While they may not exactly be miracles, many of the new and upcoming advances in biotechnology would have seemed to border on the miraculous in the not too distant past. For instance, Advaxis Inc., a development-stage biotechnology firm at the Technology Center of New Jersey in North Brunswick, is honing in on developing the sort of treatments and vaccines for cancers, immune system problems, and infectious diseases that in other eras would have been considered inexplicable. Administering these vaccines could ultimately be as simple as giving the patient a shot in the arm.
Creating vaccines for cancer is a complicated (and so far impossible) business, but the initial approach can be considered in simple terms. “The immune system did not evolve to treat cancer,” says John Rothman, Advaxis’ vice-president of clinical development. “It evolved to deal with foreign pathogenic invaders. What we are doing is modifying the pathogen, Listeria, that the body already has an immune relationship with.”
“Using our own immune systems to knock out cancer is very promising,” says Tom Moore, who took over as the CEO last month. “In preclinical trials our platform has proven very helpful for virtually all of the mice who used the vaccine, not only treating cancer but in curing it. It is also proving to be an effective preventative. In a few years we hope to be marketing a range of cancer vaccines, everything from cervical to breast to prostate.”
Advaxis has begun its first human studies in Serbia, Israel, and Mexico, and it has just announced its partner for human studies in the United States. Ten cancer patients have been dosed in Phase I and II clinical trials. “This is a therapeutic vaccine for people who already have the disease,” says Rothman. “We are very hopeful that things will progress the way we would like them to.”
When it organized in 2002, Advaxis was a virtual company with a headquarters at the Carnegie Center. Since then it has blossomed into a public company with nine fulltime staff members (including five people working in a lab), and another lab in Philadelphia has eight people.
Advaxis has a lead vaccine candidate, Lovaxin C, that targets cervical cancer as well as head and neck cancers. In addition, Listeria vaccines are in development to target breast, ovarian, and lung cancers, and Listeria also has applications in the fields of infectious disease and autoimmune disorders.
This small company has its roots in a discovery that, like many great scientific discoveries, happened almost by accident. In 1993 a University of Pennsylvania immunologist, Yvonne Paterson, was studying cytotoxic T-cells, the human body’s defenders that seek out and destroy such outsider trespassers as bacteria. She focused on Listeria, named after Joseph Lister, the 19th century surgeon who figured out that more patients survived when doctors washed their hands.
Watching T-cells attack and destroy the relatively harmless germ known as Listeria, Paterson asked herself whether the T-cells could be used in the battle against other bodily invaders such as tumors or HIV.
“People ingest Listeria, and typically nobody gets sick from it,” explains Rothman. “She modified it, attenuating it to make it less virulent, and has added some cancer antigens so that we can give an infection with it. When the infection clears, the immunity that results is now directed against a target cancer. This can be accomplished with a variety of different cancers.” Scientists at Advaxis aim to use human-engineered mice (mice bred in France to have the characteristics of humans) to transform Paterson’s research into a commercial product. Advaxis licensed her work from the University of Pennsylvania, and she heads the scientific advisory research committee. The research is supported by the U.S. Department of Defense and the National Cancer Institute.
Of course the human body’s immune system is a complex system, and success will not come without unraveling some longtime scientific conundrums. The challenge of creating a breast cancer vaccine is in convincing the body’s immune system to target cells of its own body — cancer cells — for destruction. What is required to create a vaccine is a clear understanding of how the immune system works. The key may likely rest in discovering a means to harness regulatory lymphocytes, a group of cells that control the body’s ability to recognize whether a substance is foreign or not.
Other research groups are doing similar work with different proteins, including the mammaglobin-A protein at the Washington University School of Medicine in St. Louis, and the telomerase protein currently in use at the Abramson Cancer Center of the University of Pennsylvania.
Advaxis, in contrast, is modifying Listeria to elicit HER-2/Neu protein. The Listeria technology, Advaxis says, has a number of advantages over competitive approaches, including the unusual life cycle of Listeria that results in strong, long-lived, cellular immunity. This is viewed to be essential in the creation of cancer vaccines.
Current data also demonstrates that Listeria technology is superior in inducing anti-tumor immunity. Also recent tests show that Listeria is readily cleared by innate immunity even in immunocompromised mice. This indicates that adverse events with Advaxis’ strains are less likely than in some of its competitors.
Patients and caregivers may be concerned about what would happen if the live Listeria runs rampant and triggers a bacterial infection. Researchers claim that this risk is minimal. Also the vaccination protocol can and would be stopped at any time by antibiotics if patient monitoring detects an adverse effect. In contrast to viruses, bacterial infection can be controlled, particularly when the bacterium is known and well characterized.
Rothman has been vice president for two years. The son of a businessman in Queens, and the grandson of Eastern European immigrants, he graduated from Windham College in Putney, Vermont, in 1974. He earned his PhD in pharmacology at the Tulane University School of Medicine with two Nobel Prize winners in medicine: Louis Ignarro, 1998, and Andrew Schally, 1977. He became a junior member of the first clinical group to develop genetically recombinant pharmaceutical agents and test them in human disease.
He was also responsible for the first clinical trial for AIDS when he formed and oversaw a three-city research network investigating the use of interferon. He was also a senior scientist at Hoffmann-LaRoche, where he supervised the clinical submission of the first FDA approval for interferon in the treatment of Kaposi’s sarcoma.
Rothman then spent a number of years building and selling small companies in a variety of industries while simultaneously serving as a township committeeman, police commissioner, and mayor of Tewksbury Township. Rothman commutes from Tewksbury or works from his home.
Tom Moore, who had been on the Advaxis board for several months, was appointed CEO in December. He and his wife, Avril Barton Moore, are known in Princeton for their preservation of the Tusculum estate (see page 49).
That Moore’s mother died of cancer influenced his choice of Advaxis, but he says his entire career has been influenced by his late father, an electrical engineer, who was both courageous and resourceful. He had a war-time injury that affected his speech. “Though I never heard my father complete a sentence, he made his living by lecturing — he taught business management at MIT’s Sloan School. It’s tough to make your business doing something that is so hard to do, but he was very creative. He copyrighted the slogan ‘Work smarter, not harder,’” says Moore.
Moore grew up in Boston, where he went to a heavily endowed private high school, Roxbury Latin. As a history major at Princeton (Class of 1973) he was house manager for concerts in Richardson, Dillon, and Jadwin. “I got to know how rock stars behaved behind the curtain,” he says, remembering his dealings with the likes of James Taylor, Cat Stevens, Bette Midler, and the Beach Boys.
From that campus job, he learned how to motivate employees, such as the temporary help brought in to help keep order. “To deal with crowd surge, you teach how to lock arms, and you try to preserve good humor. Managing crowds is like herding cats, and managing talented and independent business people is a lot like that.” Moore made his name at Proctor and Gamble in Cincinnati. “I worked for every product that P&G makes and was ‘running’ Tide at the age of 27,” says Moore. Though his father taught MBA students, Tom Moore didn’t get his MBA. “I found school pretty confining.”
When he left P&G in 1996 he was president of the healthcare unit to be president and CEO of Nelson Communications, a pharmaceutical PR firm with offices at the Carnegie Center and New York.
“Life is always different when you are on the service side versus on the client side,” says Moore of his tenure at Nelson. During his six year stint at Nelson he points to a rise in sales from $35 million to $145 million. Wayne Nelson, founder of the family-owned business, sold it for $250 million to a French multinational, Publicis.
“When you see what the clients look like when you are trying to be of help, it wasn’t very pretty. On the service side, you have higher highs and lower lows. You are thinking about short-term, more concrete satisfactions, versus taking 12 to 24 months to build a brand share. I prefer the client side,” says Moore.
From 2002 to 2004 he was CEO of Biopure Corporation, a Boston-based developer of oxygen therapeutics that are intravenously administered to deliver oxygen to the body’s tissues.
He left that full-time job to devote more time to his hobbies and serve on boards. He is on the board of Alteon, a public firm that focuses on diabetes and age-related diseases; El Dorado Inc., which markets to Hispanics; Medmeme, which measures medical education effectiveness; and Opt-e-scrip, which compares multiple drugs in the same patient. He is chairman of a firm that developed and patented Mayan pigment technology.
His hobbies: Yoga (at Four Winds studio in Pennington), walking (not just on his own property but also on the canal and in the Institute Woods), wine collecting (he is a partner in an African winery), and fly fishing in far-flung places like Chile, Alaska, and the Bahamas.
“The important thing is not to focus too much on catching fish but to understand how fish think,” says Moore, declining to compare this hobby to any aspect of management. “It is all about deception and leading them to happily gobble up the little hook. It is a beautiful thing to stand in a stream, see a fish, cast your fly in front of him so it sits big and juicy and totally natural, watch him rise, see him hit the fly and hold off until he actually takes the fly.” Advaxis has had two previous CEOs: J. Todd Derbin, founder of a neuroradiology device firm, and Roni Appel, a venture capitalist with LV Equity Partners who co-founded the firm and is now on the board. Also serving on the board are Thomas J. McKearn, one of the founders of Cytogen Corporation; James Patton MD, president of a Pennsylvania-based oncology treatment facility; and Richard Berman, formerly an M&A banker at Goldman Sachs and a director of seven other public technology firms.
In November Advaxis announced that it has completed the enrollment and dosing of the first cohort of patients diagnosed with advanced, recurrent or progressive cervical cancer in its Phase I/II clinical trial of Lovaxin C. A review by an independent safety panel determined that this first assessment of a modified Listeria-based live vaccine is safe. The trial is designed to test four different doses in cohorts of five patients each. Side effects have been minimal, with mild-moderate fever and chills and temporary nausea usually resolved within hours of dosing.
Dosing in the second cohort is finished, and the third set of doses begins in February. Company officials say that finding that Lovaxin C can be administered at therapeutic levels intravenously to late-stage cancer patients is a significant and very hopeful finding and a major accomplishment. Unlike current products already on the market (which are ineffective in women already infected with the papilloma virus HPV, the cause of cervical cancer) Lovaxin C is designed to treat women who have already developed this cancer.
Just announced: That Advaxis will collaborate on an NCI-funded Phase II clinical trial of Lovaxin C with the Gynecologic Oncology Group (GOG). The GOG focuses on women with pelvic malignancies, such as cancer of the ovary, uterus, and cervix, and more than 3,300 patients are registered for its trials each year.
Also on the horizon for Advaxis is the development of multiple platform approaches for the treatment of other cancers, such as melanoma, pancreatic, and prostate, These lead products in development ultimately represent a market potential in excess of $10 billion.
Advaxis has its competitors, but Moore cheers them on. Seattle-based Dendrion has filed for approval for a vaccine for prostate cancer. Genitope, based in California, is working on immunotherapy solutions to non-Hodgkins lymphoma. And California-based Cerus, a blood products firm, has developed a cancer vaccine for pancreatic and ovarian cancers. Moore points out that the Cerus Listeria is metabolically dead, without attached antigens, but he supports the concept: “In our field we root for competitors, because as more vaccines are headed for approval, investors and patients gain confidence in this approach.
Advaxis is a public company, the result of a reverse merger into a shell company. It has a “burn rate” of $180,000 per month and has enough cash to last for a year and half. “The company has had successful financing in the past, and part of my job is to make sure it has successful financing in the future,” says Moore. “Many people think curing cancer is a successful business opportunity.” Until now Advaxis has maintained itself by receiving grants from the federal government and taking on investors who have the hope of turning a profit. But how long it may take for the company to show that profit is an open question.
“Since we are in a clinical development program it is impossible to predict the data in advance,” says Rothman. “If things go swimmingly well, the FDA could approve us in a short period of time. If they have questions, well, it could take years longer.” He suggests that, like most small biotech companies, Advaxis will earn its keep by partnering with large pharmas.
Despite its small stature, the future looks bright for Advaxis. The company is a part of a community of fast growing cancer immunotherapy biotechs. “This is an area that has literally exploded during the last few years,” says Rothman. “There are expectations of having a variety of therapies available in the not too distant future. Reviewing the data, the progress we have made is absolutely spectacular. Assuming that this works out in the clinic, I think it’s going to be significant.”
Advaxis (ADXS), 675 Route 1 South, Suite 117, North Brunswick 08902; 732-545-1590. Home page: www.advaxis.com