattern of response actually stays fairly constant over a long period of time. So we're interested and excited by this because we can get an immune response that has a memory phenotype that persists long-term.

Finally, we were the recipients of another Clinical Trial Award which was originally to coordinate the evaluation of our first vaccine in a multi-center clinical trial, and that really helped launch that clinical trial, which now has industry support to really answer that question in a multi-center clinical trial.

So we're now in the middle of a randomized Phase 2 clinical trial; so while it's taken a number of years, things just take time in terms of, from preclinical development to clinical development. I've been very grateful for the support of the DoD over the last decade, and it's really helped to push things from our laboratory in a clinical direction, and we're now testing that and we're getting to the point where we're actually now able to find out whether this really makes a difference for patients. We're pretty excited about that.