NCI Pursues Vaccines to Prevent and Treat Cancer

How immune cells are activated to attack foreign invaders

How immune cells are activated to attack foreign invaders

While vaccines to prevent infectious diseases such as measles, mumps, and polio have been available for decades, prevention vaccines for cancer have been much slower to reach the commercial market. To date, the only cancer vaccine licensed by the Food and Drug Administration is a prophylactic vaccine against hepatitis B virus, an infectious agent associated with liver cancer.

However, it seems very likely that a second prophylactic vaccine will reach the market in the next few years. The promising contender is a vaccine against human papillomavirus (HPV), the primary cause of cervical cancer. Early results from a trial conducted by Merck & Co., Inc. in 1,500 young women showed that the vaccine was 100 percent effective in preventing persistent HPV infection and low-grade cervical cytological abnormalities attributable to a strain of the virus known as HPV-16. (N Engl J Med 2002;347:1645). This type of HPV accounts for about half of the cervical cancer cases world-wide. (For more information on HPV types, see BenchMarks April 2002.)

Douglas Lowy, M.D., a National Cancer Institute (NCI) scientist since 1975, has conducted research on the molecular biology and growth regulation of tumor viruses as well as early phase human trials of a vaccine against HPV-16 (J Natl Cancer Inst 2001;93:284). He and his NCI colleagues developed the technology that underlies the candidate prophylactic HPV vaccine. He is chief of the Basic Research Laboratory and the Laboratory of Cellular Oncology at the Center for Cancer Research, where he also serves as deputy director. He was interviewed by Nancy Nelson.


It seems as though the HPV vaccine would be most useful in developing countries, not only because 80 percent of the cases of cervical cancer occur in those countries, but because of the high cost of Pap smear screening and follow-up. Is that true? (In the United States, these costs are estimated to be $5 billion every year.)

Dr. Lowy: It depends. We have enough money for routine Pap smears. If everyone had routine Pap smears, we could prevent almost all cervical cancers today. However, the developing world doesn’t have the same financial resources, and the preponderance of cervical cancers occur in the developing world. There is really no alternative in the developing world, so the opportunity to save lives and reduce the incidence of cervical cancer is greater there.

Having said that, the vaccine could have a tremendous impact on women in the developed world. In the short term, it would reduce the incidence of serious abnormal Pap smears. There’s a lot of anxiety as well as morbidity that goes with those. It would also reduce the number of follow-ups needed for abnormal Pap smears and the number of surgeries needed for high-grade dysplasia.

One of the ironies is that the impact of the vaccine will be felt sooner in the developed countries than in the developing world. That’s because changes in the cervix occur relatively soon after infection. Let’s say that today you could implement world-wide vaccination. What would happen five years from now? In the developed world, there would be a reduction in abnormal Pap smears and a reduction in need for surgeries to treat high-grade dysplasia. In the developing world, the impact will be zero. That’s because cervical cancers don’t occur until 15 to 25 years
after you get infected. So actually, you will see no benefit until you get out to that time. It’s one of the “deficiencies” of a purely preventive vaccine.

One more point is that you won’t be able to eliminate cervical cancer screening because the vaccine will only target a subset of the viruses that are implicated in cervical cancer.

Is HPV infection required for cervical cancer to develop?

Dr. Lowy: Yes. If you don’t have HPV infection, you don’t get cervical cancer. The latest study, published about three years ago, showed that over 99.5 percent of cervical cancers contained HPV. Because the types of HPV linked to cervical cancer are sexually transmitted, behaviors such as beginning sexual intercourse at an early age (especially age 16 or younger) and having many sexual partners increase the chance that a woman will develop an HPV infection in the cervix.

Is HPV infection alone enough to cause cervical cancer?

Dr. Lowy: Most people don’t develop cervical cancer after infection. Even an infection with high risk HPV-16 is usually a self-limiting infection. You get it and it goes away. Probably at least 80 percent of HPV-16 infections end up going away — maybe 90 percent. Somewhere between 10 to 20 percent of HPV-16 infections will be associated with some cytological abnormality. A smaller proportion will persist and go on to become cervical cancer.

Besides exposure to HPV, what are other risk factors for cervical cancer?

Dr. Lowy: The biggest clearly identified risk factor is immuno-suppression. Survivors of renal transplant, AIDS patients, and people with impaired cell-mediated immunity are at high risk of persistent HPV infection, high-grade dysplasia, and cervical cancer. Beyond that, there is epidemiologic evidence implicating smoking. It makes some sense because there are carcinogens in cigarette smoke that can be found in the vaginal tract.

You published a paper in February 2001 in the Journal of the National Cancer Institute showing proof-of-principle for your HPV vaccine. Could you briefly describe how the vaccine was made and the results?

Dr. Lowy: The vaccine we used consists of several copies of an HPV-16 protein, L1. By way of some background, our breakthrough
observation in 1992 (Proc Natl Acad. Sci USA 1992;89:12180-12184) showed that multiple copies of the L1 protein alone can join together to form a 3- dimensional structure that resembles the virus – it has the shell of the virus but without the viral genetic information inside. When assembled, the L1 proteins are called virus-like particles, or VLPs. Besides this ability to self-assemble, our further work showed that vaccinating animals with the VLPs of animal papillomaviruses protected them from subsequent viral challenge (J Virol 1995;69:3959-3963 and Virology 1996;219:37-44). All of this earlier work led us to believe that the L1 protein of HPV-16 would be a good candidate for a human vaccine.

Using insect cells, we made a relatively pure preparation of VLPs that we used to immunize normal volunteers, looking for safety and immunogenicity.

There were four bottom line results. The vaccine was very well tolerated. There were almost no side effects due to the vaccine itself. The second point was that everybody sero-converted and developed high levels of neutralizing antibodies. No one was resistant. The third finding was that at the high dose, you didn’t need adjuvant. The last point is that the levels of antibody that people developed were similar to levels that protected animals against infection with animal papillomavirus. So, while you couldn’t say the level of antibodies in humans was protective,
you could say that people behaved the same way as rabbits and mice, in terms of making robust immunological responses.

Are you continuing to use the vaccine in future trials?

Dr. Lowy: We’ve tested the vaccine in a larger group of women to confirm the results. In phase II trials involving about 100 women, we found that the vaccine induces a durable antibody response. When we measured the antibody level six months after the last vaccination, there was a three-fold drop in level compared to one month after the last vaccination, and that’s considered a small drop in level. So, the response is durable.

The other thing we did was to measure antibody at the cervix. We found antibody at the cervix. There is one wrinkle, however. The level of the antibody is different for women who are on oral contraceptives compared with those who are menstruating. For women on contraceptives, the levels are constant, whereas for menstruating women, the antibody levels vary by a factor of 10, depending on where you are in your ovulatory cycle. Whether this has any implications for protection, we don’t know, but we’re going to look into it.

What other HPV vaccine trials are taking place?

Dr. Lowy: Merck has embarked on a large phase III trial with a vaccine against HPV types 16, 18, 6, 11. (Types 6 and 11 cause genital warts.) Tens of thousands of women in the United States, Latin America, Europe, Asia, and Australia are involved. GlaxoSmithKline is testing a vaccine against types 16 and 18.

The question now is, can you make a commercial vaccine that has multiple components that will be highly protective. Merck already has immunological data that they reported in October at the HPV international conference. They found that the immunological response to HPV-16 in the four-component vaccine is as good as the response to HPV-16 alone. In other words, there’s no suggestion of attenuation of the response as a consequence of giving multiple HPV types.

It seems like everything looks extremely hopeful for these vaccine trials. Dogs, rabbits, and calves were protected against papillomavirus infection with similar vaccines, and the early results from human trials seem to be very favorable. Is there any reason to believe that things won’t go fabulously well?

Dr. Lowy: It’s as good as you could hope for. It’s an immunogen that people see normally. You’re just giving them more of it. On the other hand, it’s possible that out of 20,000 people, two might have a terrible side effect. We certainly hope that’s not true, but we really don’t know that now, because the vaccine hasn’t been given to 20,000 people. However, barring that, it’s hard to imagine that if there’s as much protection as you see in the Merck trial, that you won’t also get protection with a multivalent vaccine. At this point, if you didn’t see protection, you might say, “Well, somebody made the vaccine wrong.”

Is immunizing men just as important as immunizing women?

Dr. Lowy: It is assumed in the developed world that it will be recommended that men be immunized, but it is not such a straight forward issue. There are several points. The first is that at the moment there is no evidence that immunizing men is beneficial. It might be useful to do studies that indeed show that the vaccine would have some protection — not so much to protect men against HPV-16, but to have a rationale for immunizing men as a way to protect women.

The second issue is that the more protective the vaccine is for women, the better off you would be in immunizing all women, rather than immunizing two-thirds of men and two-thirds of women. You would get more protection if you immunize 100 percent of women, rather than immunizing two-thirds men or two-thirds women. To make the vaccine more relevant to men, Merck is incorporating HPV-6 and HPV-11, which are the main causes of genital warts, which are as big a problem for men as women. If there is a reduction in infection with those HPV types, then men would get a direct benefit.

But, on a population-wide basis and from a public health point-of-view, the most important thing is to immunize women. If you have enough money, you may want to immunize both men and women. But the rationale for immunizing men is not as strong as women.

Animation/Video


This animation requires the Flash plug-in. If you do not have the plug-in, please click here to install. Get Flash button 

Text Transcript

The Immune System and Cancer Vaccines: Cancer vaccines, whether to prevent or treat cancers, take advantage of the immune system’s ready-made network of cells and organs that work together to defend the body against attack by “foreign” invaders. When a foreign organism or entity (an antigen) enters the body, a variety of immune cells and molecules mount an appropriate response. Lymphocytes are one of the main types of immune cells. The most common lymphocytes, B cells and T cells, patrol the blood and lymph system for foreign antigens. Cancer vaccines currently under development are designed to stimulate primarily B or T cells to mount an attack against foreign entities.

The job of the B cell is to ambush antigens circulating in the bloodstream. Protruding from its surface are antibody molecules poised to bind foreign agents such as toxins, bacteria or viruses. Only specific antigens will bind to each B cell.

Once the triggering antigen binds, the B cell digests it, and displays antigen fragments with the help of a marker molecule on the cell surface.

The antigen/marker combination is recognized by a T cell, which in response secretes lymphokines.

These, in turn, stimulate the multiplication and maturation of B cells into plasma cells. The plasma cells pour millions of identical antibody molecules into the bloodstream.

These antibody molecules ambush and inactivate the matching antigens in the blood.

While B cells attack soluble antigens in the body’s fluids, the job of the T cells is to attack cells that have either been infected by viruses or altered by cancer.

Cells that display pieces of foreign antigens on their surface with the MHC molecule are called antigen presenting cells (APC). APCs are either B cells, macrophages or dendritic cells. T cells recognize antigens only when they are bound to cell-membrane proteins called major histo-compatibility complex (MHC) molecules. Cells that display pieces of foreign antigens on their surface with the MPH molecule are called antigen presenting cells (APC). APCs are either B cells, macrophages or dendritic cells. T cells recognize antigens only when they are bound to cell-membrane proteins called major histo-compatibility complex (MHC) molecules.

When a T cell is activated by binding to the antigen/MHC complex, it secretes lymphokines. The secreted lymphokines cause several reactions.

Some Lymphokines spur the growth of Memory T cells. Memory T cells are primed to fend off additional attacks by the same antigen. These have a longer lifespan in the body and respond more readily to a second antigen assault than the original T cell. Some T cells become natural killer T cells, known as cytotoxic T cells (or CTL), which attack infected or abnormal cells directly.

Some T cells become natural killer T cells, known as cytotoxic T cells (or CTL), and attack infected or abnormal cells directly. The lymphokines also attract other immune cells, such as macrophages and neutrophils, to the site of the foreign invasion.

Treatment Vaccines: The strategy that researchers use for treatment vaccines involves injecting cancer-specific antigens into patients. The hope is that these antigens will stimulate B and T cells in the immune system to attack cancer cells without harming normal cells.

Prevention Vaccines: Prevention vaccines, on the other hand, are given to healthy individuals to stimulate the immune system to attack cancer-causing viruses and prevent viral infection. Non-infectious viral proteins from cancer-causing viruses are commonly used as antigens to stimulate the immune system for prevention vaccines. This is the same strategy used for vaccines for polio or measles.


Audio Clips

  1. Douglas Lowy, M.D., discusses pap smears and worldwide cervical cancer prevalence.

       ( Audio – Length: 00:48 )

    Text Transcript

    Douglas Lowy, M.D., discusses pap smears and worldwide cervical cancer prevalence.

    If everyone had routine Pap smears, we could prevent almost all cervical cancers today. However, the developing world doesn’t have the same financial resources, and the preponderance of cervical cancers occur in the developing world. There is really no alternative in the developing world, so the opportunity to save lives and reduce the incidence of cervical cancer is greater there.

  2. Douglas Lowy, M.D., discusses cervical cancer vaccine effectiveness.

       ( Audio – Length: 02:08 )

    Text Transcript

    Douglas Lowy, M.D., discusses cervical cancer vaccine effectiveness.

    Having said that, the vaccine could have a tremendous impact on women in the developed world. In the short term, it would reduce the incidence of serious abnormal Pap smears. There’s a lot of anxiety as well as morbidity that goes with those. It would also reduce the number of follow-ups needed for abnormal Pap smears and the number of surgeries needed for high-grade dysplasia.

    One of the ironies is that the impact of the vaccine will be felt sooner in the developed countries than in the developing world. That’s because changes in the cervix occur relatively soon after infection. Let’s say that today you could implement world-wide vaccination. What would happen five years from now? In the developed world, there would be a reduction in abnormal Pap smears and a reduction in need for surgeries to treat high-grade dysplasia. In the developing world, the impact will be zero. That’s because cervical cancers don’t occur until 15 to 25 years after you get infected. So actually, you will see no benefit until you get out to that time. It’s one of the “deficiencies” of a purely preventive vaccine.

    One more point is that you won’t be able to eliminate cervical cancer screening because the vaccine will only target a subset of the viruses that are implicated in cervical cancer.

  3. Douglas Lowy, M.D., discusses developing an HPV vaccine for men.

       ( Audio – Length: 01:30 )

    Text Transcript

    Douglas Lowy, M.D., discusses developing an HPV vaccine for men.

    It is assumed in the developed world that it will be recommended that men be immunized, but it is not such a straight forward issue. There are several points. The first is that at the moment there is no evidence that immunizing men is beneficial. It might be useful to do studies that indeed show that the vaccine would have some protection — not so much to protect men against HPV-16, but to have a rationale for immunizing men as a way to protect women.

    The second issue is that the more protective the vaccine is for women, the better off you would be in immunizing all women, rather than immunizing two-thirds of men and two-thirds of women. You would get more protection if you immunize 100 percent of women, rather than immunizing two-thirds men or two-thirds women. To make the vaccine more relevant to men, Merck is incorporating HPV-6 and HPV-11, which are the main causes of genital warts, which are as big a problem for men as women. If there is a reduction in infection with those HPV types, then men would get a direct benefit.

Photos/Stills

1. The (green) B cell has ingested an antigen and displayed part of it (bright yellow) on a molecule bound to cell surface. Once a T cell (blue) becomes activated by binding to the antigen/molecule complex on an infected or cancerous cell, it begins to divide rapidly, and differentiates into memory T cells and other subtypes of T cells. Some, called T helper cells, secrete chemical messengers known as cytokines or lymphokines(golden yellow), which mobilize many other cells and substances.

The (green) B cell has ingested an antigen and displayed part of it (bright yellow) on a molecule bound to cell surface. Once a T cell (blue) becomes activated by binding to the antigen/molecule complex on an infected or cancerous cell, it begins to divide rapidly, and differentiates into memory T cells and other subtypes of T cells. Some, called T helper cells, secrete chemical messengers known as cytokines or lymphokines(golden yellow), which mobilize many other cells and substances.


2. J. Michael Hamilton, M.D., preparing the carcinoembryonic antigen (CEA) vaccinia vaccine used to try to prevent cancer.

J. Michael Hamilton, M.D., preparing the carcinoembryonic antigen (CEA) vaccinia vaccine used to try to prevent cancer.

Science Writers Seminar Presentations

  1. Cancer Vaccines – Some General Issues

  2. Cancer Vaccines: Jeffrey Schlom, Ph.D., Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH.

  3. Design, Development and Delivery of Recombinant Vaccines for the Therapy of Human Carcinomas:Jeffrey Schlom, Ph.D., Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH.

  4. Prophylactic Papillomavirus Vaccines: Douglas Lowy, M.D., Center for Cancer Research, National Cancer Institute, Bethesda, MD.

Comments are closed.