Shot of the Future: Trends in Therapeutic Vaccines

It is said that “an ounce of prevention is worth a pound of cure.” But, when it comes to many diseases, prevention is simply not an option — or at least not in the near future. Despite great strides in the development of preventive vaccines, they may simply be unlikely or impossible for diseases such as cancer, HIV, Alzheimer’s and others. On the other hand, a therapeutic vaccine could be more feasible. Indeed, millions of individuals who have already contracted a disease are in need of a vaccine to treat them. “There are some diseases, like Alzheimer’s, that we just don’t have a clue how to prevent with a vaccine,” says Hildegund C.J. Ertl, MD, program leader in the immunology program at the Wistar Institute at the University of Pennsylvania. “But, in the future, therapeutic vaccines could be crucial for diseases that we learn how to treat but not prevent.”¹

History of Therapeutic Vaccines

Manufacturers have long been working to bring therapeutic vaccines to market. Yet, despite clinical trials showing remarkable improvements in selected small populations, very few have gained regulatory approval. Outside of the U.S. market, vaccines that have gained approval include Avax Technologies’ M-Vax (for melanoma), Intracel’s OncoVax (for colon cancer) and Corixa’s Melacine (for late-stage melanoma). However, each has been marketed in a very small number of countries, and their success has been limited by efficacy, high cost and low acceptance of unproven therapeutic vaccines among physicians.²

To date, only three vaccines have gained regulatory approval in the U.S. One vaccine, Provenge, was just recently approved by the Food and Drug Administration (FDA) at the end of April. Dendreon Corp.’s Provenge is a first-of-a-kind prostate cancer treatment that uses the body’s immune system to fight the disease. It is intended to treat cancer that has spread elsewhere in the body and is not responding to hormone therapy. Provenge is made by taking immune cells from a patient’s blood and exposing them to a protein found in most prostate cancers, which then encourages the cells to attack the cancer.³

A second vaccine is Teva Pharmaceutical’s Copolymer 1, used to treat multiple sclerosis, which was approved by the FDA in 2003. The third is Merck & Co.’s Zostavax vaccine for the treatment of shingles, also approved by the FDA in 2003. While Zostavax may be considered by some to be a preventive vaccine, according to Dr. Martin G. Myers, MD, executive director of the National Network for Immunization, “Zoster is a therapeutic vaccine because [those individuals] are already infected with the virus and [the vaccine] is altering the immune response to the virus. [The vaccine] both reduces the likelihood that the person is going to develop shingles and reduces the recurrence of the disease they got many years ago.”

Vaccines, then, such as Provenge, Zostavax and Copolymer 1 are an advancement in healthcare that could lead the way for other therapeutic disease intervention. And now, due to even greater scientific advances, a new wave of therapeutic vaccines may turn the tide.According to a 2006 report from independent market analyst Datamonitor, therapeutic vaccine development is currently heavily weighted toward cancer vaccines, which then accounted for 60.6 percent of all active pipeline projects. In addition, there is greater interest by manufacturers in providing therapeutic vaccines for HIV, Alzheimer’s, nicotine and drug addiction, as well as allergic, central nervous system and cardiovascular diseases.²

What Are Therapeutic Vaccines?

Vaccines boost the immune system’s natural ability to protect the body against foreign invaders known as microbes that can cause disease. Microbes carry antigens that “tell” the immune system they are foreign, and therefore should destroy them and remember them to prevent another infection. Microbes used in traditional vaccines are usually killed or weakened so they don’t cause disease, but are able to stimulate an immune response.⁴

While preventive (or prophylactic) vaccines are intended to prevent diseases from developing, therapeutic vaccines are intended to treat already existing diseases by strengthening the body’s natural defenses against them. For instance, the goal of therapeutic cancer vaccines is to stop cancer cell growth, cause tumor shrinkage, prevent cancer from coming back, or eliminate cancer cells that are not killed by other forms of treatment, such as surgery, radiation therapy or chemotherapy.⁴

But, diseases such as cancer and HIV pose an interesting problem for scientists developing therapeutic vaccines. The immune system doesn’t easily recognize the threat posed by an already growing cancer because cancer cells carry normal self antigens in addition to any cancer-associated antigens. Cancer cells also sometimes undergo genetic changes that lead to the loss of cancer-associated antigens, and they can produce chemical messages that suppress specific anti-cancer immune responses, thus managing to escape a strong attack. 2 On the other hand, other viruses such as HIV can overwhelm the immune system and shut it down before it can work.¹

The Makings of Therapeutic Vaccines

There are two basic types of therapeutic vaccines. Patientspecific (personalized or autologous) vaccines are created using the patient’s own tissue. Non-patient-specific (generalized or allogeneic) vaccines are made with off-the-shelf, massproduced therapies.²

The first therapeutic vaccines developed were mainly personalized vaccines. But, while personalized vaccines offer advantages to patients due to their efficacy and specificity and don’t require an in-depth understanding of the exact antigens involved, they pose many problems, including a very high cost, low scalability of manufacture, concerns over sterility and a more complex regulatory approval process. Therefore, generalized vaccines now dominate the research pipeline.²

Some specific types of therapeutic vaccines being developed include antigen vaccines, which provoke the immune system to create an antibody to fight the antigen; dendritic cell vaccines, which grab foreign germs and bring them to other immune cells that create antibodies to attack them; DNA vaccines, in which bits of DNA are injected into cells to instruct the immune system to keep revved up and alert; and tumor cell vaccines, which use actual cancer cells that are removed during surgery, killed or tweaked in some way and then introduced back into the body to trigger an immune response.These vaccines can be either patient-specific or non-patient-specific.¹

An increasing trend in therapeutic vaccines is the use of multiple antigens and adjuvants to attack microbes from multiple angles. 2 Because antigens and other substances are often not enough to make effective treatment vaccines, researchers are adding ingredients, known as adjuvants, which boost immune responses that have been set in motion by exposure to antigens or other means.⁴

Vaccines Currently Being Studied

While therapeutic vaccines are being studied for a host of diseases, the three most promising appear to be cancer, HIV and Alzheimer’s.

Cancer. Dozens of vaccines are being tested for various types of cancer, including breast, colorectal, kidney, leukemia, lung, lymphoma, melanoma, ovarian, prostate, pancreatic and others. British researchers have developed a vaccine that can be used to stop acute myeloid leukemia (AML), the most common form of cancer in adults, from returning after chemotherapy or bone marrow transplant. Once a patient has been diagnosed, the vaccine prompts the immune system to hunt down cancer cells and destroy them. To prevent a relapse, the vaccine then prompts the immune system to recognize leukemia cells if they return. The first clinical trial of the vaccine was held in early 2010 at King’s College London. The research will be published in the Journal of Cancer Immunology, Immunotherapy.⁵

Like Dendreon’s Provenge, another pancreatic cancer treatment vaccine in trials is the GVAX Precreas vaccine, which has received orphan drug status from the FDA. BioSante Pharmaceuticals, which manufactures the vaccine, also is conducting clinical trials to measure the vaccine against other cancers, including leukemia and breast cancer.⁶

Researchers in the Netherlands have created a dendritic cellbased vaccine against mesothelioma, a rare form of cancer typically affecting the lining of the lungs, and primarily caused by exposure to airborne asbestos fibers. The researchers tested the vaccine in 10 patients and achieved 80 percent effectiveness.⁷

In November 2009, researchers reported on a trial of a vaccine against the most common type of human papillomavirus, HPV-16. They investigated the immunogenicity and efficacy of a synthetic long-peptide vaccine in 20 women with HPV16-positive, high-grade vulvar intraepithelial neoplasia. Three months after the last vaccination, 12 of 20 patients had clinical responses and reported relief of symptoms. Five women had complete regression of the lesions and HPV-16 was no longer detectable in four of them.At 12 months of follow-up, 15 of 19 patients had clinical responses, with a complete response in nine of 19 patients, and the complete response rate was maintained at 24 months of follow-up.⁸

Most recently, a Phase I clinical trial tested the safety and immunogenicity in women with a previous history of cervical intraepithelial neoplasia 2/3, a precursor lesion prior to the development of cancer. The vaccine, VGX-3100 by Inovio Biomedical Corp., targets the E6 and E7 proteins of HPV types 16 and 18, and has shown strong specific antibody responses to tumor antigens.⁹

HIV. For decades, researchers have been looking for a therapeutic vaccine for HIV. The earliest study, the STEP Study, tested an Adeno 5 (adenovirus type 5) vaccine candidate in the U.S., Latin America and Australia. However, because the study did not lower the viral load among those infected, the study was stopped.

In a newer study, researchers loaded dendritic cells with killed AIDS viruses and then injected them back into the person, which triggered an effective immune response. In the 2004 study of 18 people injected with the vaccine, the amount of virus in the blood dropped by 80 percent. After one year, eight of the people still had a 90 percent drop in their viral levels.¹

New and encouraging results from pre-clinical research by Bionor Immuno AS will move the therapeutic and potentially preventive HIV vaccine candidate Vacc-C5 into a Phase I/II clinical trial. The research results indicate that Vacc-C5 may induce a protective antibody response in HIV patients similar to that found in patients with slow or non-progressing disease.¹⁰

Most recently, GeoVax Labs Inc., a Smyrna, Ga.-based biotechnology company that creates and tests HIV/AIDS vaccines, has been granted federal permission to begin a Phase I clinical trial for a treatment for people infected with HIV. The trial will monitor safety while evaluating the ability of the vaccine to elicit protective immune responses in vaccinated participants.¹¹

Currently, two Phase II and one Phase III clinical trials are in progress. See the article, Update on HIV, on page 44 of this issue.

Alzheimer’s. Existing drugs for Alzheimer’s can delay the progress of disease symptoms, but because their effect wears off relatively quickly, the disease is allowed to take its devastating course. However, several new therapeutic vaccines being studied could actually stop the disease in its tracks. The most promising is known as CAD106, a collaboration program between Novartis Pharma AG and Cytos Biotechnology. It is an experimental vaccine that may help the immune system attack a protein that plays a key role in the illness, thus slowing down its progress.

Early tests of CAD106 showed that the vaccine is highly effective at breaking up the sticky protein that clogs the brain in Alzheimer’s patients and destroys vital connections between brain cells. 12 While a study of the vaccine was suspended in 2002 after 6 percent of subjects developed brain inflammation, a year later, researchers tracked the people who received the vaccines and found that approximately 20 percent of them were making antibodies to the protein, meaning their immune system was attacking it. In addition, the group scored slightly better on memory tests than people who had not received the vaccine. 4 Different versions of the vaccine are still being studied, and a Phase II clinical trial is currently in progress.

Other therapeutic vaccines.The search for therapeutic vaccines is expanding to a host of other diseases. Great effort is being devoted to developing therapeutic vaccines against tumors, hepatitis B, tuberculosis (TB), malaria, diabetes, high blood pressure and, possibly, against the bacteria that cause gastric ulcers. Copolymer 1 (also known as glatiramer acetate), used today as a therapeutic vaccine against multiple sclerosis, “could lead to therapeutic vaccines against other autoimmune diseases such as myasthenia gravis, systemic lupus erythematosus and rheumatoid arthritis,” according to an article published by the Proceedings of the National Academy of Sciences of the United States of America. “Furthermore, current studies raise hope for vaccines against prion diseases, bovine spongiform encephalitis and Creutzfeldt–Jakob disease.”¹³

Another potential therapeutic vaccine being studied also may be applicable to other autoimmune diseases, according to a study published in the April 8 online version of the journal Immunity. Canadian researchers have successfully reversed type 1 diabetes in mice using a nanotechnology-based vaccine that appears to target solely the immune system cells responsible for the disease. Type 1 diabetes is an autoimmune disease, just like multiple sclerosis and rheumatoid arthritis, which are caused by an overactive immune system.¹⁴

Just recently, the Aeras Global TB Vaccine Foundation and the Dutch biopharmaceutical company Crucell N.V. announced the start of a Phase II clinical trial of the jointly developed TB vaccine candidate AERAS-402/Crucell Ad35 in HIV-infected adults. Earlier trials begun in 2004 support the immunogenicity and acceptable safety profile of the TB vaccine candidate at all dose levels.¹⁵

Therapeutic vaccines for addiction also are showing promise. Scientists may have created a new vaccine against cocaine addiction. The series of shots changes the body’s chemistry so that the drug can’t enter the brain and provide a high. The vaccine, called TA-CD, shows promise but also could be dangerous. Some of the addicts participating in a study of the vaccine started doing massive amounts of cocaine in hopes of overcoming the vaccine’s effectiveness. The study was published in the Archives of General Psychiatry in October.¹⁶

And, Nabi Biopharmaceuticals is partnering with GlaxoSmithKline to develop an anti-smoking vaccine, NicVAX, which will train the immune system to produce antibodies that attach themselves to nicotine. Once the antibodies are stuck to the nicotine, they will not be able to reach the brain, thus blocking the pleasurable effects of the drug. Nabi is currently in the late stages of the clinical study, and if testing is successful, GlaxoSmithKline will be responsible for getting the drug approved and bringing it to market.¹⁷

Therapeutic Vaccines: More Hope on the Horizon?

While some researchers believe that a host of therapeutic vaccines will likely become reality within the next 10 years, others are much more skeptical. The former say they likely will be because of the amount of research that is aimed at better understanding basic biology, as well as the technologies being created as part of this effort. “There are so many exciting new technologies and new understandings of diseases that have occurred in recent years,” says Myers. “I think the potential for therapeutics is very large.”

But, the latter say that while therapeutic vaccines seem to be on the horizon, they’ve seemed that way for a long time. “I remember when therapeutic vaccines were first developed for skin cancer in the 1960s,” says Richard L. Wasserman, MD, PhD, clinical professor in the Department of Pediatrics at the University of Texas Southwestern Medical School in Dallas. “But 40 years later, we still don’t have one.”¹

But, it’s possible that those delays are now over. “The real revolution of information occurred with the Internet and with microprocessing and so on, and the biologic sciences are just catching up,” explains Myers. “All of these extraordinary technologies are just becoming available about the basic understanding of the disease process, and the amount of information that is being accumulated is remarkable.” The average rule of thumb for bringing a vaccine to market “is seven to 10 years from proof of concept [showing that a vaccine is likely] to the end of Phase III trials,” adds Myers. “And, it varies significantly with a new vaccine and a vaccine concept.”