Just a shot in the dark?
The bane of childhood—the recurring trek to a doctor's office to receive vaccinations—is now looked to as a promising approach to preventing and treating certain types of cancers. In fact, one of those childhood immunizations—the "hep b" vaccine given shortly after birth—has provided protection against liver cancer since 1981.
Cancer vaccines are medicines that fall under the category of biological response modifiers, which work by stimulating or restoring the immune system's ability to fight invaders that make the body fall ill. The medicines fall under two broad headings: prophylactic or preventive vaccines, and therapeutic or treatment vaccines.
Two types of cancer preventive vaccines are available in the United States, and two cancer treatment vaccines are in limited use. Other treatment vaccines are being studied in labs across the nation.
A shot of prevention is worth a pound of cure
Currently, only vaccines to prevent the sexually transmitted human papillomavirus (HPV) and hepatitis B (HBV) are approved for use. The HPV vaccines Gardasil (Merck) or Cervarix (GlaxoSmithKline) are used to prevent only specific strains of the virus; those strains are thought to be responsible for the majority of cervical cancers. Gardasil also offers protection against two additional types of HPV—those that are implicated in 90 percent of cases of genital warts in both men and women, but do not cause cervical cancer. Cervarix offers protection against the two strains that indicate future cervical cancer, but the drug has shown additional promise in preventing infection from other strains.
Although the primary indication is to prevent cervical cancer, recent recommendations suggest that better overall prevention could be achieved if young males also receive the HPV vaccine. The Gardasil vaccine is approved for these indications in females and males ages nine to 26. Cervarix is approved for use in females ages nine to 25. The vaccines also offer some protection against other types of genitourinary cancers.
HBV, or what's known as the "hep b" vaccine, works by preventing chronic hepatitis infections that can lead to liver cancer.
Attacking cancers with a needle
Provenge is an autologous, or patient-specific, vaccine that is used to treat metastatic prostate cancer. That drug was approved by the U.S. Food and Drug Administration (FDA) in April 2010, and is manufactured by Dendreon Corp. It was the first FDA-approved vaccine specifically designed to treat cancer. According to company officials, the vaccine became available in May 2010; company officials would not share the number of patients who have been treated with the drug, which is delivered by infusion.
A drug of great promise on the horizon is BiovaxID, Biovest's late-stage personalized cancer vaccine for the treatment of non-Hodgkin's lymphoma. If approved, BiovaxID would represent the first non-immunosuppressive consolidation therapy option for patients with follicular lymphoma. Biovest has on its medical board Dr. Larry Kwak of the University of Texas MD Anderson Cancer Center, who was recognized by Time Magazine as a 2010 Person of the Year for his decade of work in the area of cancer vaccines. Kwak was unavailable for comment for this story.
What makes these shots different?
Think of the traditional influenza vaccines that are well-publicized each year. The strategy in creating these vaccinations is for scientists to make an educated guess on which strains of the flu will be most prevalent in a coming season. Then, factories must create enormous quantities of this standard formula, and distribute millions of doses of the vaccine prior to the start of the annual flu season. These vaccines contain killed or weakened versions of the annual suspect microbe, or microbes, that are implicated for that particular year. The body's immune system, when encountering these microbes, mounts a defense against them, and then "remembers" that particular invader to offer the body protection should that microbe be encountered in the future.
Cancer preventive vaccines target infectious elements that cause or contribute to the development of cancer. Both cancer preventive vaccines and traditional vaccines are based on antigens that are carried by infectious agents and that are easy for the immune system to see as not normal.
White blood cells, or leukocytes, orchestrate immune responses, and are mainly responsible for circulatory system invaders. Other types of leukocytes, known as lymphocytes, provide targeted protection against specific threats, whether from a specific microbe or a diseased or abnormal cell. The most important groups of lymphocytes are B cells and cytotoxic T cells. B cells make antibodies, large proteins that destroy foreign invaders or abnormal cells. Most preventive cancer vaccines stimulate the production of antibodies that bind to specific microbes and block their function.
T cells destroy infected or abnormal cells by releasing toxic chemicals or by causing the dangerous cells to self-destruct.
Cancer treatment vaccines are designed to work by activating B cells and T cells and sending them destroy a very specific cancer, doing their work by introducing an antigen, which causes a very specific immune response, into the patient. Antigens are also found normally in some cells; those antigens can tell the body that their presence is normal while microbes, which carry antigens that are foreign to the body, can be recognized and destroyed.
The complication with antigens that occur in cancer cells is that they carry both "signatures" of a normal and a malignant cell. The cancer-associated antigens can then trigger the actions of the B cells and T cells to attack. In addition, cancer calls can sometimes mutate to where the antigens that instigate the attack instinct of the killer cells is no longer recognized. Cancer cells can also be mightier than the T cells that come after them.
Treatment vaccines: All or part of a cure?
Cancer treatment vaccines treat cancers that have already developed. They are intended to delay or stop cancer cells and tumors from growing, prevent cancer from recurring or kill cancer cells that have not been successfully eliminated by standard cancer therapies.
Producing effective treatment vaccines has proven much more difficult and challenging than developing cancer preventive vaccines. To achieve the desired result, cancer treatment vaccines must achieve two goals. First, like traditional vaccines and cancer preventive vaccines, cancer treatment vaccines have to stimulate specific immune responses against the correct target. Second, the immune responses must be powerful enough to overcome the barriers that cancer cells use to protect themselves from attack by B cells and killer T cells.
Dendreon's Provenge is designed to stimulate an immune response to prostatic acid phosphatase, an antigen that is found on most prostate cancer cells.
Dr. Candice McCoy, senior medical director at Dendreon, says in clinical trials, the drug was shown to increase survival by more than four months over a placebo. She adds that the three-year survival rate from Provenge is 31 percent, and with a placebo, the probability of survival in three years is 23 percent.
"Both of those numbers are statistically significant," McCoy adds.
She continues that Provenge is unique in that it is customized to each patient—or what is known as an autologous vaccine.
"Patients receive three infusions of Provenge," she says. "Each dose is created individually for each patient through leukapheresis, where white blood cells are removed from that patient and shipped to one of our facilities. They are exposed to an antigen and shipped back to the patient's doctor to be administered at two-week intervals, where they are administered through infusion."
While not able to disclose details about patients, McCoy indicated that Provenge is used across the nation by both urologists and oncologists.
Tampa, Fla.-based Biovest is making strides toward a personalized vaccine for non-Hodgkin's lymphoma, with BiovaxID, but patients would still need to pair this therapy with traditional chemotherapy for success.
Dr. Sattva S. Neelapu works in the same laboratory as Kwak at MD Anderson, and is familiar with the mechanism that BiovaxID uses against lymphoma.
"BiovaxID induces both antibody and T cell responses against the ideotype (Id), which is the tumor-specific antigen expressed on B cell lymphomas such as follicular lymphoma," Neelapu says. "Antibodies induced by the vaccine can bind to the Id expressed on tumor cells and mediate killing via other immune cells. T cells induced by the vaccine also recognize Id-derived peptides on the tumor and mediate killing by secreting various cytokines and other cytotoxic molecules. Our results suggest that the T cell responses are likely to be more important than antibody responses for BiovaxID effect."
The treatment, which is still in Phase III testing, is given through a series of five vaccinations over a six-month period. The company expects to apply for approval in the United States, Canada and Europe within the next few months.
Why go after this cancer in particular? Neelapu has some specific answers: "Follicular lymphoma is historically known to be highly immune responsive, and therefore, immunotherapy such as cancer vaccines are likely to have high chance of success," Neelapu says. "The Id protein is expressed on the tumor but not in normal tissues. Thus, Id can serve as a tumor-specific antigen and an immune response elicited against the Id will target the tumor while sparing normal cells."
Even though this therapy will not cure the cancer in and of itself, this development is important for testing theories related to potential future success of these vaccines. "Although not curative," Neelapu says, "chemotherapy can induce complete remissions in the majority of patients, and therefore, follicular lymphoma provides an opportunity to test the hypothesis of whether a cancer vaccine can eradicate minimal residual disease and improve clinical outcome."
In addition, Bristol-Meyers Squibb Co. recently entered the cancer market with a vaccine to treat advanced metastatic melanoma. The vaccine is known as Yervoy, which received FDA approval.
The price is … wrong?
Although Dendreon representatives would not comment on the number of patients being treated with Provenge, other published reports suggest the enormous cost of processing personalized treatments gives doctors and patients pause.
Published reports have suggested that the $93,000 price tag for a course of treatment of Provenge induces sticker shock, and that adoption of the treatment into wide use has been slow because of it.
And any work in the lab is costly and time-consuming, even if researchers are pursuing a "orphan disease" cure, as in the work of OncoPep, another company, which is as-yet virtual, but associates with the Dana-Faber Cancer Center. It is pursuing work toward treating "smoldering myeloma" with a compound it calls PVX-410.
In addition, as in the case with BiovaxID, patients must still pair this vaccine with traditional chemotherapy.
MD Anderson's Neelapu says impressive results in trials hold promise for treatment vaccines. Developments across this space point to a clear direction for future research.
"I think the positive results from three Phase III vaccine trials reported recently in three different cancers; the FDA approval of Dendreon vaccine; better understanding of the immune system, in particular immunosuppressive mechanisms in the tumor microenvironment; and promising activity of multiple immune modulators including the FDA approval of ipilimumab have revived interest in cancer vaccines and suggested that immunotherapy can definitely improve clinical outcome in a variety of cancers, both hematological malignancies and solid tumors," Neelapu says.
"We expect to see a lot more cancer vaccine trials in the future, particularly combination trials with other immune modulators," Neelapu concludes. "The combinations are likely to be more effective than single-agent trials. I think cancer vaccines and other immune modulators are likely to play an increasing role in the fight against cancer."