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Dr. Mark Parcells is an associate professor of avian molecular virology at the University of Delaware. His main research focuses on Mareks Disease, a type of virus induced cancer that occurs in chickens. However, he has also done research on cancer vaccines. The Iconoclast asked him about this:

The Iconoclast: Can you explain the term “cancer vaccine”? Many people think that vaccines are only for bacteria and viruses. So basically, what is a cancer vaccine?

Dr. Parcells: Cancer vaccines are injections that direct the immune system to some feature of cancer cells, signaling that they are abnormal and need to be killed. Cancer vaccines tend to fall into two groups: those that direct immune responses to a virus which can cause a type of cancer, and those that direct the immune response against abnormal “self” antigen expression.  The former seem to work pretty well, as they act in a pre-emptive manner by preventing a virus from infecting enough cells to cause cancer.  In humans, most of the cancer-associated viruses take years to cause their malignancies and this usually involves the integration of the virus genome, or portions of the virus genome into the chromosomes of cells.  These integration events are rare and only accumulate over long periods of virus replication.  Examples of viruses that fall into this category are Hepatitis B virus (HBV) and Human Papillomavirus (HPV).  In animals, the vaccines that prevent Marek’s disease, a herpesvirus-induced T-cell lymphoma, also direct the immune system primarily against the virus.

The second type of cancer vaccine is directed against the abnormal cellular gene expression of a particular cancer in and of itself.  This type of expression can be a surface receptor, normally expressed at low levels in a certain tissue, at a certain time of development, that becomes elevated in cancer cells, or some internal protein unique to a particular cell type.  For instance, malignant melanoma vaccines employ proteins that are highly expressed within melanomas and are involved in pigment production. When the immune response responds to these proteins, the patient can be cleared of this very dangerous form of skin cancer, but as a side-effect, many also develop vitiligo, an autoimmune disease in which the immune system attacks normal pigment-producing cells (melanocytes). 

Another type of this anti-cancer vaccine employs cancer cells that are damaged and somehow targeted to the immune system.  Since many tumors can be grown as cell lines in culture, they can be manipulated through the introduction of genes. One strategy is to insert a gene that encodes a protein that attracts cells of the immune system.  Examples of these genes are interleukin 2 (IL-2), interleukin 12 (IL-12), interferon gamma (IFN-g) and granulocyte-macrophage colony stimulating factor (GM-CSF).  By incorporating these into the cells, they can stimulate the immune system to “see” the tumor cells as a foreign body.  The immune modulator that are being used activate particular pathways that are associated with anti-tumor responses.

A big problem with anti-tumor cell vaccines is that the antigens being expressed are still “self” proteins.  Overcoming the natural suppression of an immune response against “self antigens” can be difficult (this is called “breaking peripheral tolerance”).  It can also have unwanted side effects if some of the proteins expressed by tumors are important to normal cells.  An auto-immune reaction can occur and lead to problems in the patient.

The Iconoclast: How do the cancer vaccines from your lab work?

Dr. Parcells: Most of the work in my lab involves the anti-viral vaccines that also induce an anti-tumor response.  These are Marek’s disease vaccines and we have developed and are testing new vaccines to this disease in chickens.  These vaccines present common virus antigens to the immune system that are also expressed by field strains of Marek’s disease virus (MDV).  The vaccine also causes changes in infected cells that may make the cells look like tumor cells.  These changes also seem to be important to the anti-tumor immunity develops in chickens.

One project we also have is for canine hemagiosarcoma (HSA).  HSA is a cancer of the cells that form blood vessels.  For dogs, this can be a very deadly cancer that can go undetected until a dog suddenly faints from internal bleeding.  Removal of a hemangiosarcoma is usually followed by its rapid reappearance or spread (metastasis) and most dogs die within 6 months of the first surgery.  Our project involves a cell line made from a hemangiosarcoma (HSA-DEN) that has been engineered to make GM-CSF.  These cells are grown, collected, irradiated, washed, concentrated and injected to stimulate the dogs immune system.  We have had some success with this and are currently scaling this up for a small clinical trial.  If this works out, we would develop this as an alternative treatment for HSA.

 The Iconoclast: Why do the cancer cells you inject not cause cancer?

Dr. Parcells: We give these cells a 20X lethal dose of UV-irradiation prior to injecting the cells.  These cells then die because of the DNA damage they have incurred over the course of 1 – 3 days.  As they die, the express the immune attractant (GM-CSF) and present tumor antigens to the immune system of he dog.

The Iconoclast: What animals have you tested your vaccines on?So far, only our own dog, Princess.  We are currently developing a small clinical trial for HSA with several veterinary clinics (Nonantum Vet. Clinic in Landenberg, U. Penn. Vet. Hospital in Philadelphia, and Red Bank Animal Hospital in New Jersey).

 The Iconoclast: Did the animals experience any side effects?

Dr. Parcells: Princess has not shown any, but animals in other similar studies sometimes feel sick for a day or two following the injections.  This is a good sign, as it means that the animal is mounting an immune response.  They may lay around, run a small fever or throw up a few times, but that should only last a short time.

The Iconoclast: How successful do you think your vaccines have been?

Dr. Parcells: Currently, we are working to determine what kind of immune response, if any, the vaccine treatment is eliciting.  We have to rule out that our dog was just lucky and our vaccines did nothing.  In science, you have to assume the negative and work to show the positive.  We are therefore testing to see if Princess’s immune system recognizes and can kill the tumor cells in cell culture.  If this is the case, then we have a strong indicator that we have done something positive with the vaccine.  Increasing the number of dogs in a small study will also help to show that this was not just a special case, but that it is a repeatable event.

The Iconoclast: What are your future plans for this research?

Dr. Parcells: With the HSA treatment, we plan to see if this works in a larger number of dogs, and if this does pan out, then we plan to seek a vaccine company to help us develop this as a general treatment for HSA.

We also have a project to work on an anti-cancer treatment for feline vaccine-associated sarcoma (VAS), also known as injection site sarcoma (ISS).  This cancer occurs at sites where cats have received vaccine injections and is due to the response to a component of the vaccine (the immune stimulator aluminum sulfate has been implicated).  Feline vaccines now are not made with this chemical, so the incidence has decreased, but it is a very recurrent and very deadly cancer for cats.  We have been looking at the possibility of using viruses (Adenovirus vectors, Poxviruses) to deliver either tumoricidal proteins or immunostimulatory proteins to the feline sarcomas.