ILLUSTRATIONS: Martin Jarrie
Injection Protection
Vaccines take shots at a new array of diseases
Facing the deadly plans of an evil villain, comic-book characters rarely defend the planet as everyday humans. Instead, they call on special powers that turn them into hardnosed crime-fighters.
As it is when the body must defend against disease. Sometimes the immune system simply lacks the brawn to fight illness on its own. That is when physicians draw on the power of vaccines — injections that can give the immune system a much-needed boost.
The goal of a vaccine — whether it aims to prevent an infectious disease such as polio or means to stop cancer — is to motivate cells of the immune system into getting so mad that they rise up and drive out harmful intruders.
Fortunately, cells usually do a pretty good job without prompting by an inoculation. Most of the time, when immune cells such as B-cells or T-cells spot an unwanted invader like a flu virus or a tumor cell, they mount a toxic response and neutralize it.
But every now and then — either because invaders are overpowering or because disease or therapy weakens the immune system — people need the backup boost of a vaccine.
Researchers worldwide are on a quest to harness the power of vaccines, and City of Hope scientists are advancing the movement on two fronts: vaccines against cancer and against diseases related to cancer treatment. They also are taking lessons learned from such research and applying them to other diseases, extending the reach of their work.
From friend to foe
The word “vaccine” often conjures up childhood memories of jabs in the arm against measles, smallpox and other infectious diseases, and for good reason. Vaccines began as protective measures, stoking the immune system to be ready to mount an offensive if exposed to specific infectious attackers.
Today, two approved vaccines related to cancer do just that. Meant for healthy people, a hepatitis B vaccine defends against a virus that can cause liver cancer, and another new vaccine called Gardisil protects against certain viruses that can cause cancer of the cervix, throat and other areas.
But a newer, developing area in cancer vaccine research targets people who already have cancer. Called therapeutic vaccines, these injections aim to strengthen the body’s defenses against existing tumors, keep tumors from returning or eliminate cancer cells that remain after other cancer treatments.
City of Hope surgical oncologist Joshua Ellenhorn, M.D., has his eye on one such therapeutic vaccine.
A surgeon also trained in immunology, Ellenhorn is developing a vaccine to target cells that express high levels of a protein known as p53.
Normally, p53 plays a protective role as a tumor suppressor gene and actually blocks the out-of-control growth seen in many cancers.
But a mutation or damage to p53, which occurs in numerous cancers, deals cells a double-whammy: Not only do the cells lose cancer protection normally offered by the gene, but the defective p53 protein actually promotes tumor cell growth.
“Mutations in p53 that disable its ability to function as a tumor suppressor result in accumulation of this protein within cells,” said Ellenhorn. “About 40 to 50 percent of all malignancies overexpress mutant p53. In breast cancers, it is seen in approximately 40 percent of all malignancies — same with colon, prostate and pancreatic cancers.”
Ellenhorn has created a vaccine he hopes will eradicate human tumors that express high levels of mutant forms of p53. Interestingly, it is based on the prototype cowpox or “vaccinia” virus that English physician Edward Jenner famously pioneered 200 years ago as a vaccination against smallpox.
Together with Don Diamond, Ph.D., director of City of Hope’s Laboratory of Vaccine Research, Ellenhorn has used a similar technique for a potential p53 vaccine — but with a few modern twists.
Just like Jenner, the City of Hope researchers are using cowpox virus to fire up the immune system. But in today’s modern version, the scientists tweaked the cowpox virus’ genetic code and plugged a copy of the p53 gene into it.
Then they injected that special vaccine — along with other therapies that also rev up immune response — into mice that had cancerous tumors. The result: Most of the tumors grew smaller or disappeared altogether.
Because the engineered cowpox virus is foreign, it gets the attention of the immune system, Ellenhorn explained. “This then stimulates T- and B-cells, which are redirected toward disintegrating and attacking tumors that overexpress p53.”
These findings show the vaccine can kill tumors in mice. In a next step, the researchers successfully created and tested a human form of the vaccine in mice, and tests in human cells in the lab have shown promise, too.
Ellenhorn is confident that the vaccine will soon reach clinical trials. “Initially, the phase I trial will be in patients with advanced disease,” he said. “If the results are positive, we would take it to a group of patients in an earlier stage of the disease.”
The donor gives twice
Sometimes, the very therapies that help a patient fight cancer are so potent that they themselves are life threatening. Treatment with immunosuppressant drugs after bone marrow or organ transplant, for example, leaves transplant patients vulnerable to ordinary germs that lie dormant in healthy adults.
Several City of Hope researchers are devising vaccine therapies to encourage immune cells to fight these germs.
One such danger comes in the form of a herpes virus called cytomegalovirus, or CMV. About 50 to 80 percent of adults in the United States have been exposed to CMV, but it causes few symptoms in healthy individuals. In transplant patients with compromised immune systems, however, activated CMV may cause life-threatening pneumonia.
A team of City of Hope scientists led by Diamond has developed a vaccine to address that threat. But interestingly, care providers would administer the vaccine to the organ or bone marrow donor, not the recipient. They aim to transfer lifesaving CMV immunity — in addition to transplanted tissues — to the recipient.
According to Diamond, when the bone marrow transplantation program began at City of Hope in the 1970s, CMV infection was the main cause of most patient deaths. And although physicians have provided antiviral drugs with moderate success, the treatment sometimes can be difficult to deal with.
“The antiviral itself causes such adverse events, it probably is less positive than we first imagined,” said Diamond. “If we could prevent those, we would really be getting to a treatment that is head and shoulders above anything out there for cancer transplant.”
The result: saved lives.
Much like the p53 vaccine, Diamond’s group designed the CMV vaccine as an altered form of the cowpox virus — but with genetic code from the CMV virus attached. When introduced into the body, the vaccine launches a chain of events that activates the donor’s immune system against CMV.
Results from lab research suggest the immunity would stay elevated after transplant, protecting the recipient.
The U.S. Food and Drug Administration recently approved the first human trial of the CMV vaccine developed by Diamond’s group. That trial began with the inoculation of the first volunteer, a City of Hope employee, in May of 2007. Volunteers’ overall health and responses to the inoculation will be monitored to evaluate vaccine safety.
John A. Zaia, M.D., professor and chair of the Division of Virology, is the principal investigator of the CMV phase I clinical trial. “This is the first vaccine developed at City of Hope that has been brought to clinical trial,” he said. “Hopefully, this signifies a new era in vaccine development here.”
Stephen J. Forman, M.D., Francis and Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation, credits City of Hope for creating a research climate where basic researchers like Diamond and clinicians interact.
“We are the institute that understands this virus,” said Forman, clinical director of City of Hope’s Division of Cancer Immunotherapeutics & Tumor Immunology. “The original work identifying the signature viral immune proteins was done here in Don Diamond’s lab. That is the reason this work has been successful.”
Establishing garden-variety immunity
Viruses aren’t the only threats to immunocompromised patients. An innocent walk in a garden may expose them to spores of an ordinary, soil-dwelling fungus called Aspergillus fumigatus and cause a potentially fatal lung disease known as aspergillosis. Like CMV infection, Aspergillosis is no small threat.
According to City of Hope investigator James Ito, M.D., director of the Department of Infectious Diseases, the development of better antiviral drugs targeting other types of infection has left Aspergillus with an infamous distinction. “By default, the most devastating infections are now fungal infections,” he said. “They’ve always been around, but have moved up into first place now. In fact, Aspergillus is now the most deadly of all fungal infections.”
The gravity of the fungal threat is echoed by Markus Kalkum, Ph.D., Ito’s collaborator in developing an Aspergillus vaccine. “We all inhale several hundred Aspergillus spores a day, usually without any negative impact on our health,” said Kalkum. “However, inhalation of spores can prove fatal to bone marrow or organ transplant patients taking immunosuppressive drugs.”
In 2002, Ito and Joseph Lyons, Ph.D., a scientist in the Department of Infectious Diseases, took the first steps to create a vaccine when they inoculated mice with a
mix of pulverized Aspergillus proteins, treated the mice with immunosuppressants to mimic conditions of transplant patients, and then exposed mice to a lethal dose of fungal spores. The results were dramatic. “A hundred percent of the mice died if we didn’t vaccinate them,” reported Ito, “but a significant number of them survived if we did.”
Now, with Kalkum joining the team, the researchers have zeroed in on the specific protein in that fungal vaccine “soup” that stimulates the immune response. When they vaccinated mice with just that protein, it, like the mix, protected mice against the infectious Aspergillus.
The investigators’ next goal is to establish antifungal immunity in immunodeficient humans. Currently, they are identifying antibodies that humans make to mold proteins to determine which fungal proteins stimulate that response. Although several years away, once a vaccine is developed, it will likely be administered like the CMV vaccine to the bone marrow donor and not the recipient.
From idea to reality
Moving from an idea to a therapy is a long haul, one that is appreciated by Simon Lacey, Ph.D., associate research scientist in the Division of Virology. Lacey, who also worked on the CMV project, is conducting experiments to determine whether a vaccine might work against another virus reactivated in immunosuppressed patients: BK virus, or BKV for short.
More than 80 percent of American adults are infected with BKV, making it even more prevalent than CMV. Like those with CMV, few with BKV show overt signs of disease. However, reactivation of the virus in immunocompromised patients following organ transplant may cause an irritation of the lining of the bladder known as cystitis, even to the point of bleeding.
After a kidney transplant, potent immunosuppressants required to block rejection of the new kidney may activate the BKV — sometimes with serious consequences. “Approximately 30 percent of transplant patients show signs of elevated virus levels, 5 percent develop signs of kidney disease, and about half of those people then lose the kidney,” explained Lacey.
When viral levels rise, a physician’s only choice is to drop patients’ doses of immunosuppressive drugs. “It’s a constant balancing act,” said Lacey. “The only approach is aggressively monitoring the virus in the blood.”
Together with transplant surgeon Jennifer Singer, M.D., of the Department of Urology at UCLA, Lacey is now tracking blood and urine samples from kidney transplant patients. If they can better understand how certain patients’ immune systems successfully fight BKV infection, they might be able to create ways to predict which patients are likely to develop the disease. Their studies also could lay the groundwork for vaccine development.
So far, Lacey has shown that vaccination with a portion of BKV can get immune cells to react in mice. The first steps in humans are promising, as well. But he cautions that results are preliminary. “The logical next step is to either develop a good drug conveying a type of immunotherapy, or to develop a vaccine to protect people,” said Lacey. “But you can’t do any of those without a better idea of what you are facing.”
Poised for the long haul
Vaccine development is clearly not for quitters. Devising strategies that encourage the immune system to take a stand against invaders is long, hard work. Gardisil, the much-publicized vaccine against cervical cancer that targets human papillomavirus, took more than 20 years of development before becoming available last year.
But City of Hope excels in translational research, a process that moves laboratory science into new modes of prevention, diagnosis and treatment — and then takes lessons learned from patients back into the lab. This gives the institution a nimble advantage in areas such as successful vaccine development, according to Diamond. “City of Hope is unique among American research centers in that its philosophy is to encourage cooperation among basic scientists and physicians that leads to something tangible,” he said.
Forman echoes that optimism. “We have all the right people collected at City of Hope — the patients, the lab expertise and the doctors,” he said. “There are few other places like this anywhere.”