Virotherapy: Reprogramming the Measles Virus to Attack Cancer

Since his recruitment, in the fall of 1998 from Cambridge University in England, Stephen Russell, M.D., Ph.D., who directs the Molecular Medicine Program, has succeeded in building a unique virology and gene therapy program at Mayo that is now considered to lead the world in researching the potential of the measles vaccine virus for fighting cancers.

"The environment here is perfect for gene therapy because you need many different types of expertise to coalesce," says Dr. Russell. "You need basic scientists to create the agent and test it preclinically. You need experts to conduct toxicology studies and manufacture the vector under strict government regulation. You need clinicians who understand the science to write the clinical protocol and who can nurture it through the clinical studies. At Mayo we have all of that plus the infrastructure to support a pipeline of gene therapy studies."

As a hematologist, Dr. Russell has long known that the wild form of measles can kill blood cancer cells. However, when his team discovered that the vaccine can also kill most solid organ cancers as well, its value as a vector—a system through which genes are delivered into target cells—skyrocketed. The Molecular Medicine team then began the complex odyssey of designing a new virus. In the process, they invented several new gene therapy approaches.

Targeting the Tumor, Preserving Healthy Tissue

Kah-Whye Peng, Ph.D., was a post-doctoral fellow when she spearheaded the project that produced the engineered measles virus now being used in the clinical trial. She designed studies that demonstrated the measles virotherapy could shrink a variety of tumors with minimal damage to healthy tissue.

The team then chose a handful of specific cancers for further testing. Their choices offer opportunities to test different routes of virus delivery.

Ovarian cancer tests delivery of the virotherapy directly into the peritoneal cavity—a potential space between membrane that line the abdominal and pelvic walls—because the disease spreads within the peritoneal cavity but rarely beyond it. Multiple myeloma is ideal for intravenous delivery because it spreads throughout the body. More recently, work performed in the laboratory of principal investigator and oncologist Evanthia Galanis M.D., showed that delivery of measles virus directly into gliomas had potent antitumor activity. Gliomas, lethal tumors of the brain, represent a good target for intratumoral delivery of viral therapies because they rarely metastasize.

Increasing Potency by Cell Fusion

In 2000, Drs. Russell, Roberto Cattaneo, Ph.D., and Richard Vile, Ph.D., invented a new approach that addressed one of the limitations of previous cancer gene therapies—that they affect only the single cells that actually take up the genes. Their invention exploits the characteristics of viral fusogenic membrane glycoproteins (FMGs), which produce massive cell death by merging surrounding cells into a single protoplasmic mass.

"In this way, a single virus-modified cell can cause death of many surrounding cells," explains Dr. Russell. "We call it bystander killing."

Subsequent advances to the FMG technology have been published in many peer-reviewed journals, the most recent in Nature Biotechnology in March 2004.

Monitoring Gene Expression

In a May 2002 Nature Medicine paper, Drs. Russell and Peng described research that created the ability to monitor gene expression non-invasively—an important advance. Dr. Russell explains:

Being able to monitor viral replication is my war cry. One of the shortcomings of past gene therapy clinical trials is the inability to understand why it fails—was it failure of gene delivery, or did you get good gene expression and it just didn't work? Was gene expression too good but you had no way of knowing it and administered repeated toxic doses? Was it a short-term expression problem and if so, when was expression switched off? You can't improve the biotechnology if you don't know what part of it went wrong.

Carcinoembryonic antigen (CEA) is a soluble peptide produced by some cancers. Because it can be detected in blood tests, clinicians use it to follow the course of some anti-cancer treatments. Drs. Peng and Russell genetically engineered the measles virus vector to express the CEA peptide. The engineered virus, MV-CEA, gives clinicians the ability to follow the kinetic profile of viral gene expression in those patients whose tumors do not express CEA. And it gave the investigators the tool they needed to take their research to the next stage of translation—vector manufacture, and toxicology and efficacy studies.

Translating cell therapy into patient therapy

The degree of expertise and infrastructure necessary to manufacture a gene or virus therapy pure enough to meet the Food and Drug Administration's safety standards for testing in humans is painstakingly complex. Once the vector has been perfected to the point where it warrants clinical testing, production and purification cycles begin.

Dr. Peng co-directs the toxicology and pharmacology testing lab that handles the iterative cycles of toxicology testing, in both cell and animal models, necessary to purify and perfect each new gene or virus therapy.

"The tox/pharm study is designed to address specific concerns for the targeted clinical population," says Dr. Peng. "We need to know where the vector goes and if it persists or is expelled from the body. And we need to account for the possibility of allergic reaction, inflammation, or infection caused by the vector or for toxicity caused by expression of the transgene."

The toxicology and pharmacology team worked with the FDA to find an acceptable animal species for testing. As further indication of Mayo's expertise in this field, the FDA's choice was a transgenic mouse model developed by Dr. Cattaneo.

Mayo's FDA-compliant vector manufacturing facility, directed by Mark Federspiel, Ph.D., must uphold highly regulated standards of cleanliness and sterility as they weather many rounds of harvesting, testing, and purification.

"If we had to contract the manufacturing part of the cycle out, we would be a long way from being able to provide this experimental therapy for patients," says Dr. Federspiel. "Having the facility on campus means we can collaborate on solving problems as they arise."

Dr. Federspiel has developed collaborative relationships with the relevant advisory boards and works directly with them to address their concerns. His team has implemented the knowledge derived from manufacturing the MV-CEA clinical product into subsequent projects, making it possible to produce purer products with greater efficiency.

Beginning Human Studies

When efficacy studies showed that MV-CEA induced complete regression of 80 percent of ovarian tumors in mice, the team was ready to launch a clinical trial. It opened in April 2004.

"It's very exciting for our team to be able to take this virotherapy approach all the way from discovery to a stage where it can help patients." says Dr. Galanis, the study's principal investigator. "We have a very active clinical gene transfer and virotherapy program in the Department of Oncology having treated more than 150 patients with gene or virus therapy during the last 10 years. But this is the first time we have developed the vector at Mayo."

Every year, 14,000 women die from ovarian cancer in the United States. The disease is commonly diagnosed at an advanced stage because early symptoms are minimal. Patients enrolled in the current study have progressive ovarian cancer for which the standard treatment—radical surgery followed by chemotherapy—failed.

Mayo's "patient first" motto ensures that the majority of research at Mayo is motivated by a problem seen at the bedside. In this case, it was Lynn Hartmann, M.D., and her colleagues in the Gynecologic Oncology clinic who worked hard to ensure that the Molecular Medicine team chose ovarian cancer as the first target for translation to the bedside. In fact, translational funds from the Ovarian Group supported the initial efficacy work.

Safety is crucial in the first trial for any new drug. Besides meeting strict FDA requirements applicable to gene therapy trials, the study is closely monitored by additional safety and advisory committees, including Mayo's Institutional Review Board.

"Human studies in gene therapy for cancer have had an excellent safety record," says Dr. Galanis. "Our studies on mice with the engineered measles virus showed no evidence of toxicity despite administering 32 times more virus than the highest dose planned for humans. And because we now have a vector engineered to express the CEA peptide, we can perform real-time monitoring of the viral replication in patients for the very first time."

One of the study's goals is to optimize dose amount and timing.

"We deliver the drug into the peritoneal cavity," says Dr. Galanis. "Ovarian cancer rarely spreads beyond the peritoneal cavity so direct delivery optimizes contact between the cancer cells and the therapeutic agent."

Direct delivery into the peritoneal cavity also reduces the possibility of the virus being neutralized by antibodies produced by the patient as a result of vaccination or natural infection. However, should any viruses escape into the circulatory system the patient's immune system provides an additional safety measure.

The study will take place in the CTSA Clinical Research Unit (CRU), an outstanding institutional resource that provides an optimal setting for controlled clinical research studies, including teams of nurses and technicians specially trained in caring for patients enrolled in human studies.

Dr. Galanis reiterates why the team is so excited about this project:

"As an oncologist and translational researcher, it is very gratifying to help create a bridge between the bench and the clinic in order to address challenging clinical problems. At the end of the day, we hope to develop better treatments for cancer patients, using measles virotherapy. Ovarian cancer represents the first step in this effort with other tumors, such as gliomas to follow."

A New Paradigm

In conventional drug therapy, the new drug is taken through the clinical trial process without changing it. Dr. Russell sees gene and virotherapy as an on-going process that requires a different model for human testing.

"It's much like building motor cars—just because you build something that works does not end the need to design better models," explains Dr. Russell. "There are multiple components in the new gene therapy vectors and we can continually improve them because we have control over all stages of production. We are already working on solutions that will preempt any problems we might see in the clinical trial."

An Encouraging Future

If tests on smaller numbers of patients show promise, the new therapy for ovarian cancer will be tested on much larger numbers of patients in a Phase III trial before gaining FDA approval. Dr. Russell and his team look forward to partnering with pharmaceutical companies should that happy day arrive. Partnership with industry allows Mayo to bring its research advances to patients all over the world.

And it would mean the end of a long quest for Dr. Russell.

"I have had a passion for harnessing the destructive power of viruses and using them to destroy tumors since my medical school days," says Dr. Russell. "Coming to Mayo was the opportunity of the century for translational research."

The MV-MEA project was made possible by the following generous gifts:

• The Harold W. Siebens Foundation, the Donaldson Charitable Trust and a Fraternal Order of Eagles grant funded the virus construction and efficacy research.
• George M. Eisenberg Foundation funded the vector production facility.
• The Harold W. Siebens Foundation and the Commonwealth Cancer Foundation funded the Toxicology Core
• Additional funding was received from the National Cancer Institute.

Related Links

• Cancer Research
• Virology and Gene Therapy Training Program

Molecular Medicine Faculty

• Noel Caplice, M.D., Ph.D.
• Roberto Cattaneo, Ph.D.
• Mark Federspiel, Ph.D.
• Evanthia Galanis, M.D.
• Kah-Whye Peng, Ph.D.
• Eric Poeschla, M.D.
• Stephen Russell, M.D., Ph.D.
• Robert Simari, M.D.
• Richard Vile, Ph.D.