A Citizen of the University: Yvonne Paterson

By Lisa J. Bain

Photos by Peggy Peterson

By the age of four, Luke had twice had surgery to repair torn ligaments in his knees. So when the 120-pound German Shepherd started limping again two years later, his owners, Sherie and Dave Kerr, took him back to the orthopaedic sur­geon. An x-ray revealed something much worse than a liga­ment tear: the doctor said he was 99.9 percent sure that Luke had osteosarcoma, the most common type of bone cancer found in dogs, particularly in large breeds like German Shep­herds, Great Danes, and Golden Retrievers. “He said the only real treatment was amputation, but we did not want to put him through that after everything he had already been through,” Sherie said. They were sent home with pain medication and a prediction that Luke would survive only a few months. 

Six weeks later, a co-worker asked Dave if he had seen the news the night before. Nicola Mason, Ph.D., an associate pro­fessor at Penn’s School of Veterinary Medicine (SVM), was re­cruiting dogs with osteosarcoma that had not undergone am­putation. They would become part of a clinical trial of an ex­perimental treatment that harnesses the patient’s own im­mune system to target and destroy cancer cells. After Luke went through a grueling 12-hour evaluation, Mason informed the Kerrs that she wanted him in the study. 

The treatment Luke received – a cancer vaccine – was originally developed for humans by a small biotech company, Advaxis. It was founded in 2002 as a Penn startup by Yvonne Paterson, Ph.D., a professor of microbiology at Penn and a former associate dean for research at Penn’s School of Nurs­ing. Cancer vaccines are one form of immunotherapy, a treat­ment approach dubbed the “breakthrough of the year” by the editors of Science magazine in 2013. The field had been a long time in making its mark: That honor came more than a cen­tury after Paul Ehrlich first proposed that the immune system could be marshaled to treat cancer and nearly two decades since James Allison found a way to unblock the molecular brakes on T cells, thus stimulating them to attack tumors. Al­lison’s approach – called immune checkpoint blockade ther­apy – led in 2010 to the first immunotherapy drug of this class (ipilimumab) approved by the Food and Drug Adminis­tration (FDA) for the treatment of melanoma. Several other checkpoint inhibitors have subsequently been approved. Along with other immunotherapies like personalized cellular therapies under development at Penn, they are extending the lives of some cancer patients in ways doctors could scarcely imagine just a few years ago. In 2015, one of these was cred­ited with saving the life of former President Jimmy Carter, who had been diagnosed with stage 4 melanoma that had spread to his brain.

Paterson’s cancer vaccine uses a different approach to elimi­nate cancer. It starts with a common bacterium called Listeria monocytogenes (Lm), modified to not cause disease and to carry with it the proteins necessary to stimulate both the in­nate and adaptive arms of the immune system. Innate immu­nity refers to the rapid, non-specific response to an infection, such as inflammation. Adaptive immunity, by contrast, rep­resents the targeted response to any antigen recognized as foreign or “non-self.” These foreign antigens may come from a virus, a bacterium, a cell from another person or species, or, in the case of cancer, a protein that is unique to the tumor, that is over-expressed by the tumor compared to normal tis­sue, or that has undergone sufficient mutations to look for­eign to the immune system. Cancer vaccines are designed to make tumor antigens more immunogenic. They do so using viral or bacterial vectors, synthetic versions of tumor proteins, weakened or killed cancer cells, or DNA or RNA from cancer cells to induce immune responses to cancers. The first thera­peutic cancer vaccine was approved by the FDA in 2010 for the treatment of metastatic prostate cancer. 

Around the World and Across Disciplines: A Circuitous Path to a Cancer Vaccine 

Born in the United Kingdom, Paterson was the first in her family to finish high school. The other family members “were never interested,” she says. “For some reason, I was.” In 1979, she came to the United States from Australia, a single mother with a doctorate in biochemistry from Melbourne University and two young sons in tow. After three years at Cornell University – where she had continued to study protein folding, first as a post­doctoral fellow and later as a research associate – she had be­come bored. “I think I am a biologist at heart, so I decided I wanted to switch to immunology. What was I thinking?” she says with a laugh.

Switching fields was not a simple matter. Limiting her search to the West Coast to make it easier for her children to visit their father in Australia, Paterson began making the rounds of immunology labs. With no track record in the field, however, the opportunities were limited. Then she inter­viewed at The Scripps Research Institute in San Diego. “Scripps kind of took a chance on me,” she says. The research­ers were interested in her idea to apply the principles of pro­tein chemistry to examine how antigen and antibody inter­acted. Their risk proved warranted. In 1986, she published the results of her research in Science. Four years later, after she had moved to Penn, she followed it with another Science article. “That was probably the last protein chemistry paper I published,” she says. 

It was also during her time at Scripps that Paterson faced another unexpected challenge: she was diagnosed with breast cancer. “It was quite a shock,” she says. She had no relatives in the United States to lend support, and her two children were then 10 and 8 years old. Her overriding concern was “being around for them.” As she recalls, tumorectomies were still a new treatment, with little research supporting them. She opted for a mastectomy. The cancer, she adds, “didn’t have a huge impact on my research at the time” but “a lot of changes take place” in such a situation. For many years, Paterson re­ceived follow-up calls from a breast cancer research network based at the University of California at San Francisco, but her cancer never returned.

In 1988, Paterson was offered a tenured position at Penn in the Department of Microbiology. It was there that she crossed paths with another young assistant professor, Daniel Portnoy (now professor of biochemistry, biophysics, and structural bi­ology at the University of California, Berkeley). Portnoy was studying Lm as a model system to understand how intracellu­lar organisms spread from cell to cell and cause disease. Lm in its native stage is transmitted through contaminated milk products and can cause a serious illness called listeriosis. Portnoy told Paterson that Lm produces a factor called listeri­olysin O. When the bacteria are engulfed by macrophages or neutrophils – cells of the innate immune system that defend against infection by taking up and destroying pathogens – listerolysin O forms pores in cell membranes that allow the bacteria to escape into the cytosol (the fluid part in the inte­rior of the cell). Paterson’s idea was to use that feature of Lm as a vector to stimulate an immune response. “We reasoned that if we could get Listeria to secrete a foreign protein into the interior of the cell, it would target that pathway and would elicit a strong killer T cell response,” says Paterson. 

For the next few years, Paterson and Portnoy collaborated on a project to make a flu vaccine, and it was successful in protecting mice from infection. Then Paterson turned her at­tention to other projects, including trying to develop a pro­phylactic HIV vaccine. That effort got as far as monkey trials.

The influenza project triggered Paterson’s thinking about other diseases that could be treated by generating cytotoxic T cells. Around that time, immunotherapy for cancer was be­ginning to be considered. Early approaches focused on gener­ating antibodies to the tumor, but it had become apparent that the best way to attack a tumor was by generating a cyto­toxic T cell response, not just to antigens expressed on the surface of cancer cells but to any protein made in the cell. “I put two and two together,” Paterson says. “I had a perfect way of making cytotoxic T cells.” In 1995, in Nature Medicine, she published the first paper showing that Listeria could be used as an immunotherapeutic. “In mice, we actually made the tu­mors go away, just using Listeria and nothing else,” she says. “I think that was unprecedented at that time.” 

Translating Discoveries to Therapies

Another lesson she had learned at Scripps was the impor­tance of protecting one’s intellectual property before publishing a potentially translatable finding. So, before the paper came out, Paterson and Portnoy filed a patent for the use of Listeria for prophylactic vaccines for infectious diseases, and subsequently Paterson filed another patent for the immunotherapy of cancer using a live recombinant bacterial vaccine vector. Today, she says, she has 28 issued patents and another 12 are under con­sideration, all of them related to Listeria and its products. 

According to Paterson, she never intended to start a com­pany, but as her research progressed, it became more appar­ent that the Listeria-based cancer vaccine approach had po­tential for tackling human diseases. As a non-clinician, how­ever, she needed collaborators to move forward. At Penn, in­vestigators were more focused on other immunotherapy ap­proaches. So to move the Listeria approach forward, she founded the company Advaxis in 2002. For the first few years, the company existed in virtual space as Paterson and her co-founders raised money and recruited investigators. Today she remains a consultant for the company, which is based in New Jersey and employs more than 60 people. Advaxis re­cently initiated a phase 3 trial for advanced cervical cancer, using a strain of Lm created in Paterson’s lab by one of her graduate students, George Gunn III, Ph.D. ’01, now an associ­ate scientific director at Johnson & Johnson. The company also has treatments in clinical trials for cancers of the head and neck, prostate, anus, and other solid tumors including os­teosarcoma. Paterson’s work has been recognized with multi­ple awards: among them, she was named a fellow of the American Association for the Advancement of Science and selected as one of PharmaVOICE’s 100 most inspiring people in the life sciences. Awards to Advaxis for vaccines Paterson developed include the Medical Visionary Award from the Farah Fawcett Foundation for Collaborative Research in HPV-Associated Anal Cancer and the Vision of Hope award from the Sarcoma Foundation of America earlier this year for the canine osteosarcoma therapeutic vaccine. The vaccine used to treat osteosarcoma – ADXS-HER2 – targets human epidermal growth factor receptor 2 (HER2), a molecule over-expressed by several solid-tumor cancers, in­cluding about 25 percent of breast cancers as well as ovarian, lung, stomach, pancreatic, and esophageal cancers. Cancers that over-express HER2 tend to be more aggressive than those that do not over-express it and are associated with an in­creased risk of metastasis and relapse and lower rates of sur­vival. Human osteosarcoma is rare – only about 800 cases are reported each year in the United States, most often among children and teenagers. HER2 is expressed in about half of these osteosarcoma cases. In April 2016, ADXS-HER2 re­ceived fast-track designation by the FDA for the treatment of osteosarcoma. The fast-track program is designed to expedite the development and testing of new therapies that treat serious, life-threatening conditions, and address unmet medical needs. 

Cross-School Collaborations

Osteosarcoma is also the most common type of bone can­cer in dogs, and, according to Nicola Mason, a majority of ca­nine cases over-express HER2. About five years ago, as a newly minted assistant professor of medicine and pathobiol­ogy at the SVM, Mason gave a talk to Paterson’s lab about os­teosarcoma in dogs. She explained that, as with human osteo­sarcoma, the standard of care in dogs is amputation plus che­motherapy. Paterson, knowing that the human HER2 vaccine worked in mice and that canine HER2 was more similar to human than to mouse HER2, told her, “I’ve got a vaccine for that!” Together, and with support from Advaxis, they launched a trial of the vaccine in dogs. This first trial, con­ducted in dogs that had already undergone amputation and chemotherapy, was, Paterson says, “fabulous.” Whereas even with amputation and chemotherapy, dogs typically develop lung metastases and survive only about a year, some dogs with the vaccine have survived as long as four years. In 2013, Paterson and Mason, now an associate professor of medicine and pathobiology at the SVM, were named the inaugural co-recipients of the University of Pennsylvania One Health Award for their work in developing cancer immunotherapies for both humans and dogs. Penn’s participation in the One Health Initiative, a worldwide approach aimed at promoting human, animal, and environmental health, reflects the Uni­versity’s commitment to improving public health through cross-disciplinary and multi-school collaborations. 

Data from the first canine osteosarcoma trial led to a sec­ond trial in dogs such as Luke that had not had amputation. The studies in dogs have also provided important information about how different components of the immune response fluctuate over time and the relationship of these changes to the clinical outcome. For example, by tracking the number of HER2-specific T cells in dogs over time, Mason has seen a few cases where the numbers remain normal for some time, then go up, and then down again. Although this study is too small for researchers to draw any conclusions, Mason hypothesized that the tumor may have started to regrow, waking up the im­mune system so that appropriately primed T-cells expanded and proliferated to go after the cancer and eliminate it. 

Mason’s collaboration with Paterson reflects more than common scientific goals. Like Paterson before her, Mason de­cided to make a switch to immunology after already establish­ing herself in another discipline. An attending clinician at the SVM, she was admitted to the immunology graduate group at Penn in 1999, having never worked in a lab. Nonetheless, to get started she needed to find a lab that would take her for a rotation. “I must have trudged to four or five labs,” Mason says. “And then I went to Yvonne’s lab. I was totally expecting to be told to come back after I had done my first or second rotation.” But to her surprise, Paterson welcomed her to join the lab. “I told her, ‘I haven’t picked up a pipette, I don’t know what to do.’ And she said, ‘well, that’s why you’re here: to learn.’”

Mason completed her Ph.D. degree in another lab and then did a postdoctoral fellowship with Carl June, M.D., the Rich­ard W. Vague Professor of Immunotherapy in Penn’s Depart­ment of Pathology and Laboratory Medicine. That was when she became interested in cancer immunotherapy, which led to her faculty position at the SVM. “And again – typical Yvonne – she called me up and said, ‘You’re new faculty, you need to get out there and talk to people. Why don’t you come to my lab and tell everybody what you do.’”

A Lifelong Passion: Mentoring

Indeed, mentoring, particularly of women and minorities, has long been a passion of Paterson. In 2001, in fact, she re­ceived the Elizabeth Bingham Women’s Mentoring Award from the Association for Women in Science. Paterson was the associate dean for postdoctoral research training at Penn from 2005 to 2010 and was the architect of the Postdoc Diversity Fellowships, which are now administered by the office of the Vice Provost of Research. Until 2015, she directed the PENN-Postdoctoral Opportunities in Research Training (PENN-PORT) program, funded by the NIH division of Mi­nority Opportunities in Research at the National Institute of General Medical Sciences since 2007. PENN-PORT provides opportunities for postdoctoral fellows to teach at minority in­stitutions to try to inspire students at those schools to pursue biomedical research careers. 

Diversity is particularly near and dear to her heart. As a postdoc at Cornell University in Ithaca, supporting two chil­dren on a meager salary, she lived in a very poor section of town among an ethnically diverse population. Even before that, she says, she understood the value of racial and cultural diversity. “I come from a solid working class background. My father was a car body assembler when he was working, which wasn’t always,” she recalls. “He was a union man, organizing on the factory floor, and would bring home immigrants and other people for dinner. He instilled these beliefs of equality and egalitarianism in me, and I’ve carried it forward to my children.” Today, one of her sons is a union-side labor lawyer; the other son is a businessman in Melbourne, Australia, and very active in the Australian Labor Party. 

Although she had established herself as a leader and vision­ary in the training and mentoring of students from all walks of life, it was still a bit of surprise when she was recruited by the School of Nursing to serve as its associate dean for research. “When I was offered the position, I said, ‘I can’t do that. I don’t know anything about nursing!’” But, she notes, Afaf Meleis, Ph.D., professor of nursing and sociology and, at the time, dean of the School of Nursing, “doesn’t take no for an answer!” 

According to Meleis, Paterson was a match for what the nursing school needed at the time. “She is an impeccable, well-established scientist, and her research is very much re­lated to women and their health,” Meleis says. “She also knows how to motivate and inspire, mentor, and support.” Meleis also cites Paterson’s support for diversity in science as well as in terms of gender, cultural, and ethnic diversity. “She knows how to pick up talents from diverse backgrounds, nurture them, and invest in them.”

When Paterson took on the deanship at the SON, she de­cided to close her lab. Approaching the age of 70, she had al­ready stopped taking students and had stopped renewing her grants. “I have all these people out there [former postdocs] who are professors themselves now, and they shouldn’t be competing with septuagenarians to get grants,” she says frankly. “And the other thing, too, was what I wanted next out of the work I’d been doing for the last 20 years – to see it cure people in the clinic.” That is now being done by Advaxis. “I think if I hadn’t had the company, I would have been much more reluctant to give it up.” 

Not yet ready to retire and spend all her time with the nine grandchildren she shares with her husband of 23 years, pul- monologist Milton D. Rossman, M.D., a professor of medicine at the Perelman School, Paterson is still active scientifically. She publishes through collaborations with scientists – includ­ing several who trained in her lab – around the world. Her major driving ambition at this point, she says, is to see the first of her Listeria-based therapeutics approved by the FDA. “If they succeed, it will validate the whole platform, and I will feel like my life’s work has arrived.” The success of the osteo­sarcoma vaccine in dogs has provided additional hope. Two years after receiving his first dose of vaccine, Luke shows no signs of disease progression. Moreover, results from the ca­nine osteosarcoma trials were used to convince Advaxis and regulators to proceed with a trial in humans with HER2-posi­tive tumors. “To think Luke may be helping women with breast cancer is amazing,” said Sherie Kerr, who, like Paterson, is herself a breast cancer survivor. 

Paterson believes that her pursuit of a cancer vaccine has been motivated, in part, by personal experience with cancer – not just her own breast cancer, which she was diagnosed with in 1983, but even more the loss of her father and sister-in-law, whose lives were cut short by colorectal and ovarian cancer. Two laboratory colleagues, at both Scripps and Penn, also died of cancer. Always the teacher, Paterson uses her exper­tise as a cancer investigator to help other people with cancer, by researching techniques and explaining them to friends and family. “I like explaining stuff,” she says with a smile. “Having gone through the psychological processing myself, I understand better how frightening and bewildering a cancer diagnosis can be.”